Thymidylate synthase TS inhibitors

New agents have been developed that directly inhibit TS (in contrast to indirect inhibitors e.g. 5-FU and MTX) and interact with the folate-binding site of TS. Glutamated members utilize the folate-carrier system for entry into cells and are polyglutamated, enhancing their efficacy and intracellular retention. Non-glutamated compounds are lipophilic and may have different effects.

Raltitrexed (Tomudex) is a glutamated compound that causes prolonged inhibition of TS. It has triphasic elimination, with a rapid initial fall in concentration but very prolonged final phase. 50% of the drug is renally excreted unchanged. It is active in breast and colorectal cancer with toxicities including:

♦ Myelosuppression

♦ Transaminitis

It is usually administered IV once every 3 weeks.

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