CLINICAL-STUDIES WITH MTA

MTA (LY231514), a multi-targeted antifolate, is a classical antifolate undergoing intracellular polyglutamation, Polyglutamated MTA is a pot ent thymidylate synthase (TS) inhibitor and inhibits other folate-depe ndent enzymes, including dihydrofolate reductase and glycinamide ribon ucleotide formyl transferase, Multifocal antifolates may overcome anti folate resistance, but it is not known whether the antitumour activity of MTA depends on its TS inhibition, its primary locus of action, or whether other loci contribute. MTA was examined in three phase I trial s using different schedules: a 10-min i.v, infusion given once every 3 weeks, once weekly for 4 weeks every 6 weeks or daily for 5 days ever y 3 weeks. Dose-limiting toxicities were neutropenia and thrombocytope nia. Other consistently seen side-effects, which were manageable, incl uded mucositis, skin rashes and transient elevations of transaminases. Toxicity was highly schedule dependent: the recommended dose for the 3-weekly schedule (600 mg m(-2)) was 30 times that for the daily x 5 s chedule (4 mg m(-2) day(-1)), The 3-weekly dosing schedule was chosen for phase II evaluation. Phase II trials are underway to investigate t he activity and toxicity of MTA in several tumour types, including col orectal, pancreas, breast, bladder and non-small-cell lung cancer (NSC LC) Further phase I trials will investigate MTA in combination with ot her agents, including gemcitabine, cisplatin, 5-fluorouracil and folat e. Preliminary phase II trials results are encouraging; responses were seen in colorectal, pancreas, NSCLC and breast cancer.