Trimetrexate: Experience with Solid Tumors

Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, is biochemically and metabolically similar to methotrexate (MTX). Fundamental differences between TMTX and MTX, however, mandate investigation of TMTX in both MTX-sensitive and MTX-resistant tumors. In a number of phase II clinical trials, the antitumor activity of single-agent TMTX has been variable, in part because of the heterogeneity of doses and schedules used and in part because of diverse patient populations. Single-agent activity has been documented in some commonly occurring tumors, including breast, non-small cell lung, and head and neck cancers. Other tumors with sensitivity to single-agent TMTX include transitional cell carcinomas of the urothelium, prostate cancer, and gastric carcinoma. In a small series of children with renal cell carcinoma, significant clinical activity was suggested. The single-agent activity of TMTX, coupled with the finding that TMTX may act as a biochemical modulator of 5-fluorouracil/leucovorin, suggests that the addition of TMTX to 5-fluorouracil/leucovorin should be investigated further. The possibility that TMTX may both exhibit single-agent activity and modulate the effectiveness of other agents makes combination therapy attractive.