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Folate Biochemistry in Relation to Antifolate Selectivity

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Antifolate Drugs in Cancer Therapy

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

Abstract

This review will deal with advances in folate biochemistry related to antifolate toxicity and selectivity. Because of the interrelatedness of reactions of folate metabolism, alterations in the activity of any folate enzyme, cellular transport system, as well as the concentration of any folate metabolite may be relevant to antifolate cytotoxicity and selectivity. Therefore, it is difficult to predict the results of inhibiting a given folate enzyme on antifolate selectivity. For example, in many experimental systems, the cytotox-icity of methotrexate is caused by its ability to inhibit dihydrofolate reductase, resulting in lowered thymidylate formation, leading to lethal defects in DNA. However, its selec-tiviry is often dependent on differential cellular uptake and polyglutamylation. Favorable clinical results with aminopterin, the forerunner of methotrexate, in acute leukemia in children were reported by Farber et al. (1) in 1948. This work depended on knowledge generated at the American Cyanamid Company, Pearl River, NY, on the structure of folic acid and the chemical synthesis of analogs in addition to the insightful clinical observations of the Farber group (1). This work was done before the role of tetrahydrofolates in the metabolism of single carbon units was known. The present discussion of the current literature on folates is offered in the hope that, given the powerful analytical, structural, molecular genetic, and synthetic methods now available, new approaches to selective toxicity can be generated.

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

    Ann L. Jackman

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Kisliuk, R.L. (1999). Folate Biochemistry in Relation to Antifolate Selectivity. 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_2

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  • DOI: https://doi.org/10.1007/978-1-59259-725-3_2

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-4521-4

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