Modulation of the cellular pharmacology and clinical toxicity of 1-beta-D-arabinofuranosylcytosine.
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.
D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D003561:Cytarabine / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D003854:Deoxyribonucleotides / Q000378:metabolism; D004359:Drug Therapy, Combination; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D012265:Ribonucleotides / Q000378:metabolism; D013936:Thymidine / Q000494:pharmacology
D003854:Deoxyribonucleotides; D012265:Ribonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D004247:DNA; D012264:Ribonucleotide Reductases; D013936:Thymidine; D006918:Hydroxyurea