Future potential of thymidylate synthase inhibitors in cancer therapy

Thymidylate synthase (TS) catalyses the de novo synthesis of deoxythymidylate and is a key rate-limiting enzyme of DNA synthesis. The primary site of action of the classic antifolate methotrexate is direct inhibition of dihydrofolate reductase, but it also inhibits TS indirectly by diminishing levels of the TS cosubstrate 5,10-methylenetetrahydrofolate. Polyglutamated metabolites of methotrexate also directly bind and inhibit TS. The prototype fluoropyrimidine fluorouracil is metabolised to an irreversible inhibitor of TS and is the standard chemotherapy for gastrointestinal carcinomas. It is also frequently used in combination with other anticancer drugs against breast cancer and head and neck cancers. The clinical efficacy of fluorouracil is routinely increased by concomitant administration of the biomodulating compound leucovorin (folinic acid). Both the success and limitations of these early drugs led to a search for new, more efficacious TS inhibitors active against a broader range of neoplasms. Raltitrexed (ZD1694, Tomudex) is an antifolate TS inhibitor developed over the last decade that is similarly effective, yet better tolerated, than fluorouracil against colorectal cancer. Additional antifolate and fluoropyrimidine-based TS inhibitors continue to be developed. Many of these experimental drugs have been designed to exploit or thwart selective metabolism in neoplasms, including specific mechanisms of resistance. As the curative potential of relatively non-selective antiproliferative drugs like TS inhibitors is limited against most neoplasms, the future role of TS inhibitors will likely continue to be adjunctive in surgically resectable tumours and palliative in combination with other agents for non-resectable disease. Although TS inhibitors will eventually be supplanted by yet to be discovered agents targeting more tumour-specific cellular signalling pathways, they will probably remain important for the above uses for some time. Future advances in the effective use of TS inhibitors may be forthcoming in the form of improved dosing, fewer untoward effects and increased tumour selectivity with novel fluorouracil prodrug formulations. Furthermore, there is emerging evidence that some novel antifolate TS inhibitors are active against a broader range of neoplams, including lung carcinomas and mesothelioma, compared to classical TS inhibitors. Other possible advances to come include effective biomodulation of antifolate TS inhibitors with nucleoside transport inhibitors and individualised patient therapy based on tumour gene expression and resistance patterns (pharmacogenetics).