New antimetabolites in the treatment of human malignancies.

Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.