Modulation of the cellular pharmacology and clinical toxicity of 1-beta-D-arabinofuranosylcytosine

Abstract

The effect of thymidine (dThd) and hydroxyurea (HU) on the cellular metabolism of 1-beta-D-arabinofuranosylcytosine (Ara-C) was investigated in the human promyelocytic cell line HL-60. Both dThd and HU increased the cellular uptake and rate of formation of Ara-CTP. Measurement of ribo- and deoxyribonucleotide triphosphate pools implicated a reduction of the dCTP as the mechanism of this effect. dThd and HU had opposite effects on the incorporation of Ara-C into DNA per unit time, but both enhanced the incorporation of Ara-C per unit of newly synthesized DNA. In a Phase I trial Ara-C was given by continuous infusion for five days at 100 mg/m2, and HU by mouth every six hours with dose escalation from 0.375 to 1.78 g/m2 every six hours. Myelosuppression was the dose-limiting toxicity; the major nonhematologic toxicity was skin rash. To date responses have been observed in chronic myelogenous leukemia in blast crisis and diffuse histiocytic lymphoma.