Expert opinion on investigational drugs vol:7 issue:5 pages:823-34
Raltitrexed (Tomudex) is a new specific, mixed non-competitive inhibitor of thymidylate synthase indicated for use in the therapy of advanced colorectal cancer. Phase I and II studies defined a maximum tolerated dose of 3.0 mg/m(2) administered as a 15-min i.v. infusion every 3 weeks: this dose proved active in a range of malignancies, but most significantly in advanced colorectal cancer. Phase III studies in patients with advanced colorectal cancer indicate similar efficacy with raltitrexed monotherapy and combination therapy with 5-fluorouracil + low or high dose leucovorin (5-FU + LV) (Mayo or Machover regimens, respectively). Major toxicity in the various studies of raltitrexed included gastrointestinal effects, haematological suppression, asthenia and reversible asymptomatic increases in hepatic transaminases. However, patients receiving 5-FU + LV experienced more severe leucopaenia and mucositis than patients receiving raltitrexed: this translated into fewer toxicity-related dosage reductions. Raltitrexed is therefore as effective as but better tolerated and accepted than 5-FU + LV. Thus, raltitrexed offers the first alternative to 5-FU-based therapy in advanced colorectal cancer; furthermore, the mode of action of the drug offers the potential for synergy with agents that act via other molecular mechanisms.