Clinical, biological and biochemical effects of pyrazofurin.

Extensive conversion of Pyrazofurin to the 5 -PO, and higher phosphorylated derivatives occurs in naturally sensitive (Walker 256 carcinosarcoma) and resistant (L5178Y leukemia) tumors. A similar degree of conversion to phosphorylated derivatives was seen in acute myelogenous leukemic cells from patients. The insensitivity of the L5178Y leukemia may result from its greater capacity to utilize uridine in the presence of Pyrazofurin. Further more, L5178Y cells in culture can survive uridine depriva tion for much longer periods than can the Walker 256 tumor. Although intracellular concentrations of both uri dine triphosphate and cytidine triphosphate are depleted in culture, only a transient decrease is seen in the concen tration of cytidine triphosphate in L5178Y ascites cells from mice. The reductions in pyrimidine nucleotide pools may be responsible for the synergistic growth-inhibitory effects observed when Pyrazofurin is combined with 5fluorodeoxyuridine or 1-AŸ-D-arabinofuranosylcytosine. In patients, blockade of the metabolism of [carboxy/-14C]orotate was greater than 99% 15 min and 24 hr after a single i.v. dose of Pyrazofurin (200 mg/sq m). In 17 patients given weekly i.v. therapy, no complete remissions or major regressions of tumor masses were seen. Antitumor effect was observed in two of three patients with acute myelogenous leukemia and in one patient each with erythroleukemia, mycosis fungoides, and psoriasis. The limiting toxicity was oral mucositis; depression or erythropoiesis was apparent in all patients treated for more than 4 weeks.