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Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514)

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Antifolate Drugs in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Since the early 1950s, extensive research efforts have been devoted to the discovery and development of antifolate antimetabolites as chemotherapeutic agents for the management of neoplastic diseases. However, it was only in the last 10–15 yr, because of the rapid advances of medicinal chemistry, X-ray protein crystallography, molecular biology, pharmacology, and clinical medicine, that a significant number of new generation antifolates were brought forward for clinical development. Several folate-based antimetabolites are currently being investigated in clinical trials. These include lometrexol (6R-5,10-dideazatetrahydrofolic acid) (1–3) LY309887 (4) and AG2034 (5) which are potent and selective inhibitors of glycinamide ribonucleotide formyltransferase (GARFT), an enzyme in the purine de novo biosynthetic pathway; trimetrexate (6) edatrexate (7,8) and PT523 (9) which act on dihydrofolate reductase (DHFR); raltitrexed (10,11) AG337 (12) BW1843U89 (13) and ZD933 (14) which specifically target the enzyme thymidylate synthase (TS) involved in pyrimidine biosynthesis.

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Authors
  1. Chuan Shih
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  2. Donald E. Thornton
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Editor information

Editors and Affiliations

  1. The Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    Ann L. Jackman

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© 1999 Springer Science+Business Media New York

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Shih, C., Thornton, D.E. (1999). Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514). In: Jackman, A.L. (eds) Antifolate Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-725-3_8

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  • DOI: https://doi.org/10.1007/978-1-59259-725-3_8

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-4521-4

  • Online ISBN: 978-1-59259-725-3

  • eBook Packages: Springer Book Archive

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