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Antifolate Drugs in Cancer Therapy pp 293–321Cite as

Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates

Exploitation for Folate-Based Chemotherapy and Immunotherapy

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

Abstract

Eukaryotic cells lack the possibility of de novo biosynthesis of reduced folate cofactors that are required as one-carbon donors in the biosynthesis of thymidylate, purines, and amino acids (1).For this reason, cellular folate homeostasis depends on the delivery of reduced folate cofactors from extracellular fluids. At a physiological pH, the negatively charged α- and γ-carboxyl groups of the glutamate side chain of reduced folate cofactors change these molecules into divalent anions that cannot simply pass the plasma membrane but require (a) specific transport system(s) for their cellular entry. The importance of folate metabolism in tumor cells has been recognized for a long time as a potential target for chemotherapy (2–6). Historically, classical folate analogs such as aminopterin (AMT) and methotrexate (MTX) were recognized to disrupt folate metabolism through inhibition of dihydrofolate reductase (DHFR) (7). More recently, folate analogs were synthesized that could target other key enzymes in folate metabolism, including thymidylate synthase (TS) (8, 9) glycinamide ribonucleotide transformylase (GARTFase) (10, 11) and folylpolyglutamate synthetase (FPGS) (12). A number of these novel antifolates have demonstrated potential clinical activity (3,13–18). The majority of these folate analogs share the common feature that efficient membrane transport is the first determining factor in exerting their biological activity. This chapter will mainly focus on the role of two folate transport systems that are considered to be of the greatest relevance from the perspective of mediating folate homeostasis and the delivery of folate-based chemotherapeutic drugs into tumor cells. These transporters include the reduced folate carrier (RFC) (19–22) and a membrane-associated folate receptor (MFR) (22–25) also referred to as membrane-associated folate-binding protein (mFBP). A summary of some molecular, biochemical, and functional properties of these transporters will be given (see e.g., Table 1) along with a few examples how these properties (see Fig. 2A, B, below) may be translated into an improved biological/cytotoxic activity of antifolate drugs (see Table 2).

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    Ann L. Jackman

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Jansen, G. (1999). Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates. 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_14

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