Thymidylate synthase inhibitor

Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy.[1] This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP [2]. Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L.[3]

Examples include

• Raltitrexed, used for colorectal cancer since 1998
• Fluorouracil, used for colorectal cancer[4]
• BGC 945[5]
• OSI-7904L[6]

References

1. Jackman, A.L.; Calvert, A.H. (1995). "Folate-based thymidylate synthase inhibitors as anticancer drugs". Annals of Oncology. 6 (9): 871–881. doi:10.1093/oxfordjournals.annonc.a059353. PMID 8624289.
2. Ackland, Stephen (December 2006). "Thymidylate synthase inhibitors". Update on Cancer Therapeutics. 1 (4): 403–427. doi:10.1016/j.uct.2006.09.001.
3. "Thymidylate synthase inhibitors as anticancer agents: from bench to bedside". Retrieved 2009-01-28.
4. Papamichael, D. (1999). "The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status". Oncologist. 4 (6): 478–87. PMID 10631692.
5. Gibbs, David D.; et al. (2005). "BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to α-folate receptor-overexpressing tumors". Cancer Research. 65 (24): 11721–11728. doi:10.1158/0008-5472.CAN-05-2034. PMID 16357184.
6. Ricart AD, Berlin JD, Papadopoulos KP, et al. (December 2008). "Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors". Clin. Cancer Res. 14 (23): 7947–55. doi:10.1158/1078-0432.CCR-08-0864. PMID 19047127.