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PubMed2006

Handling anticancer drugs: from hazard identification to risk management?

The potential health hazards involved with antineoplastic agents have been known for decades. Many anticancer drugs are recognized as carcinogens and genotoxins in experimental assays. Second cancers have been recorded in follow-up studies with treated patients. The first findings on occupational exposures among hospital personnel administering chemotherapy were reported only in 1979. Since that time a magnitude of studies have been published using various chemical and biological exposure measurements. These findings prompted improvements in the handling practices of personnel working with anticancer drugs. In spite of strict guidelines for the safe handling of cancer chemotherapeutic agents and extensive improvements in the handling facilities in hospitals, also recent studies have revealed detectable, even if generally much decreased, amounts of indicator drugs in air and surface wipe samples, also including biological samples of personnel in hospital pharmacies and cancer therapy wards. Follow-up measurements show that application of strict safety precautions in hospitals decreases the biological exposure and/or effect markers to the level of unexposed referents. Open information and constant tutoring of personnel to avoid the hazards when working with anticancer drugs is absolutely necessary with the increasing use of these important drugs.

Antineoplastic Agents↗

PubMed1991

Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

Antineoplastic Agents↗

PubMed2003

Delivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfopropyl dextran microspheres.

Intratumoral injection of controlled-release microsphere formulations of anticancer compounds has the potential to selectively increase tumour exposure to drugs. This work aimed to evaluate the therapeutic effect and toxicity of microsphere formulations containing the anticancer drug, doxorubicin, in a murine tumour model. The effect of co-administration of verapamil, a P-glycoprotein modulator or chemosensitizer, was investigated. Initial in-vitro studies confirmed the ability of verapamil to enhance the accumulation of both doxorubicin and [(99mTc)]sestamibi, also a P-glycoprotein substrate, in EMT6 murine breast sarcoma cells and a doxorubicin-selected multidrug-resistant variant, EMT6/AR1.0. Ex-vivo studies using confocal microscopy demonstrated release of doxorubicin from microspheres and diffusion of the drug through tissue. For in-vivo studies, EMT6 and EMT6/AR1.0 cells were grown in BALB/c mice. Following intratumoral injection of doxorubicin-loaded microspheres, alone or in combination with verapamil-loaded microspheres, the tumour diameter was measured serially as an indication of therapeutic effect, while the weight, appearance, and behaviour of the mice were monitored as an indication of general toxicity. Intratumoral injections of doxorubicin-loaded microspheres were tolerated much better than systemic administration of equivalent drug concentrations. There was a modest (up to 34%) delay of tumour growth compared with groups receiving no treatment or blank microspheres. Co-injection of verapamil microspheres with doxorubicin microspheres produced a moderate increase in toxicity but no further delay in tumour growth. Controlled-release microsphere formulations of anticancer agents administered intratumorally were an efficient way to deliver high drug doses to the tumour with little systemic toxicity.

Animals↗

PubMed1986

Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen.

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. Km values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 microM, and that of deflavo xanthine oxidase in the range of 39-over 200 microM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxy radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.

Aclarubicin↗

PubMed1997

[Lethal drug interactions of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil].

In 1993 eighteen Japanese patients with cancer and herpes zoster, a viral disease, died from interactions of the new oral antiviral drug, sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), with oral anticancer prodrugs of 5-fluorouracil (5-FU) within 40 d after SRV was approved by the Japanese government and began to be used clinically. Before the death, most of these patients had severe symptoms of toxicity, including diarrhea with bloody flux and marked decreases in white blood cell and platelet counts. All of these patients received SRV daily for several days while being administered long-term anticancer chemotherapy with one of the oral 5-FU prodrugs. There was no acute toxic symptom in patients who received SRV alone or SRV and the other types of anticancer drugs. A toxicokinetic study was carried out using rats to investigate the mechanism of the acute death in the patients caused by drug interactions between SRV and 5-FU prodrugs. Rats were orally coadministered SRV with tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil), a 5-FU prodrug that most of the patients were considered to receive before the death. All the rats receiving SRV and FT once daily showed extremely elevated levels of 5-FU in the plasma and tissues, including bone marrow and small intestines, and died within 10 d, while the animals given the same repeated dose of SRV or FT alone were still alive over 20 d without any appreciable toxic symptom. Before their death, there were a marked damage of bone marrow, a marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported for the patients. Data obtained by in vivo and in vitro studies indicated that (E)-5-(2-bromovinyl)uracil (BVU), generated from SRV by the gut flora and absorbed through the intestinal membrane, was reduced in the presence of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the tissue 5-FU levels from FT, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU. An irreversible inactivation by BVU of rat and human DPDs, expressed in E. coli for the latter, was observed in the presence of NADPH with their purified preparations in a manner reciprocal to radiolabelling of the enzyme proteins with [14C]BVU. SRV showed no inhibitory effect on the rat and human DPDs in the presence of NADPH.

Administration, Oral↗

PubMed2005

Uncovering the hidden potential of intravenous immunoglobulin as an anticancer therapy.

Intravenous immunoglobulin (IVIg) is a safe preparation made from human plasma. The original concept of IVIg as an anticancer drug was built up over the years, after numeral reports were accumulated indicating cancer regressions after IVIg administration. Because IVIg is basically an established remedy for immunodeficiencies and several autoimmune diseases, the association between beneficial effects in cancer patients after IVIg was first seen in patients who had both cancer and autoimmune or immunodeficiency diseases. Interestingly, cancer and autoimmunity share several common features, which together enhance the notion of using IVIg to treat cancer. Several studies tested the broad range of the antimetastatic effects of IVIg. IVIg was found to operate in many different and complex ways, among them (a) induction of interleukin-12 secretion, leading to natural-killer-cell activation; (b) inhibition of matrix metalloproteinase-9 mRNA expression; (c) suppression of tumor cell growth; (d) hindrance of nuclear factor kappaB activation and IkappaB degradation; and (e) G1 cell-cycle arrest. In conclusion, IVIg is a potential anticancer treatment for several reasons: (a) the bidirectional relationship between cancer and autoimmunity; (b) the apparent association between cancer regression and IVIg administration; (c) a variety of anticancer effects of IVIg observed; and (d) IVIg is considered to be a safe preparation with minimal side effects. Obviously, prospective controlled studies that will establish the antitumor effects of IVIg are needed.

Animals↗

PubMed2000

Microbial pathogens and apoptotic anticancer therapy.

In spite of tremendous efforts to control cancer, the mortality associated with this disease has been increasing in developed countries in the recent decades. Inadequate efficiency of existing therapeutic regimens and the rise of multi-drug resistant cancer cells are the main factors which require a broadening of investigations into novel anticancer strategies. Enhancement of apoptosis in tumours has been suggested recently as a new anticancer strategy. It targets the disruption of equilibrium between cell proliferation and cell death in tumours and suggests to restore it through the use of pharmacological agents or genetic approaches. Apoptotic therapy has attracted many groups of investigators and several companies have entered the race to develop the first generation of apoptotic anticancer agents. The review discusses the role that pathogenic microorganisms may have as the source of agents for apoptotic therapy.

Animals↗

PubMed2006

Whole blood TNF-alpha production as a sensitive measure for immunotoxicity of anticancer drugs.

The immunotoxicity of anticancer drugs has been measured with whole blood TNF-alpha production induced by LPS-stimulation. Cis-platinum (CDDP) or 5-fluorouracil (5-FU) was given intravenously to mice once a day for three days. The amount of produced-TNF-alpha lowered significantly in CDDP 2 mg/kg and 5 mg/kg, while the number of leukocytes scarcely changed even when a significant decrease in body weight was observed at the dose of 5 mg/kg. On the other hand, 5-FU 20 mg/kg also caused a significant decline in the amount of produced TNF-alpha but it showed no apparent effects on the number of leukocytes and the body weight. These results indicate that LPS-induced TNF-alpha production is a more sensitive measure than leukocyte count used conventionally to detect the immunotoxicity of two anticancer drugs, CDDP and 5-FU, and suggest that it might be a more practical index for hazard identification in clinical treatment with anticancer drugs.

Animals↗

PubMed2004

Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy.

Pharmacokinetic interactions between food and orally administered drugs involve changes mainly in the absorption and metabolism of a drug, and may have clinical implications. Such interactions, in particular, may be of major clinical significance for cancer chemotherapy since the majority of anticancer agents are toxic, have a low therapeutic index and are administered long term, most often in combination with other cytotoxic agents. The purpose of this review is to compare the pharmacokinetic profiles of various anticancer drugs, including chemopreventive agents that have been examined previously in fasted and fed conditions, and to discuss the underlying basis/mechanisms of food effect in light of a drug's physicochemical and pharmacokinetic properties. Clinical pharmacokinetic parameters such as maximum concentration, area under the concentration-time curve, time to maximum concentration and half-life for each drug are compared in fasted and fed states, and specific dietary recommendations are summarised accordingly. In addition, the effects of food on the metabolite kinetics and pharmacodynamic responses, and the potential role of food effect in the modulation of oral biovariability and multidrug resistance have been extensively discussed. Overall, this comprehensive pharmacokinetic analysis indicates that a broad spectrum of food effects is seen among anticancer agents because of diverse factors regulating each drug's oral bioavailability and its interactions with food. The consideration of such effects is important, as it could lead to more rational pharmacological monitoring and possibly improve the oral chemotherapy of cancer in children, adults and the elderly.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The pursuit of optimal outcomes in cancer therapy in a new age of rationally designed target-based anticancer agents.

There have been extraordinary advances in anticancer therapy over the last few decades, particularly for patients with relatively uncommon malignancies, largely because of the advent of nonspecific cytotoxic chemotherapeutics. Although these agents have also brought improved outcomes for patients with many of the more common solid cancers, it is clear that the point of 'diminishing return' has been reached. The recent development of a plethora of rationally designed target-based anticancer agents has opened up new opportunities and extraordinary therapeutic challenges. Since these agents appear primarily to target malignant cells, they can be expected to be less toxic at clinically effective doses than the cytotoxic agents. Among the various types of rationally designed target-based agents are those that target strategic facets of cell growth signal transduction, angiogenesis, metastasis and cell cycle regulation. While the primary therapeutic benefit of these agents is expected to be decreased tumour growth, evidence suggests that objective tumour responses may also be achieved. However, because of their potentially cytostatic properties, the clinical efficacy of such biologically based agents may not be readily demonstrable with traditional phase I and II study methodologies. Additionally, their dose-toxicity relationships are likely to be less steep than those of the nonspecific cytotoxic agents, thereby rendering such concepts as the maximum tolerated dose less meaningful than alternatives such as the optimal biological dose or the biologically effective dose. Those end-points generally considered, both from a regulatory and clinical viewpoint, to be of secondary importance in trials of cytotoxic agents, such as time to disease progression, disease-related symptoms and quality of life, may evolve into primary end-points. Present findings from preclinical studies suggest that the development, evaluation and general clinical use of rationally designed target-based anticancer agents will require a radical departure from the traditional paradigms if the full potential of these new therapies is to be exploited.

Antineoplastic Agents↗

PubMed2000

Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy.

Increasing knowledge of the structure and function of the epidermal growth factor receptor (EGFR) subfamily of tyrosine kinases and of their role in the initiation and progression of various cancers has, in recent years, provided the impetus for a substantial research effort aimed at developing new anticancer therapies that target specific components of the EGFR signal transduction pathway. Selective compounds have been developed that target either the extracellular ligand-binding region of the EGFR or the intracellular tyrosine kinase region, resulting in interference with the signalling pathways that modulate mitogenic and other cancer-promoting responses (e.g. cell motility, cell adhesion, invasion and angiogenesis). Potential new anticancer agents that target the extracellular ligand-binding region of the receptor include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents. Agents that target the intracellular tyrosine kinase region include small molecule tyrosine kinase inhibitors (TKIs), which act by interfering with ATP binding to the receptor, and various other compounds that act at substrate-binding regions or downstream components of the signalling pathway. Currently, the most advanced of the newer therapies undergoing clinical development are antireceptor monoclonal antibodies (e.g. trastuzumab and cetuximab) and a number of small molecule EGFR-TKIs principally of the quinazoline and pyrazolo-pyrrolo-pyridopyrimidine inhibitor structural classes. The latter group of compounds offers several advantages in cancer chemotherapy, including the possibility of inhibiting specific deregulated pathways in cancer cells while having minimal effects on normal cell function. They also have favourable pharmacokinetic and pharmacodynamic properties and low toxicity, and some TKIs such as the reversible inhibitor ZD1839 ('Iressa') are now undergoing phase II to III clinical trials. In addition, the accumulation of evidence from laboratory studies strongly suggests that EGFR-selective TKIs will have synergistic effects with other antitumour agents or therapy such as cytostatic agents, conventional cytotoxic drugs and radiotherapy. As our knowledge of signal transduction pathways in cancer increases, it is hoped that further advances in this area will allow the therapeutic potential of these compounds as anticancer agents to be realised.

Antineoplastic Agents↗

PubMed2006

Rasburicase: a review of its use in the management of anticancer therapy-induced hyperuricaemia.

Intravenous rasburicase (Elitek, Fasturtec) is the first recombinant uricolytic agent. It is indicated for the management of anticancer therapy-induced hyperuricaemia in paediatric patients in the EU and US, and in adult patients in the EU. Rasburicase is effective and generally well tolerated in adult and paediatric patients with, or at risk of developing, anticancer therapy-induced hyperuricaemia. It is associated with potentially serious haematological adverse events and hypersensitivity reactions, which must be considered prior to and during administration; rasburicase is contraindicated in patients predisposed to haemolysis or methaemoglobinaemia and in patients with glucose-6-phosphate dehydrogenase deficiency. Unlike allopurinol, rasburicase acts on existing uric acid concentrations. Rasburicase treatment resulted in significantly less systemic exposure to uric acid and a quicker therapeutic response than allopurinol in paediatric patients; further studies are needed to determine the comparative efficacy and tolerability of rasburicase versus allopurinol in adult patients. Although further pharmacoeconomic data would be useful, rasburicase was most cost effective for the prevention of hyperuricaemia in children and for treatment of this condition in adults. Thus, rasburicase is a useful option for the prophylaxis or treatment of anticancer therapy-induced hyperuricaemia in both adult and paediatric patients.

Antineoplastic Agents↗

PubMed2006

Spotlight on rasburicase in anticancer therapy-induced hyperuricemia.

Intravenous rasburicase (Elitek), Fasturtec) is the first recombinant uricolytic agent. It is indicated for the management of anticancer therapy-induced hyperuricemia in pediatric patients in the EU and US, and in adult patients in the EU. Rasburicase is effective and generally well tolerated in adult and pediatric patients with, or at risk of developing, anticancer therapy-induced hyperuricemia. It is associated with potentially serious hematologic adverse events and hypersensitivity reactions, which must be considered prior to and during administration; rasburicase is contraindicated in patients predisposed to hemolysis or methemoglobinemia and in patients with glucose-6-phosphate dehydrogenase deficiency. Unlike allopurinol, rasburicase acts on existing uric acid concentrations. Rasburicase treatment resulted in significantly less systemic exposure to uric acid and a quicker therapeutic response than allopurinol in pediatric patients; further studies are needed to determine the comparative efficacy and tolerability of rasburicase versus allopurinol in adult patients. Although further pharmacoeconomic data would be useful, rasburicase was most cost effective for the prevention of hyperuricemia in children and for treatment of this condition in adults. Thus, rasburicase is a useful option for the prophylaxis or treatment of anticancer therapy-induced hyperuricemia in both adult and pediatric patients.

Anticarcinogenic Agents↗

PubMed2005

Update of the Preclinical Situation of Anticancer Platinum Complexes: Novel Design Strategies and Innovative Analytical Approaches

Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, side-effects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.

Antineoplastic Agents↗

PubMed2006

Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin.

In the next two decades, the world is expected to see around 20 million cases of cancer. Moreover, the types of cancer will vary considerably from country to other. Therefore, all efforts will be needed to face such a vast diversity of problems. With current annual sales of about $500 millions, the platinum(II) complex known as cisplatin [cis-(NH3)2PtCl2] is still one of the most effective drugs to treat testicular, ovarian, bladder and neck cancers. Since it was launched in 1978 there has been a rapid expansion in research to find new, more effective metal-based anticancer drugs and to study their interactions with biological systems. This study gives an up to date overview of the anticancer chemistry of the platinum group elements platinum, palladium, and nickel with an emphasis on the new strategies used in the development of new antitumor agents. Methodologies for application of bulky aromatic or aliphatic nitrogen ligands, chiral organic moieties, chelates containing other donor atoms than nitrogen, and biologically active ligands in the design of agents analogous to cisplatin are presented. The review also aims to highlight the class of the unconventional complexes that violate the empirical structure-activity rules (SAR) of platinum compounds and the common features and structural differences between the most successful anticancer complexes that are currently in human clinical trials.

Animals↗

PubMed2000

Cell cycle molecular targets in novel anticancer drug discovery.

A number of potential molecular targets for novel anticancer drug discovery have been identified in cell cycle control mechanisms. Prominent among these are the regulatory proteins, cyclins and their effector counterparts the cyclin dependent kinases (CDKs). Aberrant expression of these proteins, particularly cyclins involved in the G1 phase of the cell cycle, namely the D and E cyclins, has been associated with a variety of human cancers, including breast and colorectal cancer, B-lymphoma, prostate and non-small cell lung cancer. Inhibition of CDK kinase activity has turned out to be the most productive strategy for the discovery and design novel anticancer agents specifically targeting the cell cycle. Other potentially useful cell cycle areas for exploration include cyclin-CDK interactions, Cdc25 activation of cyclin-CDK complexes, ubiquitin-mediated proteolysis of cyclins, cell cycle check point kinases like Chk1, and recently identified oncogenic cell cycle-related aurora and polo-like kinases. Potent specific inhibitors have been identified that bind to the ATP site of CDKs, mainly cyclin B-CDK1, cyclin A-CDK2, and cyclin D-CDK4 complexes, and inhibit kinase activity. X-ray crystallographic data of CDKs, and their complexes with inhibitors have played a major role in the success of drug discovery efforts. Combinatorial chemistry, highthroughput screening, functional genomics and informatics have also contributed. CDK inhibitors currently under investigation include flavopiridol, olomoucine, roscovitine, puvalanol B, the dihydroindolo[3,2-d][1]benzazepinone kenpaullone, indirubin-3 -monoxime and novel diaminothiazoles such as AG12275. The anticancer therapeutic potential of CDK inhibitors has been demonstrated in preclinical studies, and Phases I and II clinical trials in cancer patients are currently underway.

Animals↗

PubMed2003

Anticancer antifolates: current status and future directions.

Antifolates are the oldest of the antimetabolite class of anticancer agents and were one of the first modern anticancer drugs. The first clinically useful antifolate, described in 1947, was 2,4-diamino-pteroylglutamate (4-amino-folic acid; aminopterin; AMT) which yielded the first-ever remissions in childhood leukemia. AMT was soon superseded by its 10-methyl congener, methotrexate (MTX), based on toxicity considerations; MTX remains, with one limited exception, the only antifolate anticancer agent in clinical use to this date. Because of the safety and utility of MTX, considerable effort has been invested in attempting to design more therapeutically selective antifolates or antifolates with a wider tumor spectrum. Initially, the design was based on the burgeoning knowledge of folate-dependent pathways and the determinants of the mechanism of action of MTX. These determinants include transport, the tight-binding inhibition of its target (the folate-dependent enzyme dihydrofolate reductase (DHFR)), and metabolism of MTX to poly-gamma-glutamate (Glu(n)) metabolites. These early studies led to the development of other antifolate DHFR inhibitors of two types: (1). "classical" analogs that use the same cellular transport systems as MTX and are also metabolized to Glu(n); and (2). "nonclassical" (i.e., lipophilic) analogs that do not require transport systems and that are not metabolized to Glu(n). Although several of these analogs have undergone clinical trial, none is proved superior to MTX. Detailed examination of the mechanisms of cytotoxicity and selectivity of MTX showed that inhibition of both dTMP synthesis and de novo purine synthesis, secondary to DHFR inhibition, led to DNA synthesis inhibition and subsequent cell death; inhibition of other folate-dependent pathways did not appear necessary for cell death. Further studies showed that the contribution of inhibition of dTMP or purine synthesis to cell death varied in different cell types. These data suggested that inhibition of one of these pathways individually might (at least in some cases) be therapeutically superior to the dual inhibition induced by MTX. Thus in rational design and in structure-based design studies, two new classes of antifolate enzyme inhibitors were elaborated-direct inhibitors of thymidylate synthase (TMPS) and direct inhibitors of one or both of the two folate-dependent enzymes of de novo purine synthesis. Members of each class included both classical and nonclassical types. After preclinical evaluation, several of these have moved into clinical trials. To date only one new TMPS inhibitor has successfully completed clinical trials and been approved for routine use; this drug, Tomudex (D1694, raltitrexed) is currently approved only in Europe and only for the treatment of colon cancer. This still represents a step forward for antifolates, however, since MTX is well-known to be ineffective in colon cancer; thus Tomudex extends the tumor range of antifolates. Antifolate development continues. Based on the immense body of knowledge now extant on antifolates, specific aspects of the mechanism of action have been the focus. Newer antifolates have been described that inhibit more than one pathway in folate metabolism, that have improved delivery, or that inhibit other targets in folate metabolism. These new analogs are in various stages of preclinical and clinical development.

Antimetabolites, Antineoplastic↗

PubMed2004

Anticancer agents: tumor cell growth inhibitory activity and binary QSAR analysis.

The tumor cell growth inhibitory activities (log 1/GI(50)) of 166 anticancer agents studied at the National Cancer Institute (NCI) in vitro anticancer screening program have allowed us to analyze the relative importance of physicochemical parameters in influencing the inhibitory activities. Increased molecular weight, as measured by the logarithm of molecular weight (log MW), is found to be an important contributor to the tumor cell growth inhibitory activities. The tumor cell growth inhibitory activities in different subpanels of the tumor cells are highly inter-correlated with each other. A simple binary quantitative structure-activity relationship (QSAR) model was derived from the 166 anticancer drugs, based on the tumor cell growth inhibitory activities transformed into a binary (active or inactive) data format. The model obtained can be tested with additional new data, and may be useful to identify active compounds from a large compound library to be included in high throughput screening.

Antineoplastic Agents↗