Antifolate Drugs in Cancer Therapy

ISBN-13: 9781475745214 / Angielski / Miękka / 2013 / 456 str.

Ann L. Jackman

Opis

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.

Spis treści

Antifolate Drugs: Past and Future Perspectives, Robert C. Jackson. Folate Biochemistry and Nutrition in Relation to Antifolate Selectivity, Roy L. Kisliuk. Clinical Pharmacology and Resistance to Dihydrofolate Reductase Inhibitors, Richard Gorlick and Joseph R. Bertino. Development of Nonpolyglutamatable Dihydrofolate Reductase (DHFR) Inhibitors, Andre Rosowsky. Fluoropyrimidines as Antifolate Drugs, G.J. Peters and C.H. Köhne. Raltitrexed (Tomudex™), a Highly Polyglutamatable Antifolate Thymidylate Synthase Inhibitor: Design and Preclinical Activity, Leslie R. Hughes, Trevor C. Stephens, F. Thomas Boyle, and Ann L. Jackman. Tomudex: Clinical Development, Philip Beale and Stephen Clarke. Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514), Chuan Shih and Donald E. Thronton. GW1843: A Potent, Non-competitive Thymidylate Synthase Inhibitor- Preclinical and Preliminary Clinical Studies, Gary K. Smith, Joseph W. Bigley, Inderjit K. Dev, David S. Duch, Robert Ferone and William Pendergast. Preclinical and Clinical Studies with the Novel Thymidylate Synthase Inhibitor Nolatrexed Dihydrochloride (Thymitaq™, AG337), Andy Hughes and A. Hilary Calvert. ZD9331, F. Thomas Boyle, Trevor C. Stephens, S.D. Averbuch, and Ann L. Jackman. Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887., Laurane G. Mendelsohn, John F. Worzalla, and Jackie M. Walling. AG2034: A GARFT Inhibitor with Selective Cytotoxicity to Cells that Lack a G1 Checkpoint, Theodore J. Boritzki, Cathy Zhang, Chalotte A. Bartlett, and Robert C. Jackson. Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates: Exploitation for Folate-Based Chemotherapy and Immunotherapy, G. Jansen. Folates as Chemotherapeutic Modulators, Julio Barredo, Marlene A. Bunni, Raghunathan Kamasamudram, and David G. Priest. Antifolate Polyglutamation in Preclinical and ClinicalAntifolate Resistance, John J. McGuire. Antifolates in Combination Therapy,Stephen P. Ackland, Madhu Garg, and Rosemary Kimbell. Pharmacodynamic Measurements and Predictors of Thymidylate Synthase Inhibitors, David Farrugia and Patrick G. Johnston. Moleccular Regulation of Expression of Thymidylate Synthase, Edward Chu, Jingfang Ju and John C. Schmitz. The Role of Uracil Misincorporation in Thymineless Death, G. Wynne Aherne and Shereal Brown. Thymeineless Death, Peter J. Houghton. Genetic Determinants of Cell Death and Toxicity, D. Mark Pritchard and John A. Hickman. Index.

Blurb

In Antifolate Drugs in Cancer Therapy, Ann Jackman and a panel of highly regarded researchers comprehensively review 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.

The wide and progressive scope of 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.