Open AccessModulation of the cellular pharmacology and clinical toxicity of 1‐β‐D‐arabinofuranosylcytosine
Author(s) -
Howell Stephen B.,
Streifel Jerome A.,
Pfeifle Craig E.
Publication year - 1982
Publication title -
medical and pediatric oncology
Language(s) - English
Resource type - Journals
eISSN - 1096-911X
pISSN - 0098-1532
DOI - 10.1002/mpo.2950100710
Subject(s) - toxicity , pharmacology , medicine , dna synthesis , cytarabine , leukemia , biology , dna , biochemistry
The effect of thymidine (dThd) and hydroxyurea (HU) on the cellular metabolism of 1‐β‐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/m 2 , and HU by mouth every six hours with dose escalation from 0.375 to 1.78 g/m 2 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 his‐tiocytic lymphoma.