The newer purine analogs. Significant therapeutic advance in the management of lymphoid malignancies.

There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid malignancies. These three agents, with cytotoxicity against dividing and resting lymphocytes, have revolutionized the treatment of these diseases and, accordingly, represent a significant therapeutic advance. The development of these drugs emanated from an enhanced understanding of purine metabolism in lymphocytes and the mechanism of lymphocytotoxicity in severe combined immunodeficiency disease. Preclinical studies and phase I clinical trials are reviewed, as are phase II studies of these three purine analogs in chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and the myeloid leukemias. Potential future strategies exploring possible synergy between these purine analogs and the concurrent administration of both alkylators and biologic response modifiers are explored. The development of the purine analogs and their appropriate clinical applications exemplifies the model for rational drug design and development.