High-Dose Thymidine Infusions in Patients With Leukemia and Lymphoma

Abstract

We have recently explored the cytokinetic effects of thymidine given by continuous infusion in an animal model and have demonstrated an arrest of cell cycle traverse in rapidly proliferating tissues. Similar biologic effects have been observed in clinical trials upon infusing thymidine at a dose rate of 75 g/sq m/day. Fifteen courses of at least 5 days in duration have been administered to 11 patients with either leukemia or lymphoma. Steady-state serum thymidine levels were achieved in the range of 1-2 mM and the serum half-life of thymidine was approximately 90 min upon completion of the infusion. The associated toxicity included myelosuppression, headache, anorexia, nausea, vomiting, and diarrhea. The antitumor effect was dependent on the disease being treated and the percentage of blasts in the peripheral blood. Three patients with AML and three patients with T-cell leukemia responded to the thymidine infusions with an abrupt decrease in peripheral blast count. In contrast, no response was observed in two patients with poorly differentiated lymphocytic lymphoma of B-cell origin in a leukemic phase. One patient with T-cell leukemia had a marked clinical response with resolution of hepatosplenomegaly and another patient with the same diagnosis had partial clearing of the bone marrow. The cytokinetic effect on the bone marrow or peripheral blasts was monitored by microfluorimetry and labeling with precursors to monitor DNA synthesis. These data indicate an arrest of DNA synthesis during the period of thymidine infusion. The clinical effects observed with the high-dose thymidine infusions are correlated with measurements of thymidine kinase and phosphorylase levels detected in the blasts obtained from the leukemic patients. The relative ratios of thymidine kinase to phosphorylase are predictive of cellular sensitivity to the cytokinetic effects of thymidine.