Table of contents :

The oncology market is the third largest pharmaceutical market, behind the cardiovascular and CNS therapy areas, and is currently experiencing strong growth. Worth an estimated $35 billion in 2003, analysts predict that the sector will grow to $60 billion by 2010, yielding a compound annual growth rate of 8% over this period. The top 20 cancer drugs account for 77% of global oncology revenues however the market will dramatically change as many of these drugs come off patent: In 2004, the top 20 cancer drugs in each of the seven major pharmaceutical markets generated combined sales approaching $27 billion, with the US accounting for 2/3 (66%) of this total, Japan 13% and the 5 leading EU countries 21% (Midas, IMS Health, April 2004). Collective sales in these markets represent approximately 77% of global oncology revenues, clearly demonstrating the industry's strong reliance on these specific products and geographical markets for income generation. While the economic value of these brands is undisputed, the looming threats of therapeutic competition and, of even greater significance, patent expiry provide a considerable commercial and clinical challenge to the industry. Patent expiries threaten anti-hormonal and cytotoxic sales: In breaking down the 7-market top 20 drugs by therapeutic class, the supportive care drugs including recombinant growth factors and antiemetic serotonin antagonists constitute the majority of sales (48%) exceeding those of the cytotoxics (24%), innovatives (15%) and antihormonals (13%). Over the course of the next decade, analysts predict that of the cancer drugs that currently have a top 20 position in the 7 markets, only those in the innovative and supportive care classes will maintain a positive compound annual growth rate (5.1% and 3% respectively). Conversely, members in the cytotoxic and antihormonal categories will experience declining sales over the period 2004-14, with patent expiries having the greatest influence on reducing market share. In the US, for instance, patent expiration will affect 6 of the 7 cytotoxic drugs in the current top 20, the latest date of genericization occurring in 2011 (Xeloda). Similarly, in the US market the patent on all drugs in the antihormonal class will be complete by 2009. Innovative life cycle management to provide a driver for the market: Strategies to mitigate the challenge of patent expiry, generic incursion and therapeutic competition will rely on innovative approaches to lifecycle management and sustained research and development productivity to maintain a commercially attractive product pipeline. This is well exemplified by the vinca alkaloids, which include the taxanes, the largest class of cytotoxics in terms of sales. BMS' Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival drug, Aventis' Taxotere (docetaxel). In order to maintain the dominance, Aventis will need to continue to market the drug aggressively in the light of generics. Generics are arriving on the market in two forms: commodity generics, which are clones of the original drug; and supergenerics which differ from the original product in formulation or method of delivery. Supergeneric versions of Taxol, such as Cell Therapeutics' Xyotax (polyglutamate paclitaxel) and Abraxis Oncology's Abraxane (nanoparticle albumin-bound paclitaxel) have been developed and offer significant advantages over Taxol. Product focus - Abraxis Oncology's Abraxane (nanoparticle albumin-bound paclitaxel): Abraxane has significant advantages over paclitaxel and is set to become a key cytotoxic. Abraxane is an albumin-bound nanoparticle formulation of paclitaxel developed by American Pharmaceutical Partners. Paclitaxel is difficult to administer because it is formulated in Cremophor, a mixture of castor oil and ethanol, which is extremely irritating to blood vessels and requires surgical placement of a large catheter for administration. It also may cause allergic reactions, and typically requires a minimum of three hours of intravenous infusion. Abraxane is much more soluble than paclitaxel and does not require the use of toxic solvents allowing increased dosages to be administered over 30 minutes using standard IV tubing without premedication to prevent hypersensitivity reactions. A pivotal clinical trial has demonstrated that Abraxane had superior response rate when compared to Taxol in patients with metastatic breast cancer. Abraxane is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. The Abraxane New Drug Application (NDA) was approved by the FDA on January 7, 2005 and was launched February 2005 by Abraxis Oncology, American Pharmaceutical Partners' proprietary sales and marketing division. Merrill Lynch analysts forecast Abraxane sales of $40 million in 2005 rising to $275 million by 2009. Product focus - Cell Therapeutics' Xyotax (polyglutamate paclitaxel): Xyotax (paclitaxel poliglumex) is a biodegradable polyglutamate polymer developed to selectively deliver paclitaxel to tumors for the treatment of non-small cell lung cancer, ovarian cancer, and other cancers where taxanes are widely used. Xyotax is 80,000 times more water-soluble than paclitaxel, allowing it to be infused in the absence of Chremophor over 10 minutes through standard IV tubing and at higher doses than can be achieved with paclitaxel. Also, because Xyotax is water-soluble, its administration does not require routine premedication with steroids and antihistamines to prevent severe allergic reactions. Furthermore studies have shown that Xyotax benefits from passive tumor targeting. This is because the size of the polymer ensures that Xyotax is preferentially taken up by the more permeable tumor vasculature. Once in the tumor milieu, Xyotax is taken up into cancer cells through endocytosis locking it into the cells prior to liberation of free paclitaxel. Cell Therapeutics initiated 3 pivotal phase III non-small cell lung cancer trials (STELLAR trials) of Xyotax in 2002. Enrollment for STELLAR 3 was completed in 2003 and data are expected imminently (mid-march, 2005) prior to an NDA filing with the FDA . A phase III trial in ovarian cancer patients is also in progress. Analysts expect peak annual sales for Xyotax to reach $500 million. Significant sales to continue in the supportive care market: A Roper Starch survey of chemotherapy patients found that prior to starting treatment, 32% reported surviving cancer as their biggest concern versus 40% who said side effects were their biggest concern. The most serious adverse effects of chemotherapeutic agents include anemia and related fatigue; neutropenia and associated risks of infection; and nausea and vomiting. Anemia-related fatigue affects 76% of patients undergoing chemotherapy and a large proportion of these patients report that fatigue resulting from this anemia affects their lives more than any other side effect, including nausea, pain, and depression. Neutropenia is a serious clinical problem and affects half of cancer chemotherapy patients. Consequently the development of supportive care products to combat fatigue and neutropenia has played an important role in oncology research and development. This is well illustrated in the US, where in 2004 the epoetins and granulocyte colony-stimulating factors (G-CSFs) contributed $6.7 billion in sales. Epoetins including Johnson & Johnson's Erypo/Procrit and Amgen's Epogen are commonly employed for the treatment of fatigue and indeed the increasing use of epoetins to treat cancer-related anemia has resulted in these agents becoming the leading US oncology drugs, with sales estimated at $2.4 and $2.2 billion respectively. G-CSFs, which are used to treat neutropenia, include Amgen's two products Neupogen (filgrastim) and pegylated filgrastim, Neulasta (pegfilgrastim). Neulasta was launched in 2002 and its worldwide sales increased 40% to $426 million in the second quarter of 2004 (compared to 2003 figures). This mirrored a fall in Neupogen sales to $295 million in the second quarter of 2004 versus $331 million in the prior year and reflects the advantage of Neulasta in that only one administration is required per cycle of chemotherapy due to its increased half-life. The patent expiry of Zofran is set to change the antiemetics market: According to the National Cancer Institute, over 500,000 Americans received chemotherapy in 2004. Patients receiving chemotherapy for cancer reported a greater degree of treatment-induced nausea and vomiting than generally recognized. An estimated 75% suffer from nausea or vomiting within 24 hours of treatment, and about 90% of all patients suffer from chemotherapy-induced nausea or vomiting 2-5 days after treatment (delayed onset chemotherapy-induced nausea and vomiting). If left untreated, chemotherapy-induced nausea and vomiting can result in a delay or discontinuation of chemotherapy and the majority of patients thus receive an antiemetic. The 5-HT3 receptor antagonists revolutionized the treatment of chemotherapy-induced nausea and vomiting. All major antiemetic treatments currently on the market (Roche's Kytril,GlaxoSmithKline's Zofran, and Aventis' Anzemet) are 5-HT3 antagonists and the market is dominated by Zofran (Ondansetron), generating annual US sales worth approximately $1.0 billion in 2003. The product patent expires in June 2006. While this opens the way for generic competition, novel formulation with improved efficacy may also compete for this market. Hana Biosciences is developing one such agent, a lingual spray formulation of ondansetron. The company has recently announced a clinical study that will compare the pharmacokinetic profile of this formulation with that of Zofran. Based on successful results of this pilot bioequivalence trial in healthy volunteers, Hana intends to file an Investigational New Drug (IND) Application with the aim of making the oral spray version available in 2007. Such a formulation is expected to increase the speed of therapeutic onset; avoid the need to swallow a tablet is also of obvious benefit in patients suffering emesis. Alternative 5HT3 antagonists with improved profiles may also capture the ondansetron market. For example MGI Pharma's Aloxi (palonosetron), which was approved in 2003, has an improved pharmacokinetic profile and may therefore provide an extended duration of action. Aloxi is currently approved for the prevention of acute nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy, and the prevention of delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Recent data suggest however that approval of higher doses of palonosetron could offer a new treatment for delayed emesis produced by highly emetogenic chemotherapy. First treatments entering the market for oral mucositis: Severe mucositis resulting from destruction of the mucosa can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation as well as 80% of patients with head and neck malignancies receiving radiotherapy, plus many other cancer patients on standard chemotherapy. In total this translates to approximately 400,000 patients per year who may develop acute or chronic oral complications during chemotherapy. Up until recently there were no approved treatments of oral mucositis, however in 2004 the FDA approved Amgen's Kepivance (palifermin) for the treatment of severe oral mucositis in patients with hematologic cancers undergoing high-dose chemotherapy, with or without radiation, followed by a bone marrow transplant. Kepivance is a human recombinant keratinocyte growth factor (KGF), a protein in the fibroblast growth factor family. Binding of KGF to its receptor result in proliferation, differentiation, and migration of epithelial cells. At present approval of Kepivance is limited to patients being treated for hematologic cancers and its initial sales potential has been approximated to $200 million, however the potential could be increased to $1billion if Kepivance is effective in treating mucositis in patients with solid tumors. While immediate efforts are falling on supportive care and improved delivery of cytotoxics, the longer term focus will be on the development on molecular-targeted treatments with improved efficacy and fewer adverse effects: Cytotoxics have been a cornerstone of cancer therapeutics and will remain to do so. Patent expiries have driven companies to prolong the life cycle of cytotoxics through the development of supergenerics with improved drug delivery and pharmacokinetic properties. This in turn promises a reduction in the adverse effects of this class. Although these supergenerics will provide competiton for commodity generics, the latter will remain extensively employed driving the development of supportive care therapeutics. Long term goals are however to develop innovative therapeutics that are targeted towards molecular mechanisms selectively affected in cancer. While in most of the markets, the presence of innovative class members in the top 20 was limited to Biogen-Idec/Roche's MabThera, OSI/Genentech/ Roche's Herceptin and Novartis' Glivec, analysts predict that the continued research and development focus on molecular-targeted treatments will see their emergence as the key players in the delivery of cancer pharmacotherapy. Analysts believe that the future use of molecular-targeted treatments in combinatorial treatment approaches with traditional cytotoxic chemotherapy, together with their use in the setting of chronic disease management, will see them constitute an increasing proportion of the top 20 cancer drugs by 2014. Already angiogenesis inhibitors and growth factor inhibitors have enjoyed significant success. The therapeutic importance of angiogenesis inhibitors took a leap forward in 2004 with the US approval of Genentech/Roche's Avastin (bevacizumab), followed closely by European approval. Fourth-quarter financial results reported sales of Avastin to be approximately $200 million, a figure expected to swell to peak sales of between $845.3 million and $1.7 billion now that European approval has been granted. Despite renewed confidence in the angiogenesis inhibitors there is a lack of late-stage development and the only competitive threat to Avastin is likely to come from Novartis' PTK787 in the short to medium term. A more distant threat to Avastin is AstraZeneca's orally active VEGF-2 receptor antagonist, ZD6474. ZD6474 blocks VEGF pathways but in contrast to Avastin which bind to VEGF, ZD6474 selectively inhibits VEGF-2 tyrosine kinase activity producing inhibition of VEGF-stimulated endothelial cell proliferation. ZD6474 has additional activity against the epidermal growth factor receptor in parallel with Iressa. ZD6474 successfully emerged from Phase I clinical development and interim results are expected in the next few weeks on a phase II study combining ZD6474 with chemotherapy in the treatment of non-small cell lung cancer patients. Another class of innovative and targeted therapeutics that has attracted considerable attention is the growth factor inhibitor class and in particular Glivec, Iressa and Tarceva. Glivec was one of the first targeted anti-cancer agents to be be approved. Targeting the kinase activity of Bcr-Abl (an oncogene responsible for chronic myeloid leukaemia) as well as c-kit, Glivec was approved for the treatment of CML and gastrointestinal stromal cell tumors in 2001-2002. The approval of Glivec was followed by that of AstraZeneca's Iressa (Gefitinib, ZD1839), a small molecule that specifically inhibits the tyrosine kinase activity of the EGFR type 1 by interfering with the ATP binding site. The side effect profile of gefitinib is good with the most common side effects being are low-grade rash or diarrhea. Based on data from pivotal phase II trials, IDEAL 1 and 2, which showed Iressa to shrink tumors and to improve symptoms, gefitinib received accelerated approval on May 5, 2003 by the FDA as a monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Disappointingly however, in a press release on December 17th, 2004, AstraZeneca announced that the initial analysis of the IRESSA Survival Evaluation in Lung cancer (ISEL) showed that IRESSA failed to significantly prolong survival in comparison to placebo in the overall population or in patients with adenocarcinoma. This dissapointing news contrasts with the progress of Tarceva which has recently been approved for the treatment of non-small cell lung cancer. This EGFR-1 tyrosine kinase inhibitor, which is being developed by Roche in collaboration with OSI Pharmaceuticals, differs significantly from Iressa in that it can extend survival time by up to 40%. According to OSI, a strong post-approval development plan is in place seeking to expand the label and use of Tarceva to other forms of cancer where EGFR is implicated and where indications of activity have been seen. Current forecasts for US Tarceva sales in 2006 range from $300 million to $600 million and between 0.5 and $1 billion in by 2008.

• the drug must make its way through the vasculature, cross the vascular wall, and then struggle through the extracellular matrix (ECM) of the tumour. 2-photon fluorescence-correlation microscopy (TPFCM) allows in vivo measurements of transport parameters in tumours to be made. Tracers undergo both a slow and a fast component of diffusion. The tumour interstitial matrix is thought to be composed of 2 phases - viscous and aqueous. This is the first to direct evidence that these 2 phases affect the transport of molecules within the tumour matrix. The hyaluronan and collagen components of the ECM are thought to be the main barriers to drug delivery, so some researchers have proposed treating tumours with enzymes that degrade these structures. Tumours exposed to hyaluronidase and collagenase have increased fraction of the fast-diffusing component : conversely hyaluronidase treatments reduces te percentage of fast-diffusing molecules. As hyaluronan forms a cage-like structure that contains water-filled spaces, through which molecules diffuse quickly, collapsing these structures is likely to increase viscous hindrance^ref.
• Goals
• primary, preoperative, presurgical or neoadjuvant chemotherapy is administered before surgical ablation to allow volume reduction and hence aesthetic or functional conservative locoregional surgery, e.g. in rectal cancers, laryngeal cancers, breast carcinoma. Unfavorable kinetics due to large tumor volume.
• adjuvant chemotherapy : cancer chemotherapy employed after the primary tumor has been removed by some other method (favorable kinetics and prior to onset of new mutations) : e.g. colorectal cancer, breast carcinoma, ovarian cancers, testicular cancers
• Scheduling :
• combination chemotherapy / polychemotherapy : the use of several different agents at once in order to enhance effectiveness; seen particularly in cancer chemotherapy
• biochemical modulation : in combination chemotherapy, the use of one substance to modulate negative side effects of the primary agent, increasing the effectiveness or allowing a higher dose of the primary agent.
• dose-dense or sequential chemotherapy : different drug every 8 weeks; increased dose intensity for each drug, no negative interactions, decreased toxicity
• alternating chemotherapy : different drug every week; e.g. MOPA/PVD in Hodgkin's disease
• continue infusion chemotherapy : for drugs with short half-life, cell-cycle phase specific drugs (e.g. 5-FU, S-phase specific), reversible drugs, drugs with slow uptake and activation, drugs rapidly excreted by cells, tumors with slow growth fraction
• high-time, long-term or metronomic dosing : low doses for up to 6 days prevent time for repair of damage to the tumour vasculature, thereby increasing therapeutic benefit. Logically, HSC and gut epithelial tissues should also sustain more damage because of the lack of recovery time between cycles of chemotherapy, but such side effects, at least in the short term, seem to be much less severe as endothelial cells have a higher level of apoptosis than cancer cell lines or fibroblasts. Although the lack of thrombospondin-1 (TSP1) does not affect the rersponse to the maximum-tolerated dose of cyclophosphamide, it does prevent the effects of metronomic chemotherapy. As soluble, circulating TSP1 was observed after in vitro metronomic dosing, it might be a useful surrogate marker for monitoring the clinical outcome of metronomic chemotherapy treatments^ref.
• high dose intensity chemotherapy : for leukemia and lymphomas; HSCT allows increase of MTD; PBSCT repopulates bone marrow more rapidly (heterologous HSCT also allows GVT effects)
• regional chemotherapy : high dose-intensity chemotherapy, especially for cancer, administered as a regional perfusion.
• endoarterial chemotherapy :
• liver : floxuridine (used for CRC metastases but not for hepatocellular carcinoma (HCC) metastases) has 69-92% liver extraction fraction, increasing local concentrations by 100 to 400-folds
• head and neck
• limbs
• intraperitoneal chemotherapy
• intraperitoneal hyperthermic chemotherapy (IPHC) following cytoreductive surgery (ideally to less than 5 mm deposits or just microscopic deposits) lengthens overall survival in patients with peritoneal dissemination of GI neoplasm. Patients are cooled to a core temperature of 34-35°C. Then mitomycin C heated to 39°C is perfused through inflow and outflow catheters placed percutaneously into the abdominal cavity, at a flow rate of approximately 800 mL/min for approximately 2 hours. Heating the drug serves 2 purposes: it potentiates the effect of chemotherapy and decreases tumor resistance to chemotherapy. Intraperitoneal perfusion also increases the concentration of the drug delivered to the tumor compared with conventional systemic chemotherapy. Median survival after IPHC was 45.1 months vs. 3.1 months when patients are treated conventionally. In peritoneal dissemination of appendiceal neoplasms treated with cytoreductive surgery and IPHC between 1993 and 2004, the 1-year survival rate was 83.8%, and the 5-year survival rate was 56.8%. Cytoreductive surgery and IPHC has benefit in treating peritoneal carcinomatosis arising from multiple sites, including the appendix, colon/rectum, mesothelium, ovary and stomach : assessments performed for 86 patients every 3 months for up to 1 year showed significant improvements in overall quality of life, with physical functioning improved at 6 months. For those people who have a good performance status and have disease localized to abdomen, if you can surgically debulk that tumor down to minimal size, this procedure would be the treatment of choice
• intrapleural chemotherapy
• intratechal chemotherapy for leukemia and lymphomas (also allows to bypass a pharmacological sanctuary)
• isolation-perfusion technique : a technique for administering high doses of a chemotherapy agent to a region while protecting the patient from toxicity: the blood flow of the region is isolated, as by application of a tourniquet to an extremity, and the region is perfused by means of a pump-oxygenator; the drug is added to the perfusate, which may be heated by a heat exchanger to provide hyperthermia
• Xenobiotics ...
• against proliferating cells
• inducing differentiation
• RARs agonists
• the synthetic retinoid fenretinide [N-(4 hydroxyphenyl)retinamide (4-HPR)] induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs, thus providing opportunities for novel approaches to cancer therapy. The upstream signaling events induced by fenretinide include an increase in intracellular levels of ceramide, which is subsequently metabolized to GD₃. This ganglioside triggers the activation of 12-LOX leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak. Increased evidence suggests that the apoptotic pathway activated by fenretinide is p53-independent and this may represent a novel way to treat tumors resistant to DNA-damaging chemotherapeutic agents.
• bexarotene 300 mg/m²/day PO daily. Leukopenia moderate (7%) or moderately severe (4%), anemia mild (4%), moderate (2%) or moderately severe (2%), severe infection (2%), hyperlipidemia (34%), pruritus (14%), skin disorder (11%), edema (5%), hypothyroidism (4%), severe rash (4%), severe exfoliation (2%) => dose-limiting toxicities occurred in 66% of patients (50% at 300 mg/m²/day and 89% at > 300 mg/m²/day), monitor for hyperlipidemia. Nausea level 1^ref
• VDR agonists
• HDAC inhibitors^ref, by promoting histone acetylation, permit chromatin to assume a more relaxed state, thereby allowing transcription of genes involved in various cellular processes, including differentiation, particularly in malignant hematopoietic cells^ref. However, when administered at higher concentrations, HDAC inhibitors induce apoptosis, a phenomenon that has been related to induction of oxidative injury^{ref1, ref2}. 2 such compounds are the short chain fatty acid sodium butyrate (NaB)^ref and suberoylanilide hydroxamic acid (SAHA), an agent that is currently undergoing clinical evaluation in patients with hematological malignancies^ref. Recently, preclinical studies indicate that SAHA exhibits significant activity against MM cells in vitro^ref, raising the possibility that HDAC inhibitors may have a role to play in myeloma treatment.
• inducing senescence (terminal cell-cycle arrest)
• NOS2 inhibitors
• inducing apoptosis : most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasize without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the 'bad news' genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option^ref.
• vitamin C : In 1976, Cameron, Campbell and Pauling reported beneficial effects of high-dose vitamin C (ascorbic acid) therapy for patients with terminal cancer^{ref1, ref2, ref3, ref4}. Subsequent double-blind, randomized clinical trials at the Mayo Clinic failed to show any benefit^{ref1, ref2}, and the role of vitamin C in cancer treatment was discarded by mainstream oncologists^{ref1, ref2}. Vitamin C continues, however, to be used as an alternative cancer therapy^{ref1, ref2}. A key distinction between conventional, science-based medicine and alternative therapy is the presence or absence of scientific plausibility^ref. In conventional medicine, the efficacy of treatment is proven by properly conducted clinical trials. Many treatments are still used if there is moderately good, albeit inconclusive evidence of efficacy ("clinical plausibility"), especially when treatment rationale agrees with biologic facts (conferring "biological plausibility")^ref. Vitamin C is an alternative cancer therapy because the results obtained in original studies that suggested clinical benefit were not confirmed by controlled clinical trials, and the notion that high-dose vitamin C was selectively toxic to cancer cells was biologically implausible. New information is available pertaining to biological plausibility. Although similar doses of vitamin C were used in the Cameron–Pauling and Mayo Clinic studies, the Cameron–Pauling studies combined intravenous and oral administration whereas the Mayo Clinic studies used only oral administration^{ref1, ref2, ref3, ref4, ref5}. Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (> 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with acvanced cancer^ref. At high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. In 17 healthy hospitalized volunteers, vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g. Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (+/-sd) peak plasma concentrations of 134.8 +/- 20.6 mmol/L compared with 885 +/- 201.2 mmol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 mmol/L and 13 400 mmol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses^ref. When the treatment is unorthodox, alternative explanations, even if highly unlikely, tend to be preferred^ref (Buckman R, Sabbagh K. Magic of Medicine? An Investigation of Healing and Healers. Amherst, N.Y.: Prometheus Books, 1995). Subjects consuming 200–300 mg per day of vitamin C in 5 or more daily servings of fruits and vegetables have fasting steady state plasma concentrations of about 70–80 µmol/L^{ref1, ref2}. Even with maximally tolerated oral doses of 3 g every 4 hours, peak plasma concentrations are estimated to not exceed 220 µmol/L^ref. Intravenous administration of vitamin C bypasses tight control for several hours, until homeostasis is restored by renal excretion. Depending on the dose and infusion rate, peak plasma concentrations obtained intravenously are estimated to reach 14 000 µmol/L, and concentrations above 2000 µmol/L may persist for several hours. Concentrations of 1000–5000 µmol/L are selectively cytotoxic to tumour cells in vitro^{ref1, ref2, ref3, ref4, ref5}. Emerging in vitro data show that extracellular ascorbic acid selectively kills some cancer but no normal cells by generating hydrogen peroxide^ref. Death is mediated exclusively by extracellular ascorbate, at pharmacologic concentrations that can be achieved only by intravenous administration. Vitamin C may serve as a pro-drug for hydrogen peroxide delivery to extravascular tissues, but without the presence of hydrogen peroxide in blood. These data are consistent with clinical pharmacokinetics of vitamin C administered intravenously^ref. Of note, only a minority of cancer patients reported by Cameron and colleagues responded to intravenous and oral vitamin C therapy^{ref1, ref2, ref3, ref4}, and not all cancer cells were killed by ascorbic acid in vitro^ref. Further basic investigation of pharmacologic vitamin C concentrations in mediating cell death will facilitate discovery of the mechanisms responsible for sensitivity and resistance in vitro and in vivo. The in vitro biologic evidence and clinical pharmacokinetics data confer biological plausibility to the notion that vitamin C could affect cancer biology and may explain in part the negative results of the Mayo Clinic trials^{ref1, ref2, ref3, ref4}. Thus, sufficient evidence has accumulated, not to use vitamin C as cancer treatment, but to further explore the therapeutic concept. One way to increase the clinical plausibility of alternative cancer therapies is rigorous, well-documented case reporting, as laid out in the US National Cancer Institute (NCI) Best Case Series guidelines^{ref1, ref2}. Such case series might identify alternative therapies that merit further investigation^{ref1, ref2}. Case reports of apparent responses by malignant disease to intravenous vitamin C therapy have appeared^ref (Riordan HD, Jackson JA, Riordan NH, et al. High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney. J Orthomol Med 1998;13:72-3; Riordan HD, Jackson JA, Schultz M. Case study: high-dose intravenous vitamin C in the treatment of a patient with adenocarcinoma of the kidney. J Orthomol Med 1990;5:5-7; Jackson JA, Riordan HD, Hunninghake RE, et al. High-dose intravenous vitamin C and long-time survival of a patient with cancer of the head of the pancreas. J Orthomol Med 1995;10:87-8; Riordan NH, Jackson JA, Riordan HD. Intravenous vitamin C in a terminal cancer patient. J Orthomol Med 1996;11:80-2; Riordan NH, Riordan HD, Casciari JJ. Clinical and experimental experiences with intravenous vitamin C. J Orthomol Med 2000;15:201-3), but only 3 patients had sufficient detail or complete follow-up for evaluation and conformed to NCI Best Case Series guidelines, including pathologic confirmation^ref (Riordan HD, Jackson JA, Riordan NH, et al. High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney. J Orthomol Med 1998;13:72-3). Original diagnostic material obtained before treatment with vitamin C was reviewed by pathologists at the National Institutes of Health (NIH) who were unaware of the diagnoses and treatments^ref. On the basis of emerging clinical and in vitro data, early-phase clinical trials of intravenous vitamin C therapy alone and in combination with conventional chemotherapy are currently in the planning and execution phase, including a formal phase I trial in progress at McGill University^{ref1, ref2, ref3}. It is likely that high vitamin C intakes have low toxicity, except under certain conditions^ref (Food and Nutrition Board; Panel on Dietary Antioxidants and Related Compounds. Vitamin C. In: Anonymous Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington DC: National Academy Press, 2000:95-185). Intravascular hemolysis was reported after massive vitamin C administration in people with glucose-6-phosphate dehydrogenase deficiency^ref. Administration of high-dose vitamin C to patients with systemic iron overload may increase iron absorption and represents a contraindication^{ref1, ref2}. Ascorbic acid is metabolized to oxalate, and 2 cases of acute oxalate nephropathy were reported in patients with pre-existing renal insufficiency given massive intravenous doses of vitamin C^{ref1, ref2}. Therefore, patients with renal insufficiency or renal failure, or who are undergoing dialysis, should not receive high doses of vitamin C^ref. It is controversial whether high-dose vitamin C use is associated with oxalate kidney stones, and patients with hyperoxaluria or a prior history of oxalate kidney stones have a relative contraindication to high-dose vitamin C^ref. Rare cases of acute tumour hemorrhage and necrosis were reported in patients with advanced cancer within a few days of starting high-dose intravenous vitamin C therapy, although this was not independently verified by pathologic review^{ref1, ref2}. Although tumour hemorrhage suggests an anticancer potential for ascorbate, there is the potential for risk to some patients.
• PPARa agonists
• PR agonists
• DNA topoisomerase II / DNA gyrase inhibitors
• BTB domain peptide inhibitors (BPI) bind with very high specificity to Bcl-6 and block recruitment ofc the SMRT, NCoR and BCoR corepressors in vivo, impairing its ability to silence critical genes that need to be off for B cell lymphomas to survive. In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest^ref
• limonoid glucosides in orange juice induce apoptosis in neuroblastoma cells
• anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w inhibitors (its expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival) : ABT-737, with an affinity 2 to 3 orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice^ref.
• local release or activation of anticancer drugs
• ultrasound (US)-mediated burst opening of tiny drug-containing capsules injected into the bloodstream : the capsules target the tumor through antibodies or other molecules coating the capsule surface
• photochemotherapy (PCT) / photoradiation or photodynamic therapy (PDT) / phototherapy : administration of a photosensitizing chemical (photosensitizer) and subsequent exposure to light. Following the absorption of light, the sensitizer is transformeed from its ground state into an excited stae. The activated sensitizer can undergo 2 kinds of photoreaction :
• type 1 reaction : the sensitizer can react directly either with the substrate, such as the cell membrane or a molecule, transferring a hydrogen atom to form radicals (O₂-independent formation of mono- and bifunctional adducts in DNA). The radicals interact with oxygen to produce oxygenated products (¹O₂)
• type 2 reaction : the activate sensitizer can transfer its energy directly to oxygen to form singlet oxygen (¹O₂) - a highly reactive oxygen species (ROS)
Strategies :
• antivascular PDT of tumors with palladium-bacteriopheophorbide (TOOKAD) relies on in situ photosensitization of the circulating drug by local generation of cytotoxic reactive oxygen species, which leads to rapid vascular occlusion, stasis, necrosis and tumor eradication. It can be monitored with BOLD-MRI
• psoralen and UV-A-II (PUVA)
• 8-methoxypsoralen / methoxsalen (Oxsoralen-Ultra^®, 8-MOP^®, Oxsoralen^®)
• 4,5,8-trimethylpsoralen / trioxsalen (Trisoralen^®)
• S-59
Minimal phototoxic dose (MPD) : dose of PUVA required to produce an E+/- erythema 48 to 72 hours after exposure. This grade should not be exceeded in phototherapy.
Indications : psoriasis (Goeckerman treatment by applying ointments of tar followed by irradiation with UVB), wavelengths shorter than 290 nm are far more erythemogenic than therapeutic as the proliferative compartment and stratum corneum are thicker than that of normal skin. Longer wavelengths are more efficient than shorter ones because of their ability to penetrate deeply into thick psoriatic plaques.
Side effects : increased incidence of cutaneous squamous cell carcinoma and melanoma.
Photopheresis / extracorporeal photochemotherapy is the standard therapy for cutaneous T-cell lymphomas (CTCL) (mycosis fungoides and Sezary's syndrome). Preliminary tests in a range of studies from around the world suggest that photopheresis might be beneficial in T-cell mediated autoimmune diseases such as ACD, pemphigus, MS, RA, Scl, SLE, and most recently, heart transplant rejection and GvHD^ref.
The photopheresis machine separates the blood into RBCs, WBCs, and plasma. The WBCs receive 8-methoxypsoralen and are irradiated with UV-A within the machine before blood is returned to the patient. The process of photopheresis takes about 3 1/2 hours. After treatments at monthly intervals patients begin to show a response after 3.5 months of therapy. Because only a small portion of the patient's malignant cells are ever treated it has been assumed that an immune response has been induced
• 311-312 nm narrow-band UV-B : a more recent successful development is the availability of the so-called  Philips TL-01 fluorescent tube, with a distinct peak at 311-312 nm, with minor spikes at 304 and 334 nm. The photosensitizing chemicals used are :
• calcipotriene
• tazarotene
• chrysarobin and its synthetic derivative anthralin / 1,8-dihydroxy-9-anthrone / dithranol (Drithocreme^®) inhibit cellular respiration by inactivation of mitochondria.
Indications :
• psoriasis

Side effects : asymptomatic blisters on psoriatic plaques are an uncommon adverse effect caused by the quick reduction of acanthosis and desquamation before defensive mechanisms, i.e. the increase in the thickness of the stratum corneum and pigmentation, develop.
• atopic dermatitis
• photodermatoses
• severe seborrhoeic dermatitis
• rose bengal (RB) in cells transfected with firefly (Photinus pyralis) luciferase. Finally, they flip the "switch" by adding luciferin, lighting up the cell like a microscopic lightning bug. Once illuminated, the rose bengal produces a toxic form of O₂ called singlet oxygen (¹O₂) that destroys the cells by rupturing their membranes (BioLuminescence Activated Destruction (BLADe))
• erythrosin B (EB) : a red compound, used as a histologic stain.
• erythrosine sodium : a coloring agent used to disclose plaque on teeth; applied topically in solution, or tablets containing erythrosine sodium are chewed, after which the mouth is rinsed with water
• m-tetra(hydroxyphenyl)chlorin (m-THPC) / temoporfin (Foscan^®, Biolitec AG) : potential indications for head and neck tumours (approved in EU), prostate and pancreatic tumours. Activation wavelength = 652 nm.
• porphyrins :
• d-aminolevulinic acid (d-ALA) (Levulan Kerastick^®; DUSA Pharmaceuticals, Inc.) : potential indications for actinic keratosis (approved in EU), basal cell carcinoma, head and neck cancers, and gynaecological tumours. Diagnosis of brain tumours, head and neck cancers, and bladder cancers. Activationwavelength = 635 and 375-400 nm
• 5-ALA methylesther (MLA / M-ALA) (Metvix^®; PhotoCure ASA) : indication for actinic keratosis (approved in EU) and basal cell carcinoma (approved in EU). Activation wavelength = 635 nm
• 5-ALA benzylesther (Benzvix^®) : indication for gastrointestinal cancer. Activation wavelength = 635 nm
• 5-ALA hexylesther (Hexvix^®) : indication for diagnosis of bladder cancers. Activation wavelength : 375-400 nm
• tin ethyl etiopurpurin (SnET2) / Sn etiopurpurin / rostaporfin (Photrex^®, Purlytin^®; Miravant Medical Technologies) : indication for cutaneous metastatic breast cancer, basal cell carcinoma, Kaposi's sarcoma, and prostate cancer. Activation wavelength = 664 nm
• boronated protoporphyrin (BOPP^®) : potential indication for brain tumours. Activation wavelength = 630 nm
• 2-(1-hexyloxyehtyl)-2-devinyl pyropheophorbide-a (HPPH) (Photochlor^®; Rosewell Park Cancer Institute) : potential indication for basal cell carcinoma. Activation wavelength = 665 nm
• texaphyrins : a class of rationally designed porphyrin-like molecules capable of stably coordinating lanthanide and nonlanthanide metals that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers. Metallotexaphyrin compounds include :
• europium texaphyrin (Eu-Tex)
• dysprosium texaphyrin (Dy-Tex)
• manganese texaphyrin (Mn-Tex)
• lutetium texaphyrin / PCI-0123 (Lu-Tex^®, Lutex^®, Lutrin^®) : potential indictions for cervical cancer, prostate cancer and brain tumours. Activation wavelength = 732 nm
• motexafin lutetium (MLu) / lutetium(III) texaphyrin (Lu-Tex) (Antrin^®, Lutrin^®, Optrin^®; Pharmacyclics Inc.) in patients with recurrent breast cancer, atherosclerosis (photoangioplasty) and age-related macular degeneration
• motexafin gadolinium (MGd) / PCI-0120 (Xcytrin^®; source : Pharmacyclics Inc.) : in vitro studies have shown that it is synergistic with radiation and varied chemotherapeutic agents. A phase III international study has shown that the onset of neurologic progression is significantly delayed in patients with brain metastases from lung cancer treated with whole-brain radiation and motexafin gadolinium (compared with radiation alone). Recent preclinical data have shown that motexafin gadolinium alone is cytotoxic to cancers such as multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia through redox and apoptotic pathways. Multiple clinical trials examining motexafin gadolinium as a single agent and in combination with radiation and/or chemotherapy for the treatment of solid and hematopoietic tumors are underway. Motexafin gadolinium is a novel tumor-targeted agent that disrupts redox balance in cancer cells by futile redox cycling. Motexafin gadolinium is currently in numerous hematology/oncology clinical trials for use as a single agent and in combination with chemotherapy and/or radiation therapy^ref.
• phthalocyanine-4 (Pc 4^®) : potential indictions for cutaneous/subcutaneous lesions from diverse solid tumour origins. Activation wavelength = 670 nm
• taporfin sodium / NPe6 / mono-L-aspartyl chlorin e6 / taporfin sodium / LS11 (Talaporfin^®; Light Science Corporation) : potential indications for solid tumours from diverse origins. Activation wavelength = 664 nm
• benzoporphyrin derivative-monoacid ring A (BPD-MA) / verteporfin (Visudyne^®, Novartis Pharmaceuticals) : a mixture of regioisomers I and II. Potential indications for basal cell carcinoma. Activation wavelength = 689 nm
• hematoporphyrin derivative (HpD) partially purified, porfimer sodium (Photofrin^®; Axcan Pharma, Inc.). Potential indications for Barrett's oesophagus (approved in EU and USA), cervical dysplasia (approved in Japan), cervical cancer (approved in Japan), endobronchial (approved in Canda, Denmark, Finland, France, Germany, Ireland, Japan, The Netherlands, UK, and USA), oesophageal cancer (approved in Canada, Denmark, Finland, France, Ireland, Japan, The Netherlands, UK and USA), papillary bladder cancer (approved in Canada) and gastric cancers (approved in Japan), and brain tumours. Activation wavelength = 630 nm
• dihematoporphyrin ethers (DHE)
• photosan-3 (PS-3)
• photofrin-II
• meso-tetrakis-phenylporphyrin (TPP)
• tetraphenylporphinesulfonate (TPPS4)
Complications  :
• porphyrins are taken up by any rapidly proliferating tissue, including the skin, leading to photosensitivity to sunlight
• some porphyrins are activated only by light that cannot penetrate more than a few millimiters into tissues
• some biological pigments normally present in skin, such as hemoglobin and melanin, also absorb light and in doing so can prevent a porphyrin from being activated. Even the porphyrin itself can cause this problem if it accumulates to such high levels that it asborbs all the light in the superficial layers of the tissue.
Following ECP, lymphocytes become apoptotic and untreated monocytes, exposed to post-ECP lymphocytes, reduce proinflammatory cytokine secretion. ECP-treated lymphocytes can reduce the ability of LPS-stimulated monocytes to produce some proinflammatory cytokines (IL-1aand IL-6); however, this effect is not dependent on phosphatidylserine externalization^ref.
Targeting delivery system for photodynamic therapy : the rationale for the use of molecular delivery systems for photosensitizers is similar to that for the delivery of chemotherapeutics and toxins. Carrier-mediated delivery allows increased accumulation of sensitizer at the targeted site and the use of photosensitizers that have efficient photochemistry but cannot accumulate in tumours adequately. Carriers therefore broaden the clinical repertoire of sensitizers, and minimize the amount of precision that is needed in light delivery. Furthermore, the sensitizer does not need to dissociate from carriers for activation to occur, and additional target specificity can be achieved by controlling the location at which light activates the drug. Various delivery systems have been tested in preclinical models. Photoimmunotargeting uses monoclonal antibodies that recognize tumour antigens. For example, chlorin e6-monoethylenediamine monoamide (CMA), haematoporphyrin or mTHPC can be coupled to a selective monoclonal antibody^{ref1, ref2, ref3}. Ligands against receptors that are upregulated in tumour cells could be another delivery vehicle. For example, tumour cells that express the low-density lipoprotein (LDL) receptor have been shown to internalize a LDL-coupled photosensitizer^{ref1, ref2, ref3}. Another strategy is to target the sensitizer to the peripheral benzodiazepine receptor^ref or oestrogen receptor in hormone-dependent tumours^ref. Finally, liposomes and immunoliposomes can be used in conjunction to photosensitizers^{ref1, ref2}. However, the main problem is that many physiological barriers, such as spatially and temporally heterogeneous blood flow and vascular permeability, can still hinder the delivery of these sensitizers to tumours^{ref1, ref2}.
Warning : avoid exposure to sunlight after treatment
Web resources : Photodermatology.com
• ... against cancer cells

The problem with many available cancer therapies is that, because of their genomic instability, cancer cells rapidly develop resistance to the treatment.
• inducing senescence of cancer cells (terminal cell-cycle arrest)
• NOS2 inhibitors
• inducing apoptosis of cancer cells (increased by type I IFNs, which upregulate p53 expression)
• inhibitors of DNA replication
• inihibitors of DNA synthesis (antimetabolites : they are cell cycle stage-specific)
• inhibitors of pyrimidine synthesis
• N-phosphonoacetyl-L-aspartate (PALA)
• inhibitors of thymidylate synthase
• inhibitors of dihydrofolate reductase (DHFR)

C667 SNP in methylenetratrahydrofolate reductase (MTHFR), which is present in about 35% of the North-American population, is 35% less active, so 5,10-methylene THF accumulates (10% higher levels associated with 12% lower levels of 5-methyl-THF) in cancer cells and alter the chemosensitivity to antifolate drugs 5-FU and MTX, which are widely used to treat breast and colon cancer^ref.
Associated with leucovorin / folinic acid calcium as healthy cells recover more easily than neoplastic ones => decresed side effects
Side effects : increase of transaminases (24%), leukopenia (87%), opportunistic infections (9.5%), methotrexate pneumonia (7%), stomatitis (2%).
Premedication for pemetrexed : dexamethasone 4 mg PO BID day before, day of, and day after treatment, folic acid 350-1000 mg PO QD starting 5-7 days prior to treatment, continued throughout treatment and for 21 days after last treatment, vitamin B₁₂ 1000 mg IM 7 days prior to treatment and every 2 cycles thereafter
• pyrimidine analogs
• fluoropyrimidine analogs
• 5-fluorouracil (5-FU) (Adrucil^©, Fluorplex^®, Efudex^®, Efudix^®). It is catabolyzed by dihydropyrimidine dehydrogenase (DPD).

All the compounds (except N-carboxy-fluoro-ß-alanine (CFBAL)) are represented in neutral form. U (uracil) and CDHP (5-chloro-2,4-dihydroxypyridine) are inhibitors of the enzyme dihydropyrimidine dehydrogenase. Abbreviations: 5-FUH₂ = 5,6-dihydro-5-fluorouracil; FUPA = a-fluoro-ß-ureidopropionic acid; FBAL = a-fluoro-ß-alanine; F^- = fluoride ion; FMASAld = fluoromalonic acid semi-aldehyde; FHPA = 2-fluoro-3-hydroxypropanoic acid; Facet = fluoroacetaldehyde; FAC = fluoroacetate.
Associated with leucovorin / folinic acid calcium that stabilizes 5-FdUMP, increasing inhibition of DNA synthesis
PN401 / triacetyluridine, an oral prodrug of uridine yields more bioavailable uridine than oral administration of uridine itself. PN401 may therefore be useful for permitting dose escalation of 5-fluorouracil (5-FU) with consequent improvements in antitumor efficacy^ref
• floxuridine / 5-fluoro-2'-deoxyuridine (FUdR / 5-FdUrd) (FUDR^©, Floxuridine^®)
• capecitabine (CAP) / N⁴-pentoxycarbonyl-5'-deoxy-5-fluorocytidine (Xeloda^©) : oral administration mimics continuous 5-fluorouracil infusion while remaining convenient with higher patient acceptance and compliance rates and avoiding intravenous administration-associated complications and financial costs. It provides intra-tumour selective activation by TK, thus potentially facilitating local management and therefore improved anti-tumour activity as well as reduced systemic toxicity. The concentration of thymidine phosphorylase (an enzyme essential for capecitabine activation in tumour cells) increases after exposure to cytotoxics such as taxanes, cyclophosphamide, gemcitabine or vinorelbine, which results in synergistic activity. It has been tried both as monotherapy and in combination with other chemotherapy agents both in first-line regimes and in previously treated patients against metastatic colorectal cancer and breast cancer, results being very good in terms of efficacy and tolerability.


• 5'-deoxy-5-fluorocytidine (5'-dFCR)
• 5'-deoxy-5-fluorouridine (5'd5-FUrd) / doxifluridine (Furtulon^®)
• ftorafur (FTO) / 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur^© or Futraful^©)
• uracil + FTO (UFT^©)
• UFT^© capsules copackaged with leucovorin (LV) / folinic acid calcium tablets (Orzel^©)
• S-1 / TS-1 (FTO + 5-chloro-2,4-dihydroxypyridine + potassium oxonate (OXO))
• 5'-deoxy-5-fluorouridine (5'd5-FUrd)
• 5-chloro-2,4-dihydroxypyridine (CDHP)
• BOF-A2 = emitefur
• eniluracil (source : Adherex)

• idoxuridine / 5-iododeoxyuridine
• cytidine analogs :
• 5-azacytidine (AZA)
• gemcitabine / 2',2'-difluorodeoxycytidine (dFdC) (Gemzar^©)
• decitabine (DAC) / 5-aza-2'-deoxycytidine (Dacogen^©), also used for sickle cell anemia
• cytarabine ocfosfate / cytosine arabinoside (AraC) (Aracytin^©, Cytosar-U^©, Depocyt^©, Tarabine PFS^©)
• troxacitabine / b-L-dioxolane cytidine (Troxatyl^©)
• inhibitors of purine synthesis^ref
• inhibitors of purine ring biosynthesis / purine analogues need to be activated by deoxycytosine kinase
• 6-mercaptopurine (6-MP) (Purinethol^©)
• 6-thioguanine (6-TG) (Lanvis^©)
• azaguanine : a mitotic poison that resembles the purine guanine but is actually incorporated into nucleic acids and acts to block nucleic acid synthesis by competitive inhibition.
• clofarabine / 2-chloro-9-(2-deoxy-2-fluoro-b-D-arabinofuranosyladenosine) (CAFdA) (Modrenal^©, Clofarex^©)
• cladribine / 2-chloro-2'-deoxyadenosine (CdA) (Leustatin^©)
• fludarabine / 9-b-D-arabinofuranosyl-2-fluoroadenine (Fana-A) phosphate (Fludara^©) 25-30 mg/m² iv days 1-5. Grade 4 neutropenia (56%), grade 3 neutropenia with infections (9%), thrombocytopenia (25%), nausea (3%), mucositis (2%), diarrhea (2%), and neuropathy (4%)^{ref1, ref2, ref3}. Fludarabine synergizes with rituximab by downregulating CD55 membrane expression
• nelarabine / 506U78
• vidarabine / arabinosyladenine (AraA) (Vira-A^©)
• 2-deoxycoformycin (DCF) / pentostatin (Nipent^©)^ref for hairy cell leukemia (HCL). In a clinical investigation in patients with refractory CLL using Nipent at the recommended dose in combination with fludarabine phosphate, 4 of 6 patients entered in the study had severe or fatal pulmonary toxicity.
Thiopurine S-methyltransferase (TPMT) irreversibly transfers a methyl group from S-adenosylmethione (SAM) to 6-mercaptopurine (6-MP) producing 6-methyl MP and S-adenosylhomocysteine (SAH). The adenosyl moiety of SAH is subsequently cleaved and homocysteine can be remethylated to methionine. The methyl donor for this folate-dependent remethylation cycle is 5-methyltetrahydrofolic acid, which is formed in a reaction catalysed by 5,10-methylenetetrahydrofolate reductase (MTHFR). Polymorphisms in enzymes catalysing SAH recycling may thus indirectly impact on TPMT activity and the capacity to methylate thiopurine drug metabolites. Intracellular SAM and SAH levels are known to be influenced by two common polymorphisms in the MTHFR gene C677T and A1298C. A further polymorphism, R653Q, in the MTHFD1 gene is also associated with significant disturbance in folate-dependant methylation. The MTHFR 677TT genotype significantly modulates the red cell TPMT activity. This finding is particularly important within the context of TPMT testing prior to the start of AZA therapy and explains some lack of concordance between TPMT genotype and phenotype^ref.
• inhibitors of adenosine deaminase (ADA)
• inhibitors of dihydrofolate reductase (DHFR)
• inhibitors of purine nucleoside phosphorylase (PNP)
• compounds which form adducts with DNA
• alkylating agents : not only induce apoptosis, but also damage tumor cells' DNA. Iin specially bred mice, this injury activated the DNA repair protein PARP, which depletes NAD, a coenzyme necessary for the metabolism of ATP : because a mature tumor cell gets all of its energy from the metabolism of glucose by oxygen (while most normal cells can live on the catabolism and the production of ADP from multiple substrates), alkylation destroys tumor cells by necrosis in mice deficient in the pro-apoptotic genes p53 and BCL-2^ref. Providing another source of energy to both apoptotic-deficient tumor cells and tumors from wildtype apoptotic-competent mice prevented both groups of cells from dying. If new ways to activate PARP or deplete NAD coudl be found, they could kill tumor cells without damaging the cells' DNA. Anyway some apoptosis might still be going on alongside the necrosis, using apoptotic regulators not knocked out, particularly ones not yet discovered : the mice he used may not occur naturally in nature, in part because tumor cells deficient in both of BCL-2's proteins, bax and bak, have never been observed and if apoptosis normally kills tumor cells before necrosis ever gets a chance to, necrosis may be largely irrelevant. Necrosis is the more promising mechanism than apoptosis because death by apoptosis suppresses the immune system, while death by necrosis activates it, providing an additional way to kill tumor cells : anyway while that is probably true of sporadically occurring apoptosis, it is not true of the massive apoptotic death normally caused by chemotherapy and radiotherapy, in which so much cellular debris piles up that the immune system sends in phagocytic white cells to digest and remove it. In fact, it is a breakdown in such immune suppression that is thought to cause the temporary presence of anti-dsDNA antibodies in mononucleosis patients.
• uracil mustard : a cytotoxic alkylating agent that is the uracil derivative of nitrogen mustard, used as an antineoplastic in the treatment of chronic lymphocytic and chronic granulocytic leukemia, NHL, mycosis fungoides, and polycythemia vera; now generally replaced by more effective agents.
• nitrogen mustards
• mechlorethamine hydrochloride / HN2 / nitrogen mustard (Caryolisine^©, Mustargen^©) : used primarily for the treatment of disseminated Hodgkin's disease, especially in the MOPP treatment regimen, administered intravenously; it is also used in the treatment of CLL and CML, NHL, mycosis fungoides, polycythemia vera, and bronchogenic carcinoma. Mechlorethamine is also administered intraperitoneally, intrapericardially, and intrapleurally for the palliative treatment of malignant effusion and has been applied topically in the treatment of mycosis fungoides
• oxazaphosphorines :
• cyclophosphamide (CP) (Cytoxan^©, Endoxan^©, Neosar^©, Procytox^©) : it is activated by CYP2B6 to 4-OH-cyclophosphamide, that breaks imidazole ring in G leading to depurination of GMP residue. Cyclophosphamide is a widely used chemotherapeutic drug that was recently applied as either an antiangiogenic/antivasculogenic or an immunostimulatory agent in combination with cancer immunotherapies. It has been previously shown that cyclophosphamide augments the efficacy of antitumor immune responses by depleting CD4⁺25⁺ T_reg cells and increasing both T-lymphocyte proliferation and T memory cells. Furthermore, cyclophosphamide was shown to mediate killing of circulating endothelial progenitors. However, the molecular basis for these observations has not yet been elucidated. The cyclophosphamide-mediated inhibition of iNOS is directly linked to its immunostimulatory but not to its antivasculogenic effects. Moreover, combined application of cyclophosphamide with a novel, oral DNA vaccine targeting PDGF-B, overexpressed by proliferating endothelial cells in the tumor vasculature, not only completely inhibited the growth of different tumor types but also led to tumor rejections in mice. These findings provide a new rationale at the molecular level for the combination of chemotherapy and immunotherapy in cancer treatment^ref. It may also modulate galectin-1 expression and function during tumor growth and metastasis with critical implications for tumor-immune escape and immunotherapy^ref.

Side effects : hemorrhagic cystitis (60%) and bladder carcinoma (6%)
Prevention : mesna
• 4-hydroperoxycyclophosphamide (4-HC) (Pergamid^©)

Ex vivo cytoprotection : amifostine
Among other things, it offers the possibility of in vitro purging of the bone marrow in autologous bone marrow transplantation (ABMT)
• ifosfamide (Ifex^©) : CYP3A4 seems to be the most important CYP isoform in both bioactivation and N-dechloroethylation of the alkylating prodrug ifosfamide, but informations about possible gender-related differences are lacking^ref

Side effects : hemorrhagic cystitis (60%) and bladder carcinoma (6%)
Prevention : mesna
• mafosfamide (MAF), unlike cyclophosphamide, does not require a particular enzyme for activation. Among other things, it offers the possibility of in vitro purging of the bone marrow in autologous bone marrow transplantation (ABMT)

Ex vivo cytoprotection : amifostine
• trofosfamide (TRO) (a prodrug)
• melphalan / L-sarcolysin / L-phenylalanine mustard (L-PAM) (Alkeran^©) :
• MEL100 : 100 mg/m²_BSA
• MEL200 : 200 mg/m²_BSA
• chlorambucil (Leukeran^©) 0.1 mg/kg/day p.o.^{ref1, ref2} in 2-mg or 5-mg caps for Waldenstrom macroglubulinemia and chronic lymphocytic leukemia
• bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole
• ethylenimines and methylmelamines
• hexamethylmelamine (HMM) / altretamine (Hexalen^©)
• triethylenemelamine (TEM)
• thiotepa (Thioplex^©) => triethylene thiophosphoramide (TEPA)
• alkyl sulfonates
• busulfan (BSF) (Myleran^©, Busulfex^©)
• nitrosoureas
• carmustine / 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) (Bicnu^©). Gliadel^© (polifeprosan 20 with carmustine implant) wafers into cavities are implanted by neurosurgeons after tumor removal, circumventing its feeble ability to penetrate the blood-brain barrier, turning carmustine into a more targeted drug by avoiding the systemic toxicity that would result from carmustine injections.
• estramustine (Emcyt^©, X-trant-Estramustine^©)
• lomustine / 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) (CeeNu^©)
• prednimustine : ester of chlorambucil and prednisolone used as a combination alkylating agent and synthetic steroid to treat various leukemias and other neoplasms. It causes gastrointestinal and bone marrow toxicity.
• semustine / methyl-CCNU (MeCCNU)
• streptozocin / streptozotocin (Zanosar^©) (antibiotic) : contains a methylnitrosourea (MNU) moiety and causes type I diabetes mellitus.
• chlorozotocin
• triazenes
• dacarbazine / 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) (Dacarbazine^©, DTIC-Dome^©)
• procarbazine / N -methylhydrazine (MIH) (Matulane^©, Natulan^©)
• imidazotetrazine derivative
• temozolomide (TMZ) (Temodal^©) : it has almost 100% oral bioavailability, can cross the blood-brain barrier, demonstrates linear pharmacokinetics, and has minimal, noncumulative myelotoxicity. Pilot studies of temozolomide in adults with high-grade and low-grade gliomas have shown it to be active, producing objective radiographic responses. The initial studies used a regimen of temozolomide 150 mg/m² per day for five days of treatment every 28 days. A subsequent regimen of temozolomide 75 mg/m² per day for 6 to 7 weeks at a time has been piloted in patients with malignant gliomas and has been found to be well tolerated and to provide a greater delivered dose over time. The initial phase I study suggested that the continuous dosing regimen was more efficacious than the 5-day regimen, but this finding was not confirmed in a subsequent phase II study. Used also in the treatment of melanoma
• pipobroman (PB) (Vercyte^©) is a neutral amide of piperazine with a chemical structure close to that of alkylating agents, although the exact mechanism of action of PB has not been demonstrated. Used for treatment in polycythemia vera (PV) and essential thrombocythemia (ET)
• mitomycin C (Mutamycin^©)
• platinum coordination complexes : not cell cycle stage-specific; prodrugs activated by hepatocytes. Although the mechanistic details of their cellular uptake and mode of action remain incomplete, the platinum drugs appear to act by intercalating into the DNA helix through covalent bonding at guanine resiudes and supplementary hydrogen bonding. This intercalation subsequently interferes with transcription and DNA replication to trigger apoptosis of the cell. The ligand-exchange reaction for Pt(IV) is very slow, on the order of days, resembling the division time of cancerous cells, and this may be an important factor in their efficacy. The copper transporter 1 (CTR1) / SCL31A1 protein has been implicated in the uptake of Pt into cells, as has passive diffusion, although the details of transmembrane uptake are unknown. Although Pt(IV) compounds are rapidly reduced to Pt(II) after ingestion, they do not need to be injected. Pt(II) is also effective in di- or trinuclear complexes in which the Pt(II) units interect cooperatively to increase the strength of binding with the DNA nucleotides. Cancers of various types, including colorectal cancer, lung, and ovarian, that are intrinsically resistant to cisplatin and carboplatin, are consequently much less resistant to the newer higher order Pt(II) complexes.
• cisplatin / cis-diamminedichloroplatinum (II) (Cis-DDP) (Platinol-AQ^©)

Side effects :
• nausea and vomiting treated with antiemetics
• hypomagnesemia
• hypocalcemia
• hypokalemia
• nephrotoxicity (chronic glomerulonephritis, chronic tubulointerstitial nephritis, acute tubular necrosis (ATN), nephrogenic diabetes insipidus) treated with vigorous rehydratation
• sensory polyradiculoneuropathy, targeting dorsal root ganglia (DRG). It causes a dose-dependent and dose-limiting sensory neuropathy, which is often disabling and from which recovery is often slow and incomplete (gene therapy).
• carboplatin (CBDCA) (Paraplatin^©) : a cyclobutanedicarboxylato analog of cisplatin
• carboxyphthalatoplatinum
• iproplatin (CHIP)
• nedaplatin
• tetraplatin
• ormiplatin
• 3^rd generation
• oxaliplatin / trans-1-diaminocycohexane oxalatoplatinum / LOHP (Eloxatin^©)
• Aroplatin^©
• inhibitors of DNA topoisomerases
• DNA topoisomerase I inhibitors are cell cycle stage-specific drugs (acting during S phase). Once inside the cell, bleomycin acts as an enzyme creating single- and double-strand DMA-breaks.
• bleomycin has been delivered also by electrochemotherapy, augmenting its cytotoxicity by several 100-fold. Drug delivery by electroporation has been in experimental use for cancer treatment since 1991 and electrochemotherapy has been used for malignant cutaneous or subcutaneous lesions, e.g., metastases from melanoma, breast or head- and neck cancer. Electroporation was performed using plate or needle electrodes under local or general anaesthesia. Bleomycin was administered intratumourally or intravenously prior to delivery of electric pulses. The rates of complete response (CR) after once-only treatments were between 9 and 100% depending on the technique used. The treatment was well tolerated and could be performed on an out-patient basis^ref.
Side effects : little myelosuppresion; diarrhea, cutaneous toxicity (hyperpigmentation, hyperkeratosis, erythema, and even ulceration of the elbows, knuckles, and other pressure areas) and pulmonary fibrosis (bleomycin : 5-10%; 1% die), hyperthermia, headache, nausea, and vomiting, acute fulminant reaction in 1% of patients with lymphomas (profound hyperthermia, hypotension, and sustained cardiorespiratory collapse due to release of endogenous pyrogen), exacerbations of rheumatoid arthritis; Raynaud's phenomenon and coronary artery disease in patients with testicular tumors treated with bleomycin in combination with other chemotherapeutic agents.
Indications : colorectal cancer (camptothecins), breast carcinoma (antibiotics), lung cancer, ovarian cancers
Premedication : acetaminophen 650 mg PO 30 minutes prior to treatment, repeat q4h PRN
• DNA topoisomerase II / DNA girase inhibitors are cell cycle stage-specific drugs. Sabarubicin has lower cardiotoxicity and efficacy in a vast series of human gynaecological tumours and tumours of the lung and prostate xenotransplanted onto naked mice.

Side effects : toxic myocarditis
• epigenetic drugs
• inhibitors of DNA methylation
• 5-azacytidine : a cytidine analogue that can be incorporated into RNA and DNA; unlike cytidine it cannot be 5-methylated, a process that is important in gene regulation and post-transcriptional processing of RNA; 5-azacytidine is an investigational antineoplastic agent for myelodysplastic syndromes (MDS)
• inhibitors of ribonucleotide reductase : the ability of HU to induce mutation in cell culture studies results from the generation of nitrogen dioxide via the autoxidation of nitric oxide, a product of HU metabolism. However, we argue that autoxidation would not occur in vivo, leading to the conclusion that generation of the mutagen nitrogen dioxide is peculiar to cell culture systems and has little relevance to the use of HU in the management of polycythemia vera (PV) and essential thrombocythemia (ET)^ref.
• inhibitors of cancer cell RNAs
• P30 / ranpirnase (Onconase^©) (i.v.), a homolog of RNAse A from oocytes and ESCs of Rana pipiens, the leopard frog. The toxicity of P30 and RNase A variants relies on their ability to evade the cytosolic ribonuclease inhibitor protein (RI) and degrade cellular RNA. Indicated for unresectable malignant mesothelioma (see also immunotoxin)
• inhibitors of cancer cell protein synthesis
• L-asparaginase (L-Asp) (i.v. or i.m.), which catalyzes the hydrolysis of extracellular L-asparagine to ammonia and L-aspartic acid (starving leukemic cells only as they do not express asparagine synthetase, on the contrary of normal cells) and hydrolysis of some b-aspartylpeptides^ref, is currently used in acute lymphoblastic leukemia (ALL) (5,000-30,000 UI/m²/day) and lymphoblastic lymphoma in children and natural killer (NK) lymphoma^ref (6000 U/m²/day) in adults

	half-life	administration schedule
Escherichia coli L-asparaginase (Colaspase©, Cras-Nitin© (Bayer), Elspar©, Kidrolase©, Leucogen©, Leunase©, Medac©(Kyowa Hacco Kyogo => Medac)) : 1 U generates 1 mM of NH4+/min at pH = 7.3 and T = 37°C; more coagulation abnormalities but higher efficacyref; patients with anaphylactoid reactions are switched to ...	1.2 days	every other day
Erwinia chrysanthemi L-asparaginase / NSC-106977 (Porton asparaginase©) : less immunogenic, induce fewer coagulation disorders; patients with anaphylactoid reactions (8% develop Abs, of importance only during a second period of asparaginase therapyref, unrelated to the risk of relapse, sometimes measurable for > 1 year after asparaginase therapy) are switched to ...	0.65 days	daily
PEGylated Escherichia coli L-asparaginase / pegaspargase (Oncaspar©) : unlike L-asparaginase (which is associated with a high incidence of hypersensitivity reactions (up to 73%), including life-threatening anaphylaxis, pegaspargase has a decreased incidence of hypersensitivity reactions, and when doses every 14 days, provides comparable efficacy to L-asparaginase; however, it is much more expensive per single-dose vial and there is crossreactivity between patient antibodies raised against natural E. coli and pegaspargase but not Erwinia asparaginaseref.	357 hours = 5-7 days	1-2 times weekly
Pectobacterium carotovorum (a.k.a. Erwinia carotovora) L-asparaginase (ECAR-LANS) : Km = 98 x 10-6 M for the main physiological substrate L-Asn and 3400 x 10-6 M for L-Gln. ECAR-LANS has low relative glutaminase activity (1.2%) at physiological concentrations of L-Asn and L-Gln in the bloodref. It very highly specific activity and stability during of purification, existing only single therapeutically active isoform of enzyme, more strong antileukemic activity and less profound immunologic toxic effects

ASNASE hydrolyzes L-aspartic b-hydroxamate (AHA) to L-Asp and hydroxylamine, which can be determined at 710 nm after condensation with 8-hydroxyquinoline and oxidation to indooxine
• L-methionine a-deamino-g-mercaptomethane lyase (methioninase, METase) [EC 4.4.1.11] from Pseudomonas putida^ref has been previously cloned and produced in Escherichia coli^{ref1, ref2, ref3} to target the abnormally high methionine dependence of tumor cells. L-methionine + H₂O => a-ketoburyrate + methanethiol + ammonia. rMETase is found in Pseudomonas (Pp), Aeromonas, and Clostridium, but not in yeast, plants, or mammals^ref. rMETase is a homotetrameric PLP enzyme of 172-kDa molecular mass. rMETase has 398 amino acid residues per subunit. The amino acid sequence of rMETase is homologous to the g-family of PLP enzymes that catalyze a,g-elimination and g-replacement reactions, such as cystathionine g-lyase, cystathionine g-synthase, and O-acetylhomoserine o-acetylserine sulfhydrylase^ref. In rMETase, tyronsine 114 has been shown to be important in g-elimination of the substrate^ref. rMETase has been crystallized^{ref1, ref2}. The structure of rMETase has been determined at 1.7Å resolution using synchrotron radiation diffraction data and found to be a homotetramer with 222 symmetry. 2 monomers associate to build the active dimer. The spatial fold of the subunits have 3 functionally distinct domains. Their quaternary arrangement is similar to those of L-cystathionine ß-lyase and L-cystathionine g-synthase from E. coli^ref. Previous studies have extensively documented that a broad range of human tumors are sensitive to rMETase in vitro. The IC₅₀ was several fold less for a wide variety of cancer cell lines compared to non-neoplastic cells. Sensitivity was particularly exquisite for breast, kidney, colon, lung, and prostate tumor cell lines^{ref1, ref2} . Subsequent evaluation of rMETase on a variety of tumor cell lines in mouse xenograph models demonstrated a similar sensitivity to rMETase^ref. In addition, plasma methionine depletion by rMETase resulted in a remarkable increased sensitivity of the tumors to several different types of chemotherapeutic agents^ref. However, the short in vivo half-life of rMETase and evidence of immunogenicity indicated the need to prolong the survival of the enzyme, prolong the period of methionine deprivation, and reduce potential immunogenicity that might result from repeated administration of the enzyme. PEGylation shows benefits^ref
• inhibitors of cancer cell proteins
• arsenic trioxide (ATO) (As₂O₃) (Trisenox^®, Cell Therapeutics Inc., Seattle, WA) at low doses induces leukemia cells (acute promyelocytic leukemia (APL) and multiple myeloma) to undergo apoptosis and at higher doses causes blood flow to solid tumors to shut down.
• cyanoaziridines do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. They do not alkylate DNA nor react with the e-amino groups of L-lysine, despite the presence of an aziridine ring. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.
• imexon, a cyclized 2-cyanoaziridine-1-carboxamide
• inhibitors of microtubules / antitubulin agents / tubulin polymerization inhibitors / tubulin-interacting drugs / antimitotic agents / microtubule-damaging agents (MDA) (=> blockers of formation of mitotic spindle in M phase)
• Vinca rosea alkaloids are cell cycle stage-specific drugs :
• vinblastine (VLB) sulfate (Velban^©) : in contrast with the 2 other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. The X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD) has been reported. Vinblastine introduces a wedge at the interface of 2 tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the a-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate^ref.
• vindesine / des-acetyl vinblastine amide sulfate (Eldisine^©)
• vincristine (VCR) sulfate (Oncovin^©, Vincasar PFS^©, ...)
• vinorelbine (Navelbine^©)
• vinflunine (VFL) (Javlor^©) presently in phase III experimentation for treatment of bladder cancer and non small lung cancer
Side effects : peripheral neuropathy; necrosis due to drug extravasation
• taxanes (taxol derivatives) inhibit tubulin depolimerization and have negligible oral bioavailability due to their degradation by CYP3A. This is a common problem with large molecule, natural product-derived antineoplastics and results in many examples of this class of drug being administered intravenously (IV) rather than orally.
• paclitaxel is labeled for many different cancer treatments and is used primarily for breast cancer,ovarian cancers and non-squamous cell lymphoma. Dosing has been limited because of the toxic solvents that are included in the formulation.
• Xyotax^© in a biodegradable polyGlu polymer
• Taxol^© (source : Bristol-Myers Squibb; Princeton, NJ) contains 50% of a polyethoxylated castor oil vehicle (carrier) known as Cremophor EL^© (CrEL, that can reverse multidrug resistance (MDR) mediated by ABCB1 / MDR1 / Pgp) and ethanol. The paclitaxel/Cremophor EL™/ethanol formulation has also been shown to induce allergic reactions with most of the atypical human side-effects attributed to the Cremophor EL™ component. This has necessitated prophylaxis with GR agonists and extremely long infusion times : 3- or 6-hour intravenous infusions (but not 24-hour infusion) of paclitaxel can yield end-of-infusion plasma Cremophor concentrations > 1 mL/mL, which are sufficient to reverse MDR in vitro by at least 50%
• self-emulsifying drug delivery system (SEDDS)
• ABI 007 (Abraxane^©; source : American Pharmaceutical Partners) is an albumin-stabilised, solvent-free, nanoparticle-coupled formulation of paclitaxel designed to overcome insolubility problems, allowing researchers to administer about 50% more paclitaxel per treatment without steroid pretreatment. Nanoparticles are able to permeate microvessels and rapidly deliver higher doses of the drug to the tumour, but less to normal healthy cells
Premedication : dexamethasone 20 mg PO at 12 hours and 6 hours prior to paclitaxel or 20 mg IV as a single dose 30 minutes prior to paclitaxel, diphenydramine 25-50 mg IV or PO 30 minutes prior to paclitaxel, H₂-receptor antagonist (cimetidine 300 mg IV or PO, famotidine 20 mg IV or PO, ranitidine 50 mg IV or 150 mg PO) 30 minutes prior to paclitaxel. For weekly paclitaxel regimens, the starting dose of dexamethasone can be reduced to 10 mg and tapered as tolerated over time to 4 mg^{ref1, ref2}
• docetaxel (Taxotere^©; Aventis Pharmaceuticals Inc.; Bridgewater, NJ). Premedication : dexamethasone 8 mg PO BID x 3 days, starting the day prior to treatment. For weekly docetaxel regimens, dexamethasone 8 mg PO BID x 3 doses (24 mg/week), starting the evening prior to treatment, is often used^ref
• BMS 184476^ref
• BMS 188797
• BMS 275183
• IDN 5109 / BAY 598862
• RPR 109881A
• RPR 116258
• imidazole-based combretastatin analogs
• epothilones are naturally occurring 16-membered macrolides obtained from the fermentation of the cellulose degrading myxobacteria (Sorangium cellulosum) with the ability to promote tubulin polymerization in vitro and to stabilize preformed microtubules against Ca²⁺- or cold-induced depolymerization, resulting in potent inhibition of cancer cell proliferation at nM to even sub-nM concentrations. . In contrast to paclitaxel epothilones are also active in vitro against multidrug-resistant cancer cell lines as well as cell lines whose paclitaxel-resistance is derived from specific b-tubulin mutations^{ref1, ref2}. The chief components of the fermentation process are
• epothilone A
• epothilone B / EPO906 (the most active form)
..., and in smaller amounts :
• epothilone C
• epothilone D / KOS-862 / NSC-703147^ref
Trace amounts of other epothilones have also been detected :
• deoxyepothilone B
• epothilone B lactam / BMS-247550
• BMS-310705 : water-soluble analog
• (+)-discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta and is far more potent than Taxol against tumors that have developed multiple-drug resistance, with an IC₅₀ in the low nanomolar range
• dolastatins
• dolastatin 10 (dolavaline-valine-dolaisoleuine-dolaproine-dolaphenine) and derivatives :
• symplostatin 1
• symplostatin 3 has ben isolated from a tumor selective extract of a Hawaiian variety of the marine cyanobacterium Symploca sp. VP452. It differs from dolastatin 10 only in the C-terminal unit; the dolaphenine unit is substituted by a 3-phenyllactic acid residue. Symplostatin 3 possesses IC₅₀ values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than dolastatin 10, correlating with the weaker in vitro cytotoxicity^ref.
• synthetic dolastatin 10-based / auristatins
• auristatin E (AE)
• auristatin PE / TZT-1027 (dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine)
• auristatin PHE (pentapeptide dolavaline-valine-dolaisoleuine-dolaproine-phenylalanine-methyl ester)
• monomethylauristatin E (MMAE)
• dolastatin 15
• dolastatin 16
• homodolastatin 16
• isodolastatin H isolated in low yield from the sea hare Dolabella auricularia
• malevamide D, a highly cytotoxic peptide ester, and the known compound curacin D were isolated from a Hawaiian sample of Symploca hydnoides^ref
• targeted therapies : inhibitors of tumour-associated enzymes
• signal transduction inhibitors (STI)
• protein tyrosine kinase inihibitors (TKI)
• mTOR inhibitors^ref
• lipophilic inhibitors of SERCA cause apoptosis by disrupting intracellular free Ca²⁺ levels, and are then effective against both proliferative and quiescent (i.e., G₀-arrested) cells
• urokinase plasminogen activator receptor (uPAR) binds pro-urokinase plasminogen activator (pro-uPA) and thereby localizes it near plasminogen, causing the generation of active uPA and plasmin on the cell surface. uPAR and uPA are overexpressed in a variety of human tumors and tumor cell lines (epithelial, mesenchymal, and haematopoietic), and expression of uPAR and uPA is highly correlated to tumor invasion and metastasis. A constructed mutated Bacillus anthracis toxin-protective antigen (PrAg) proteins in which the furin cleavage site is replaced by sequences cleaved specifically by uPA is activated selectively on the surface of uPAR-expressing tumor cells in the presence of pro-uPA and plasminogen. The activated PrAg proteins causes internalization of a recombinant cytotoxin, FP59, consisting of anthrax toxin LF_1-254 fused to the ADP-ribosylation domain of Pseudomonas aeruginosa exotoxin A, thereby killing the uPAR-expressing tumor cells. Anthrax toxin protective antigen (PrAg) forms a heptamer in which the binding site for lethal factor (LF) spans 2 adjacent monomers : this suggested that high cell-type specificity in tumor targeting could be obtained using monomers that generate functional LF-binding sites only through intermolecular complementation. PrAg mutants with mutations affecting different LF-binding subsites and containing either uPA or matrix metalloproteinase (MMP) cleavage sites had low toxicity as a result of impaired LF binding, but when administered together to uPA- and MMP-expressing tumor cells, they assembled into functional LF-binding heteroheptamers. The mixture of 2 complementing PrAg variants had greatly reduced toxicity in mice and was highly effective in the treatment of aggressive transplanted tumors of diverse origin. These results show that anthrax toxin, and by implication other multimeric toxins, offer excellent opportunities to introduce multiple-specificity determinants and thereby achieve high therapeutic indices^ref.
• farnesyl transferase inhibitors (FTI) prevent activation of ras oncoproteins
• TERT inhibitors
• proteasome inhibitors
• N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)
• MG132
• TMC-95A/B
• PSI
• PS-341 / LDP-341 / MLN341 / bortezomib (Velcade^©) a dipeptide boronic acid. 1.3 mg/m² IV days 1, 4, 8, 11. Repeat cycle every 21 days
• lactacystin
Preliminary data on bortezomib in haematological malignancies :
• inhibits proteasomal degradation of IkB, allowing NF-kB to remain sequestered in the cytoplasm. This blocks NF-kB's ability to translocate to the nucleus, where it would normally induce expression of anti-apoptotic target genes, sensitizing tumour cells to chemotherapeutic agents and radiation. Furthermore, bortezomib downregulates expression of adhesion molecules by myeloma cells, and decreases bone-marrow cell expression of cytokines that mediate myeloma cell growth, survival and migration
• decrease MAPK signalling, as well as to upregulate activity of p53 and the cell-cycle inhibitor p27.
• induce apoptosis in cell types characterized by overexpression of BCL-2
• stabilizes cell-cycle regulation
• anti-angiogenic
• synergistic effects with taxanes and gemcitabine
• sensitizes cells to doxorubicin and melphalan
• weak MDR substrate
Effects of bortezomib on leukemia cell interactions with stromal and endothelial cells :
• inhibitory effect on AML blasts
• selected effects on AML blast interaction with endothelial monolayers
• inhibitory effects of bortezomib persist in the presence of microenvironmental components
• adhesion-mediated or microenvironmental-mediated resistance of AML blasts to chemotherapeutic agents such as cytarabine (ara-C) is preserved in the presence of bortezomib
Bortezomib activity in MDS :
• study design and baseline information : 32 MDS patients studied; median age 71 years, males = 25, primary de novo MDS = 26, normal karyotypes = 9. Bortzomib was given at 1.5 mg/m2 IVP over 3-5 seconds once weekly for 4 weeks followed by a 2-week recovery (6-weeks = 1 cycle) for a total of 8 cycles
• results : 20 patients completed at least 2 cycles and were evaluated for response using the IWG criteria :
• stable disease = 5 (25%)
• partial response = 7 (35%)
• disease progression = 8 (40%)
• TNF-a decreased at the end of 2 cycles following therapy in 11 patients (P < 0.009)
• apoptosis detected in 11 of the 16 patients studied. No significant decrease in the rate of apoptosiswas noted in these patients at the end of 2 cycles : although 1 of the patients who showed a late response demonstrated a marked decrease in the level of apoptosis at study end
• bortezomib has important clinical and biological effects in MDS patients, including significant anti-TNF activity
Side effects : neutropenia grade 3 (11%) or 4 (3%), anemia grade 1-2 (13%) or 3 (8%), grade 3 pneumonia (5%), thrombocytopenia (31%), grade 3 asthenia (18%), fatigue (12%), peripheral neuropathy (12%), vomiting (9%), diarrhea (8%), nausea (6%), arthralgia (5%), paresthesia and dysesthesia (3%), constipation (2%), myalgia (2%) => follow dose modifications provided by manufacturer if peripheral neuropathy develops. Emetogenic potential : days 1, 4, 8, 11 level 2.
• small-molecule antagonists of the MDM2-p53 interaction that activate the p53 pathway in cancer cells : nutlins are cis-imidazoline analogues that displace p53 from its complex with MDM2 with IC₅₀s in the nanomolar range^ref. small-molecule antagonists of MDM2 have been developed^ref. These molecules, termed nutlins, have shown the ability to activate the p53 pathway in vitro and in vivo. Nutlins represent a class of cis-imidazoline analogues that bind to the p53 pocket on the surface of MDM2 in an enantiomer-specific manner. MDM2 interacts through its 100-residue N-terminal domain with the N-terminal transactivation domain of p53 (residues 1-75). This protein-protein dialogue inhibits the p53-MDM2 interface by mimicking the interaction of the 3 critical p53 amino acid residues within the hydrophobic cavity of MDM2. Of importance, this interaction, while blocking MDM2-mediated inhibition of p53, does not interfere with p53 function and has little toxicity in animal models. Thus, it would be anticipated that nutlin can activate the p53 pathway with resultant antitumor effects. This has been shown now for a wide variety of human cancer cell lines; however, the antitumor activity is greater in overexpressing MDM2 cell lines^ref. Oral administration of the compound, which is well-tolerated, results in 90% inhibition of tumour growth of established tumour xenografts in mice relative to vehicle controls, compared with 81% inhibition using intravenous administration of the MTD of doxorubicin. Although 50% of human tumours have lost wild-type p53 and so would not be affected by inhibitors of the p53-MDM2 interaction, activating the tumour suppressor capability of p53 with such compounds might be beneficial in the other 50% of cancers in which the wt-p53 is retained
• nutlin-3 has been shown to induce apoptosis in hematologic malignancies including acute myeloid leukemia and myeloma cell lines^{ref1, ref2}. In the latter case, nutlin-3 was shown to be cytotoxic even when myeloma cells were being sustained by the presence of stromal cells. This advantage was also noted in the context of little apparent damage to stromal cells by exposure to nutlin-3. B-CLL cells exposed to nutlin-3 generated p53 pathway activation and concomitantly induction of apoptosis in cells with wild-type p53, but not mutant p53^ref. Nutlin-3 was synergistic with several commonly used drugs in CLL: chlorambucil and fludarabine. Nutlin-3 can induce apoptosis in almost 100% of CLL B-cell clones tested^ref. Not only were p53 protein levels increased but also that gene profiling after nutlin exposure revealed the up-regulation of several p53-responsive genes. What kind of toxicity profiles are to be expected with the use of nutlinlike drugs in CLL? In the earlier CLL study^ref, it was found that blood T cells are not as susceptible to killing by nutlin-3 as B-CLL cells, suggesting relatively low toxicity toward the immune system, a very welcome attribute in CLL therapy. Further encouraging findings in the study by Secchiero et al are that despite induction of p53 in normal lymphocytes, there was less cytotoxicity for other cells including bone marrow and CD34⁺ cells. Thus, nutlin-3 has a growing array of positive attributes; it can be used orally, penetrates cell membranes, is effective preclinically at very low doses (100-300 nM), does not have a high level of toxicity, and synergizes with traditional chemotherapies. It is important to remember that nutlin-3 should be effective only in leukemic cells that possess a functional p53 pathway. In CLL, the structural changes in p53 required to inactivate p52 are usually rare and more often late in the disease. An additional point is that induction of apoptosis by p53 is complex, and therefore, is a likely target for inactivation in tumor cells, which could obviate any significant clinical impact. Despite these caveats, the recent work on nutlin-3 seems almost too good to be true, and we await the results of clinical trials with this agent in CLL as well as other hematologic malignancies.
• HSP90 inhibitors
• geldanamycin (GA / GM) is an exquisitely specific, membrane-permeable inhibitor of the Hsp90 family^ref that binds to the ATP-binding pocket of Hsp90 and blocks the ATPase cycle. As a result, most Hsp90 substrates fail to mature properly and are targeted to the proteasome for degradation
• 17-allylaminogeldanamycin (17-AAG) : Hsp90 binds with higher affinity to 17-AAG in tumor cells where Hsp90 is in multichaperone complexes (e.g., p23, HOP, where the binding affinity for ATP is 10-fold higher) (IC₅₀ = 6 nM) than in normal cells (IC₅₀ = 6 nM) ; Hsp90 tumor complexes also show a higher ATPase activity (something that Hsp90 chaperone function is dependent on) that is inhibited by 17-AAG^ref
Novel membrane-impermeable inhibitors with pharmacological properties entirely different from GA targeting extracellular functions of Hsp90 might represent potent anti-metastatic drugs for a large variety of cancers.
• Aurora kinases inhibitors cause cell-cycle arrest (mitosis occurs in the absence of cytokinesis, with accumulation and subsequent decrease of cyclin B1) : VX-680^ref
• MMP inhibitors have not had success as apart from promotion of invasiveness they also have anti-tumour effects : MMP8 protexts against development of skin tumours in male mice and female mice with depleted estrogen^ref
• glycolysis inhibitors : slow growing hypoxic cells in solid tumours are difficult to target selectively but differ from normal cells in that they depend on anaerobic glycolysis
• 2-deoxy-D-glucose (2-DG) (source : Threshold Pharaceuticals)^ref
• hormonal therapy for hormone-dependent cancers : cytostatic rather than cytotoxic => lifelong therapy, biologically active dose rather MTD => ferw side effects
• sexual steroids
• ablative hormonal therapy : pharmacological destruction of endocrine gland
• adrenocorticolytic
• mitotane / o,p'-dichlorodiphenyldichloroethan (DDD) (Lysodren^©)
• inhibitory hormonal therapy
• CYP11A inhibitors
• CYP19 / aromatase inhibitors for breast carcinomain postmenopausal women : in fertile women estrogen synthesis by ovaries is subjected to hypothalamic-pituitary feedback compensatory loops tha nullify activity of aromatase inhibitors. On the other hand, in postmenopausal women estrogen synthesis occurs exclusively in extragonadal tissues, which are not sensitive to feedbacks. They achieve greater responses compared with the non-steroidal ER antagonist tamoxifen due to the partial agonist effects of tamoxifen, which can limit its clinical effectiveness. Aromatase activity in peripheral tissues and local malignant and normal breast tissue supplies breast cancer cells with the oestrogen that stimulates cancer growth. The molecular control of this process in breast cancer seems to involve increased COX-2 expression. High plasma oestradiol levels are now known to be associated with an increased risk of breast cancer in postmenopausal women, so use of aromatase inhibitors might provide a novel prevention strategy in the future. In ER⁺ breast carcinomas that co-express the growth-factor receptors ERBB1 / EGFR and/or ERBB2, oestrogen deprivation might be more effective than tamoxifen at inhibiting tumour growth. This is consistent with emerging data that confirm cross-talk between growth-factor-receptor and steroid-receptor pathways that leads to tamoxifen resistance as a result of an increased agonist response. Acquisition of resistance during long-term oestrogen deprivation might also involve cross-talk pathways. ER expression might be increased in these cells, with receptors becoming activated and hypersensitive to low residual levels of oestradiol. Strategies to prevent this occurring with various signal-transduction inhibitors and oestrogen-receptor downregulators are now being tested.
• competitive hormonal therapy
• PR antagonists
• ER antagonists (antiestrogen therapy) : 5-years adjuvant chemotherapy in breast carcinoma. Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of SERMs. The function of vulnerable C-terminal zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the ER to its responsive element and subsequent transcription, providing a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding^ref.
• AR antagonists (antiandrogen therapy) in prostate adenocarcinoma : increase in AR mRNA and protein is the only change consistently associated with the development of resistance to antiandrogen therapy, amplifying signal output from low levels of residual ligand. Furthermore AR antagonists show agonistic activity in cells with increased AR levels; this antagonist-agonist conversion is associated with alterations in the recruitment of coactivators and corepressors to the promoters of AR target genes
• CXCR4 antagonists : CXCR4 is expressed in adult glioblastoma multiforme (GBM), 90% of pediatric medulloblastomas and 60% of anaplastic astrocytomas. Signalling via CXCL12 / SDF1is known to cause chemotaxis, increase proliferation and decrease apoptosis : AMD 3100 increases apoptosis in GMB, but has no effect on proliferation, whereas apoptosis is increased and proliferation reduced in medulloblastomas^ref
• additive hormonal therapy
• GR agonists in leukemia, lymphomas, and prostate adenocarcinoma
• ER agonists in breast carcinoma
• AR agonists
• GnRH-R agonists in prostate adenocarcinoma and pre-menopausal breast carcinoma
• T₄to suppress TSH incretion in patients with thyroid carcinoma
• SST (Di Bella's therapy when in combination with VDR agonists and RAR agonists) to inhibit incretion of GH in patients with neuroendocrine tumors (islet cell tumors and carcinoids).
• pro-apoptosis agents :
• mTOR / FRAP1 inhibitors induce apoptosis via 4E-BP1 => JNK activation => c-Jun hyperphosphorylation. In cells that lack functional p53 formation of ASK-WAF1 complex is uneffective and can't impair c-Jun hyperphosphorylation.
• BCL-2 inhibitors : HA14-1^ref
• XIAP inhibitors^ref :
• phenoxodiol / 2H-1-benzopyran-7-O1,3-(4-hydroxyphenyl) (a synthetic derivative of the plant isoflavone daidzein, analog of genestein; source : Marshall Edwards, Inc.) (also DNA topoisomerase II / DNA girase inhibitors^ref) targets a regulator sphingosine kinase, so depriving the cell of XIAP and FLIP (inhibitors of caspases) the cancer cells then undergo apoptosis : now in trials for patients with chemoresistant ovarian cancers in combination with docetaxel.
• 8 polyphenylurea-based compounds are identified that bind to the BIR2 domain of XIAP, which is responsible for the inactivation of caspase-3 and caspase-7 (XIAP also supresses an upstream initiator caspase-9 thorugh the BIR3 region)r^ef. It is under study as oral dosage form for patients with cervical cancer while intravenous dosage form has already completed a phase II trial for patients with chemoresistant ovarian cancers. Caspases are overexpressed in tumours, but so are IAPs, and, therefore, failure to activate caspase could create resistance to apoptosis
• ATPinduces apoptosis by acting on P2X₇
• as systemic delivery of tumour suppressors is limited as the large proteins cannot cross the plasma membrane, a p53-activating peptide delivered to mice with advanced-stage peritoneal carcinomatosis using peptides containing a cell-penetrating peptide (CPP) domain (D-isomer RI-TATp53C' peptide) activates p53 in cancer cells, but not normal cells, resulting in increased lifespan and disease-free animals^ref
• cyclopamine kills medulloblastoma cells impairing Hedgehog (Hh) signaling (ligand-independent activation of this pathway has been shown to occur in medulloblastoma, caused either by mutations that render Smo insensitive to regulation by Ptch, or by mutational inactivation of Ptch)
• plant-derived terpenes
• diterpenes of the phorbol and simaroubolide types
• triterpenoids^ref
• cycloartane
• lupane
• ursane
• oleanane
• friedelane (especially quinone methides)
• dammarane
• cucurbitacin
• limonoid
• withanolide
• sesquiterpene lactones
• ecteinascidin-743 (ET-743) (Yondelis^©)
• aplidine(Aplidin^©)
• kahalalide F
• ES-285
• aziridinyl benzoquinone (AZQ)
• myriaporone
• marine 18-membered antitumor macrolides (+)-tedanolide and (+)-13-deoxytedanolide
• bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former is less than that of the corresponding cyclopropane-containing compounds.
• 6-hydroxymethylacylfulvene (HMAF; MGI 114; irofulven) is a semisynthetic analogue that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound; it has a unique mechanism of action involving macromolecule adduct formation, S-phase arrest and induction of apoptosis
• percutaneous ethanol injection (PEI) therapy (PEIT) : ethanol stagnates within the capsule of parathyroids or hepatocellular carcinoma (HCC) (no capsule in metastases => poorly effective) and causes protein denaturation => coagulative necrosis of all cells within capsule

Indications : patients with few nodules sized < 3-5 cm, neither cirrhosis nor portal thrombosis
Regimens : one-shot or long-course
Inherent limitations :
• inhomogeneous perfusion
• intratumoral septa
• extracapsular spread / satellite nodules
Other injected compounds :
• acetic acid
• astins
Combination chemotherapy regimens / multiple agent therapy (MAT)
Optimal dose and interval (expressed as dose intensity (DI) [mg/m²_BSA/wk]) are required to achieve reduction of tumor volume, ie. of tumor cell number.
Chemoresistance directly relates to number of cell clones resistant to maximum tolerated dose (MTD) : anyway MTD value can be increased with supportive therapies (GFs, HSCT, ...).
• temporary resistance :
• pharmacological sanctuaries (blood-tissue barriers) may be bypassed by increasing dose (e.g. for  and araC), choosing a lipophilic drug (e.g. nitrosoureas) or local drug administration (e.g. endorachid)
• decreased perfusion may be reversed with surgical or radiotherapeutical debulking, increased dose or cyclic chemotherapy (kills a fixed % of tumor cells each time). Hypoxic cells within tumours are refractive to clinically relevant chemotherapeutic agents and it is reasonable to infer that the quiescent nature of hypoxic cells may render them insensitive to agents that target rapidly dividing cells.
• bioreductive prodrugs can be reduced by cellular reductases to species that cause DNA damage under hypoxic conditions, but in the presence of molecular oxygen they are efficiently back-oxidized to the non-toxic parent compound, such that little or no DNA damage occurs. Of importance is the relative toxicity of bioreductive drugs under hypoxic versus aerobic conditions. Preferably, the drug should possess a high hypoxic cell cytotoxicity ratio (HCR; the ratio of the dose required to kill a proportion of aerobic cells to that required to kill an equal proportion of the same cells exposed to the drug under hypoxic conditions), leading to maximum hypoxic tumour cell killing with minimal toxicity to aerobic tissues.
• mitomycin C
• NF-167
• Ro-038799
• nitroimidazoles
• etanidazole / SR 2508 (Nitrolmidazole^©)
• metronidazole
• misonidazole (MISO)
• nimorazole (NIMO)
• pimonidazole
• tirapazamine (Tirazone^©, Sanofi^©)
• low mitotic index can be reversed with cyclic chemotherapy, administration of growth factors, debulking (reversing the growth curve to an exponential phase) or non-cycle specific chemotherapeutical agents
• genetic or permanent resistance (exponential onset) : Goldie-Coldman model^ref (1979) relates the drug sensitivity of a tumor to its own spontaneous mutation rate towards phenotypic drug resistance. The proportion as well as the absolute numbers of resistant cells will increase with time and the fraction of resistant cells within tumor colonies of the same size with vary depending on whether mutation occurs as an early or late event. Analysis of the model indicates that the probability of the appearance of a resistant phenotype increases with the mutation rate. Furthermore, for any population of tumors with a non-zero mutation rate the likelihood of there being at least one resistant cell will go from a condition of low to high probability over a very short interval in the tumor's biologic history.
• increased gene expression
• increased expression of the target protein (e.g. : DHFR for methotrexate)
• inactivating enzyme
• outward membrane transporter (see MDR proteins)
• enzyme to bypass inhibited pathway
• decreased gene expression
• activating enzyme (e.g. TK for 5-FU, polyglutamylase for methotrexate)
• inward membrane transporter
• acquired defects in component of the apoptotic pathway
• mucin 1 (MUC1) overexpression, which occurs in most carcinomas : MUC1 is cleaved in the ER and forms a heterodimer comprising the amino and carboxyl termini that localiizes to the cell surface. The C terminus can be phosphorylated at tyrosine-46 (Y46) by the EGFR after heregulin (but not EGF) binding, and this induces its binding to b-catenin and mitochondrial localization, so forming a link between the EGFR and WNT signalling pathways. MUC1 also attenuates apoptosis induced by TRAIL, which acts through the extrinsic death-receptor pathway^ref
It can be reversed with
• polychemotherapy (synergic or to reduce likelihood to develop chemoresistance)
• increased dose or dose intensity
• early chemotherapy (e.g. adjuvant chemotherapy after surgical or radiotherapeutical debulking, when cells are in exponential growth phase)
• MDR inhibitors
• gene therapy
• associations with immunotherapy (sequential chemoimmunotherapy (SCIT))
• antiangiogeneic therapy
• anti-growth factor drugs
• buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agents
Side effects from toxicity on other rapidly proliferating cell types (narrow therapeutic index) : selected NCI common terminology criteria for adverse events
• immediate
• fever with chills
• grade 1 : 38.0-39.0°C
• grade 2 : 39.0-40.0°C
• grade 3 : > 40.0°C for < 24 hrs
• grade 4 : > 40.0°C for > 24 hrs
• febrile neutropenia
• grade 3 : present
• grade 4 : life-threatening consequences (eg. septic shock, hypotension, acidosis, necrosis)
• chemotherapy-induced nausea and vomiting (CINV)
• nausea
• grade 1 : loss of appetite without alteration in eating habits
• grade 2 : oral intake decreased without significant weight loss, dehydration or malnutrition; IV fluids indicated < 24 hrs
• grade 3 : inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN indicated >= 24 hrs
• grade 4 : life-threatening consequences
• vomiting
• grade 1 : 1 episode in 24 hrs
• grade 2 : 2-5 episodes in 24 hrs; IV fluids indicated < 24 hrs
• grade 3 : >= 6 episodes in 24 hours; IV fluids, or TPN indicated >= 24 hours
• grade 4 : life-threatening consequences
• highly emetogenic drugs : cisplatin, cyclophosphamide, dacarbazine
• moderately emetogenic chemotherapy (MEC) : Adriamycin^©, anthracyclines, nitrosoureas
• poorly emetogenic drugs : methotrexate, 5-FU, bleomycin, Vinca alkaloids
Prevention : antiemetic drugs
• skin eruption
• anaphylaxis
• local extravasation damages
• early
• bone marrow cells => pancytopenia (including immunodepression => increased risk or secondary neoplass). When fever is absent hospital admittance is contraindicated as would expose the patient to nosocomial infections.
• leukopenia
• grade 1 : WBC =LLN-3000/mm³
• grade 2 : WBC =3000-2000/mm³
• grade 3 : WBC =2000-1000/mm³
• grade 4 : WBC < 1000/mm³
• neutropenia :
• grade 1 : ANC/AGC = LLN-1500/mm³
• grade 2 : ANC/AGC = 1500-1000/mm³
• grade 3 : ANC/AGC = 1000-500/mm³
• grade 4 : ANC/AGC < 500/mm³
Selected risk factors :
• increasing age (> 65 years)
• performance status (ECOG 2-4)
• bone marrow involvement
• cycle 1 nadir absolute neutrophil count (ANC) < 500/mL
• serum albumin concentration < 3.5 g/dL
• pre-existing or previous neutropenia
Incidence of infection during induction therapy in neutropenic patients with acute leukemia :

2002 Infectious Disease Society of America (ISDA) guidelines for antibiotic treatment of neutropenic patients with cancer^ref :

• infection :
• grade 2 : localized, local intervention indicated
• grade 3 : IV antibiotic, antifungal, or antiviral intervention indicated; interventional radiology or operative intervention indicated
• grade 4 : life-threatening consequences (eg septic shock, hypotension, acidosis, necrosis)
• aplastic anemia
• grade 1 : hemoglobin < LLN-10.0 g/dl
• grade 2 : hemoglobin 10.8-8.0 g/dl
• grade 3 : hemoglobin 8.0-6.5 g/dl
• grade 4 : hemoglobin < 6.5 g/dl
Prevention : Epo
• thrombocytopenia
• grade 1 : platelets < LLN- 75000/mm³
• grade 2 : hemoglobin 75000-50000/mm³
• grade 3 : hemoglobin 50000-25000/mm³
• grade 4 : hemoglobin < 25000/mm³
Hematological toxicity from paclitaxel begins to increase at doses above 190 mg/m², which is only about 10% higher than the correct dose.
• gastrointestinal mucositis (inflammation of a mucous membrane)
• stomatitis
• grade 1 : erythema of the mucosa
• grade 2 : patchy ulcerations or pseudomembranes
• grade 3 : confluent ulcerations or pseudomembranes; bleeding with minor trauma
• grade 4 : tissue necrosis; significant spontaneous bleeding; life-threatening consequences
Prevention : ice application induces vasoconstriction and reduces drug distribution to oral mucosa; remove mobile devices; practice oral hygiene with bicarbonate washings
• gastritis
• enterocolitis => diarrhea
Prevention & therapy :
• L-glutamine counteracts treatment-induced metabolic deficiencies
• amifostine
• benzydamine HCl reducs pro-inflammatory-cytokine production, scavenges ROS, stabilizes membrane and acts as an antimicrobial
• N-acetylcysteine is an antioxidant that suppresses NF-kB actvation
• FGF10 / keratinocyte growth factor 2 (KGF-2)
• sphingomyelinase and ceramide synthase inhibit ceramide-pathway-induced apoptosis inhibitors
• SOD2 detoxifies ROS
• COX2 inhibitors suppress NF-kB, reduce pro-inflammatory-cytokine production and inhibit angiogenesis
• hair => alopecia
• kidney => renal failure
• direct damage
• tumor lysis syndrome (TLS) => acute urate nephropathy

Prevention : urine alkalinization, hydratation, allopurinol or uricosuric drugs
• fatigue
• grade 1 : mild fatigue over baseline
• grade 2 : moderate or causing difficulty performing some ADL
• grade 3 : severe fatigue interfering with ADL
• grade 4 : disabling
• late
• gametes => irreversible hypogonadism => amenorrhea and azoospermia. Prevention : ovariectomy followed by autologous ovarian transplant after cessation of chemotherapy
• cardiotoxicity from anthracyclines. When doxorubicin is used at 400 mg/m²_BSA, 5% develop CHF; 16% at 500 mg/m²_BSA; 26% at 550 mg/m²_BSA; 48% at 700 mg/m²_BSA.
• neurotoxicity
• hepatotoxicity
• veno-occlusive disease of the liver
• keratinocytes => skin eruptions
• bladder urothelium (from cyclophosphamide and ifosfamide) => hemorrhagic cystitis (60%) and bladder carcinoma (6%)
• pulmonary fibrosis
• deficient dental root development has been reported after conventional pediatric anticancer therapy and after stem cell transplantation (SCT) recipients (most extensive in the patients 3.1-5.0 years at SCT)^ref
Severity of side effects is established as follows :
• grade 0 : none
• grade I : mild and tolerable
• grade II
• grade III : life-threatening, with need to change therapy
• grade IV
Prevention :
• avoid mistakes in dosage : the USP lists a number of recommendations to decrease the likelihood of errors with oncolytic drugs. Here are just a few of them :
• include oncolytics on your list of high-risk, high-alert medications.
• use standardized, preprinted order forms for commonly used chemotherapy regimens, or computerized prescriber order entry systems. Don't permit verbal orders for these drugs.
• don't use abbreviations, acronyms or "nicknames" when prescribing these drugs, and establish a list of required elements on the medication order, including specific information about the patient. And review the oncolytic drugs in your formulary to assess the possibility of errors due to look-alike products.

Cytoprotectant agents	adverse effect modulated	common adverse effects	uncommon adverse effects	management of adverse effects
amifostine / WR-2721 / S-2[3-aminopropylamino] -ethylphosphorothioic acid (Ethyol©; source : Medimmune Oncology), a thiophosphate molecule, is dephosphorylated by tissue-bound alkaline phosphatase enzymes to form the active compound WR1065, a sulfhydryl-containing molecule that passively enters cells to confer a cytoprotective effect.The cytoprotective effect of WR1065 is thought to be mediated through scavenging free oxygen radicals and small reactive molecules, which deter macromolecular damage, and hydrogen ion donation, which facilitates macromolecular repair and reduces pro-inflammatory-cytokine production.	ex vivo protection of mafosfamide- or 4-hydroxyperoxy cyclophosphamide -purged stem cells high-dose melphalan-induced mucositis cyclophosphamide induced hemorrhagic cystitis cyclophosphamide, external-beam radiotherapy (EBRT) or melphalan-induced bone marrow suppression cisplatin- and carboplatin-induced bone marrow suppression, nephrotoxicity, and neurotoxicity concurrent carboplatin and external-beam radiotherapy (EBRT)-induced mucositis, thrombocytopenia, xerostomia external-beam radiatherapy (EBRT)-induced xerostomia and mucositis myelodysplastic syndrome-induced myelosuppression hematologic protection in bone marrow transplantation (BMT) paclitaxel-induced arthralgia, bone marrow suppression, myalgia, neurotoxicity	infusion-related systemic arterial  hypotension (less common with amifostine 200 mg/m2/dose I.V. push over 3'.), nausea and vomiting, somnolence, sneezing, hypocalcemia	metallic taste, flushed feeling, fever, chills, rash, malaise, hiccups, hypomagnesemia	oral or I.V. dexamethasone 10-20 mg (not recommended for 200-mg doses) and an oral or I.V. 5-HT3 antagonist;  supine position and stable baseline blood pressure (patients prescribed antihypertensive medications should omit  doses 24 h preceding infusion) : measureblood pressure immediately before infusion, every 1-5'  during infusion, and 5' following completion. For asymptomatic blood pressure decrease of 20%-30% or greater, or symptomatic decrease in  blood pressure, stop infusion, place the patient in a Trendelenburg position, and infuse of 0.9% NaCl 150-250 mL/h (100-150 mL/m2/h)
dexrazoxane / ICRF-187 (Cardioxan©, Cardioxane©, Zinecard©; source : Pharmacia) : a piperazine-containing bicyclic molecule, becomes an active bichelator after intracellular hydrolysis. The bichelating moiety exerts a cytoprotective effect by prohibiting formation of the Fe3+-doxorubicin complex responsible for generating membrane-destructive oxygen free radicals. Epirubicin-based chemotherapy causes an early increase of the QT and QTc dispersion, which is attenuated by dexrazoxane supplementation. Therefore, dexrazoxane can reduce the arrhythmic risk in patients treated with epirubicinref	anthracyclines extravasation-induced cardiotoxicity (lesser for liposome formulations)	bone marrow suppression, pain at injection site	neurotoxicity, hypersensitivity
leucovorin / folinic acid calcium is a reduced form of folic acid capable of antagonizing the effects of dihydrofolate reductase inhibitors	methotrexate-induced bone marrow suppression, mucositis	none	hypersensitivity, may obscure hematologic signs of  pernicious anemia
mesna (Mesnex©, Uromitexan©), a sulfhydryl-containing molecule, is dimerized to dimesna, which represents the circulating drug species. Dimesna remains contained within the vascular space until it is filtered by the glomerulus of the kidney. The acidic environment of the kidney and bladder facilitates chemical reduction of dimesna to the active monomeric moiety, mesna. The sulfhydryl group of mesna subsequently binds and inactivates urotoxic\ oxazophosphorine metabolites, including acrolein, 4-hydroxyfosfamide, and 4-hydroxycyclophosphamide	cyclophosphamide and ifosfamide-induced uroepithelial toxicity	parageusia	diarrhea, limb pain, headache, fatigue, nausea,  systemic arterial  hypotension, allergy
diethyldithiocarbamate	modulation of cisplatin-induced nephrotoxicity
glutathione	modulation of cisplatin-induced neurotoxicity
lisofylline	modulation of regimen-related toxicity after bone marrow transplantation (BMT)
sodium thiosulfate	modulation of cisplatin-induced nephrotoxicity

Web resources : Cancer medications and chemotherapy terms by Joella Seiwert

• ... against tumor-associated vascular endothelial cells (vascular targeting agents (VTAs)) : they do not affect vasculogenic mimicry.
• VEGFR1 inhibitors
• methionine aminopeptidase-2 (MetAP-2) inhibitors
• PDGFR inhibitors
• ET_A antagonists
• CD117 / c-Kit inhibitors
• FLT-3 inihibitors
• HIF-1a inihibitors
• inhibitors of signal-transduction pathways :
• RAF kinase inhibitors : BAY 43-9006 / sorafenib is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, VEGFR2, VEGFR3, mVEGFR2, FLT-3, PDGFR, p38, and c-kit among other kinase (clinical trials for renal cell carcinoma^ref)
• mTOR / FRAP1 inhibitors : CCI-779 (clinical trials)
• CSI : celebrex (clinical trials)
• MEK inhibitors : PD98059 (not in clinical use)
• ERBB2 inhibitors : trastuzumab (approved agent)
• EGFR inhibitors : ZD-1839, OSI-774 (clinical trials)
• BCR-ABL and PDGFRinhibitors : imatinib (approved agent)
• small-molecule inhibitors of HIF-1 activity :
• microtubule polymerization inhibitors : 2ME2 (clinical trial)
• HSP90 inhibitors : 17-AAG (clinical trial)
• topoisomerase I inhibitors : camptothecin, topotecan (approved agent)
• thioredoxin 1 inhibitors : pleurotin, 1-methylpropyl 2-imidazolyl disulphide (not in clinical use)
• not determined : YC-1 (not in clinical use)
• anginex / betapep-25 : b-sheet-forming peptide 33-mer (betapep peptides) that prevents adhesion/migration on the ECM of angiogenically activated endothelial cells => induces anoikis, resulting in an up to 90% inhibition of migration in the wound assay
• SLC24A3 / adenine nucleotide translocator (ANT) inhibitors induce apoptosis in endothelial cells, while much higher concentrations are needed for a similar effect on tumour cells
• 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO)
• phenylarsine oxide (PAO) is lipophilic and hence toxic to all cells
• c-SRC inhibitors : tumour angiogenesis suppression by quinolines (TASQ)
• 4-anilino-3-cyanoquinolines
• 4-anilinoquinazolines
• roquinimex (Linomide^®)
• 4-anilinoquinoline-3-carbonitrile
• combretastatin A-4 disodium phosphate (CA4DP)
• flavone-8-acetic acid (FAA)
• 5,6-dimethylxanthenone-4-acetic acid (DMXAA) : cytokines, 5-HT and nitric oxide (NO) released in response to FAA and DMXAA may induce a sustained increase in the permeability of tumor vascular cells, leading to cessation of blood flow and induction of tumor necrosis
• hydralazine (HDZ)
• nicotinamide (NTA)
• low-dose metronomic chemotherapy : the minimization of total tumor burden, rather than complete eradication by maximum tolerated dose (MTD) paradigm, may often be the more practical objective and administration of certain cytotoxic agents at low doses (1/10 to 1/3 of the MTD : doses no longer cytotoxic for cancer cells) is the best way to achieve it. As a corollary, it is found that the more efficient ability of the tumor endothelial cells to resensitize following dosing predicts a targeting bias towards the endothelial compartment of a tumor when metronomic dosing is employed. This lends theoretical support to recent empirical studies showing that regularly spaced dosing schedules with no extended rest periods act more antiangiogenically, thereby delaying or avoiding the onset of acquired resistance.
• HMG-CoA reductase inhibitors inhibt the secretion of CCL-2 / MCP-1 and interfere with signalling downstream of VEGFR1
• integrin-linked kinase (ILK) inhibitors block ILK in both tumour cells (where it acts downstream of PI3K and upstream of AKT) and endothelial cells (where it stimulates migration and vasculogenesis)^ref
• O-(chloracetyl-carbamoyl) fumagillol / TNP-470 is a potent endothelial-cell inhibitor in vitro and inhibits the growth of most types of primary and metastatic tumours in mice. However, dose-limiting neurotoxicity has prevented the efficacy of these agents from being released in the clinic. TNP-470 can be conjugated to the non-immunogenic and non-toxic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, which is a water soluble synthetic polymer that is taken up by leaky tumour vessels and accumulates there because of poor lymphatic drainage (enhanced permeability and retention (EPR) effect), and Gly-Phe-Leu-Gly linker : when the TNP-470 conjugate enters the lysosomal environment of endothelial cells, enzymes - such as cathepsin B, which is overexpressed in tumour endothelial cells - cleave the linker sequence between the polymer and the drug, so releasing the active drug. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. The activity of the conjugated drug is similar to that of free TNP-470 in vitro - both are cytotoxic to endothelial cells and inhibit vascular sprouting in a chick aorta Matrigel assay. The conjugate either has a longer circulation life or accumulates more near proliferating endothelial cells^ref.
• apratoxin A (a cyanobacterial metabolite) mediates its antiproliferative activity through the induction of G₁ cell cycle arrest and an apoptotic cascade, which is at least partially initiated through antagonism of FGF signaling via STAT3^ref
However, some tumours can lose responsiveness to anti-angiogenic therapy because of genetic mutations that make cancer cells able to grow in relative hypoxia (e.g. deficiency of the tumour suppressor p53)
Web resources :
• Anti-angiogenesis information (endostatin and other angiogenesis inhibitors) at Cancer Trials, CancerNet
• Angiogenesis and anti-angiogenic factors at OncoLink
• Fighting cancer with angiogenesis inhibitors in Kimball's Biology Pages
• prostate cancer hope (PC-SPES) is herbal combination that appears to be effective for some kinds of prostate carcinoma if given at 4 small capsules per day (1.28 grams per day). It contains :
• whole mushroom, or just the fruiting body, or the mycelium of Ganoderma lucidum
• entire plant of Rabdosia rubescens (donglingcao), formerly called Isodon rubescens (90-120 grams of the fresh herb, corresponding roughly to 30-40 grams of dried herb)
• tetracyclic diterpenoid compounds
• oridonin
• ponicidin
• pedalitin
• rubescensin E(I)
• kaurenoids
• taibairubescensin A
• taibairubescensin B
• leaf and root of Isatis indigotica (6-10 grams per day)
• root of Scutellaria baicalensis (9-15 grams of the herb in decoction per day)
• Scutellaria barbata(30-60 grams per day)
• Chrysanthemum indicum
• flower of Chrysanthemum x morifolium
• Glycyrrhiza glabra
• Glycyrrhiza uralensis
• Angelica sinensis
• Panax ginseng
• Panax notoginseng
• Panax pseudoginseng
• Serenoa repens (320 mg/day)
Recent work has demonstrated estrogen-like and anti-testosterone activity of PC-SPES although has not found commonly-used estrogens in the mixture (these would have to be additives, as they do not occur in any significant quantity in plants). Side effects : sexual impotence (100%), nipple tenderness (42%), breast swelling (8%), hot flashes (7%), deep venous thrombosis (2%), pulmonary embolism and hemorrhage (due to coumadin from Scutellaria). Synthetic contaminants have been found : alprazolam, diethylstilbestrol (DES). Anyway Chinese medical literature is relatively silent on treatment of prostate cancer, excepted PO liquid extract of geranium leaf. PC-SPES disrupts microtubules by reducing the rate and overall amount of tubulin polimerization and down-regulating a-tubulin expression : microtubule stabilization induced by microtubule-modulating chemotherapeutic agents is antagonistic to those caused by PC-SPES.
• Zyflamend^©, which is produced by New Chapter, Inc., in Brattleboro, Vermont, is composed of herbs (Rosmarinus officinalis, Curcuma longa, Zingiber officinale, Ocimum basilicum, green tea, hu zhang, Chinese goldthread, Berberis spp., Origanum vulgare and Scutellaria baicalensis) with the ability to trigger apoptosis of prostate carcinoma cells by inhibiting COX-2
• Trifolium pratense extract (Trinovin^©) kills prostate carcinoma cells
• Side effect :
• acute hypersensitivity reactions (HSRs)
• taxanes : virtually all patients demonstrating HSRs to paclitaxel and docetaxel are able to successfully tolerate re-treatment following discontinuation and administration of diphenhydramine and hydrocortisone
• platinum compounds : re-treatment has generally been less successful with recurrent HSRs occurring in up to 50% of patients following desensitisation protocols
• asparaginases : patients sensitised to asparaginase are often able to tolerate the alternative preparations, Erwinia carotovora asparaginase or polyethylene glycol-modified Escherichia coli asparaginase
• epipodophyllotoxin : there is very little experience with re-treatment following sensitisation
• tumor lysis syndrome (TLS)

Aetiology : a potential complication in therapy of highly sensitive tumors, especially :
• childhood cancers
• Burkitt lymphoma
• acute leukemias
• Langerhans cell histiocytosis (LCH)
• rare in the treatment of adult solid tumors
• small cell lung cancer (SCLC)
... following massive lysis of malignant cells
Symptoms & signs :
• hyperuricemia => acute urate nephropathy
• hyperkalemia
• hyperphosphatemia
• hypocalcemia
Complications include acute renal failure and metabolic acidosis.
Prevention (begin treatment 24-48 hours after prophylaxis) and therapy :
• hydratation (3,000 mL/m²/die)
• allopurinol (400 mg/m²/die for a few days and then reduced to 200 mg/m²/die)
• urine alkalinization with sodium bicarbonate
• i.v. calcium gluconate
• i.v. uricase
• ion exchange resins
• hemodialysis or continuous arteriovenous hemofiltration in patients unresponsive to drugs, hyperkalemia > 6 mEq/L, hyperuricemia > 10 mg/dL, symptomatic hypercalcemia, rapidly increasing or > 10 mg/dL hyperphosphoremia, and hyperhydratation
• Anti-cancer drug delivery : researchers may have found a better way to target anti-cancer drugs at tumours: they attach the medicine to hormones. The technique turns a traditional way of tackling cancer on its head, as researchers often try to inhibit tumour growth by blocking these hormones. One of the main difficulties in cancer treatment is delivering drugs to tumours, and only tumours. Many current chemotherapy treatments use medicines that also kill normal cells, with side-effects that range from hair loss to infertility. So Tamara Minko of Rutgers in Piscataway, New Jersey, and her colleagues decided to take advantage of the fact that many tumour cells produce abundant receptors for a hormone known as luteinizing hormone-releasing factor (LHRF) / GnRH. Cancer cells, particularly those from the breast, ovary and prostate, are known to contain more receptors for this hormone than normal cells. No one knows why, although it is assumed that it helps to promote a cancer cell's uncontrolled growth. In the past, researchers have attempted to block the action of the factor, but Minko's team decided to take advantage of it. The team attached a portion of LHRF to a drug called camptothecin, which kills cells by disrupting the repair and replication of DNA. 20 times more cells died in mice tumours treated with the drug when it was joined to the hormone. More important, most of the camptothecin reached cancerous cells and it hardly affected healthy organs such as the heart, lung and liver. And female mice dosed with the drug had just as many babies as those who did not get the medicine. The result is more targeted than many drug delivery approaches that have been tried in the past, says the team, though they still need to test exactly how accurate the technique is^ref.
• Web resources
• Cancer treatment at OncoLink
• Chemotherapy at OncoLink
• Cyberbotanica : botanical compounds used in cancer treatment
• About herbs, botanicals & other products by Memorial Sloan-Kettering Cancer Center
• Cancer Trials Databases by the UK Coordinating Committee on Cancer Research (UKCCR)
• MedScape's hematology-oncology treatment update
• oralchemo.org : the online oral chemotherapy resource for patients and families
• CancerNet
• Treatment options
• Cancer Trials

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