Future potential of thymidylate synthase inhibitors in cancer therapy.

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