This collection of cutting-edge reviews comprehensively examines the current status of novel antifolates, an important class of anticancer drugs. The distinguished contributors discuss the preclinical and clinical pharmacology of methotrexate, other dihydrofolate reductase inhibitors, 5-fluorouracil, and the new generation of antifolates-the thymidylate synthase and glycinamide ribonucleotide formyltransferase inhibitors. In addition, they review in depth the modulation of antifolate drugs, folate and antifolate transport mechanisms, polyglutamation, resistance, and drug combinations, as well as pharmacogenomics, pharmacodynamics, regulation of gene expression, and mechanisms of cell death. Antifolate Drugs in Cancer Therapy provides entré to exciting new avenues for future research and constitutes a new standard reference for all basic scientists and clinicians engaged in cancer therapeutics.

Klappentext

Antifolates are an important class of anticancer drugs originally developed as anti leu kemic agents, but now used, usually in combination with other drugs, for the treatment of a wide range of tumors, notably carcinomas of the head and neck, breast, germ cell tumors, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and osteogenic sar comas. 5-Fluorouracil and its prodrugs also target, in part, the folate-dependent enzyme, thymidylate synthase. Furthermore, folate supplementation in the form of leucovorin, modulates 5-fluororuacil activity. 5-Fluorouracil is widely used in the treatment of colorectal and gastric cancer and in combination for other solid tumors such as breast and head and neck cancers. Ongoing clinical trials with the newer antifolates suggest that the range of solid tumors where these agents will be of use may broaden further. Half a century ago, interesting scientific and clinical discoveries suggested that folie acid was a vitamin involved in vital cellular metabolic processes. The folate analogs, aminopterin and methotrexate, were synthesized by the American Cyanamid Company in an attempt to interfere with these processes and were shown to have anticancer activity by Farber and his colleagues. Hence, the principle of antimetabolite therapy for the treatment of cancer was established. Biomedical research over the following years led to a deeper understanding of the complex biochemical pharmacology of folates and antifolates. Selective antimicrobial agents were discovered, but more tumor-selective anticancer agents did not immediately emerge.

Zusammenfassung
A collection of reviews which comprehensively examines the status of novel antifolates, an important class of anticancer drugs. This book discusses the preclinical and clinical pharmacology of methotrexate, other dihydrofolate reductase inhibitors, 5-fluorouracil, and a new generation of antifolates.

Inhalt
1 Antifolate Drugs: Past and Future Perspectives.- 2 Folate Biochemistry in Relation to Antifolate Selectivity.- 3 Clinical Pharmacology and Resistance to Dihydrofolate Reductase Inhibitors.- 4 Development of Nonpolyglutamatable DHFR Inhibitors.- 5 Fluoropyrimidines as Antifolate Drugs.- 6 Raltitrexed (Tomudextm), a Highly Polyglutamatable Antifolate Thymidylate Synthase Inhibitor: Design and Preclinical Activity.- 7 Tomudex: Clinical Development.- 8 Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514).- 9 GW1843: A Potent, Noncompetitive Thymidylate Synthase InhibitorPreclinical and Preliminary Clinical Studies.- 10 Preclinical and Clinical Studies with the Novel Thymidylate Synthase Inhibitor Nolatrexed Dihydrochloride (Thymitaqtm, AG337).- 11 ZD9331: Preclinical and Clinical Studies.- 12 Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887.- 13 AG2034: A GARFT Inhibitor with Selective Cytotoxicity to Cells that Lack a G1 Checkpoint.- 14 Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates: Exploitation for Folate-Based Chemotherapy and Immunotherapy.- 15 Folates as Chemotherapeutic Modulators.- 16 Antifolate Polyglutamylation in Preclinical and Clinical Antifolate Resistance.- 17 Antifolates in Combination Therapy.- 18 Pharmacodynamic Measurements and Predictors of Response to Thymidylate Synthase Inhibitors.- 19 Molecular Regulation of Expression of Thymidylate Synthase.- 20 The Role of Uracil Misincorporation in Thymineless Death.- 21 Thymineless Death.- 22 Genetic Determinants of Cell Death and Toxicity.