THYMIDYLATE SYNTHASE INHIBITORS IN CANCER-THERAPY - DIRECT AND INDIRECT INHIBITORS

Purpose and Methods: Although fluoropyrimidines, in particular, fluoro uracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, ther apeutic selectivity, resistance, and efficacy have been a major limita tion in cancer therapy, Preclinical and clinical results in advanced a nd adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary tar get, can be improved significantly with leucovorin (LV) modulation. Wi th the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive pr eclinical and clinical evaluation, primarily in patients with colorect al cancer, with demonstrable activity, The direct TS inhibitors have b een shown to be potent, with a high level of specificity under therape utic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect in hibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) h as been completed and showed similar activity but reduced toxicity in favor of ZD1694, Results: Recognition that greater than 95% of the inj ected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydro genase (DPD) to therapeutically inactive products, but with toxicity t o normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU, Several inhibito rs in combination with 5-FU are under preclinical and clinical evaluat ion, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulato rs of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a m odulator of 5-FU. Conclusion: In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination. (C) 199 7 by American Society of Clinical Oncology.