'Tomudex' (raltitrexed) development: preclinical, phase I and II studies.

Raltitrexed ('Tomudex', formerly ZD1694) is a new active drug for advanced colorectal cancer, an area that has been without new drugs for over 40 years. It has a convenient dosing schedule and a potential for lower toxicity which represent important advantages over existing treatments. Advanced colorectal cancer is currently treated with 5-fluorouracil, generally in combination with other agents such as leucovorin. This leads to complex dosing schedules with increased activity but potentially serious toxicity. Raltitrexed is a novel cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other current agents, raltitrexed inhibits thymidylate synthase directly, specifically and non-competitively, which may lead to an improved toxicity profile. It is retained within cells as polyglutamate metabolites, allowing a more convenient dosing schedule than for 5-fluorouracil. Phase I and pharmacokinetic studies established the optimum dosing schedule as 3 mg/m2, administered in a single 15-min intravenous infusion once every 3 weeks. In a phase II study in 177 patients with advanced colorectal cancer, this dose produced a response rate of 26% and median survival of 11.2 months. The safety profile was acceptable, the main adverse events being myelosuppression, gastrointestinal toxicity, asthenia and transient asymptomatic increases in liver transaminases without evidence of any other liver dysfunction. Activity of raltitrexed has also been observed in a range of other solid tumours, including breast, pancreatic, non-small-cell lung and refractory ovarian cancer.