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Thymidylate synthase inhibitors as anticancer agents: from bench to bedside

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Abstract

Thymidylate synthase (TS) is a folate-dependent enzyme that catalyzes the reductive methylation of 2′-deoxyuridine-5′-monophosphate to 2′-deoxythymidine-5′-monophosphate. This pathway provides the sole intracellular de novo source of 2′-deoxythymidine-5′-triphosphate; therefore, TS represents a critical target in cancer chemotherapy. 5-Fluorouracil (5-FU) was synthesized in 1957 and represents the first class of antineoplastic agents to be developed as inhibitors of TS. While 5-FU has been widely used to treat various human malignancies, its overall clinical efficacy is limited. Therefore, significant efforts have focused on the design of novel, more potent inhibitor compounds of TS. These agents fall into two main categories: folate analogs and nucleotide analogs. Five antifolate analogs are currently being evaluated in the clinic: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L. Our laboratory has identified a novel mechanism of resistance that develops to TS inhibitor compounds, namely drug-mediated acute induction of new TS synthesis; this mechanism is directly controlled at the translational level. The ability of cancer cells to acutely induce the expression of TS may represent a novel mechanism for the development of cellular drug resistance. The future success of TS inhibitor compounds in the clinic may depend on novel strategies to selectively inhibit TS and on novel combination therapies to overcome cellular drug resistance.

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Acknowledgements

The authors wish to thank the Yale Cancer Center and VA CT Cancer Center for their support. This work was supported by grants from the National Cancer Institute (CA75712 and CA16359).

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  1. Cancer Center – 111D, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA

    Edward Chu, Marc A. Callender, Michael P. Farrell & John C. Schmitz

  2. Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06516, USA

    Edward Chu, Marc A. Callender, Michael P. Farrell & John C. Schmitz

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  1. Edward Chu
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Correspondence to Edward Chu.

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This work was presented at the 18th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, "New Strategies for Novel Anticancer Drug Development", 8–9 November 2002, Nagoya, Japan.

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Chu, E., Callender, M.A., Farrell, M.P. et al. Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol 52 (Suppl 1), 80–89 (2003). https://doi.org/10.1007/s00280-003-0625-9

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