Effect of granulocyte-macrophage colony-stimulating factor on the metabolism of arabinosylcytosine triphosphate in blasts during therapy of patients with chronic myelogenous leukemia.
Because in vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates arabinosylcytosine (ara-C) metabolism in leukemia blasts, we analyzed the pharmacokinetics of ara-C triphosphate (ara-CTP) in the blasts of patients with chronic myelogenous leukemia who were undergoing therapy with GM-CSF and ara-C. Patients received a 2-h infusion of 1.0 g/m2 ara-C followed by daily infusions of GM-CSF (125 micrograms/m2/day i.v. over 6 h) for 2-4 days. After the last GM-CSF infusion, a second, identical dose of ara-C was administered. The cellular pharmacokinetics of ara-CTP in circulating blasts were determined during and after each ara-C dose, and the area under the accumulation and elimination curve (AUC) measured over 12 h was compared before and after GM-CSF. Ara-CTP accumulation peaked within 1 h after the end of each ara-C infusion. Comparison of the AUC of ara-CTP before and after GM-CSF administration suggested that in the blasts of three of four patients, GM-CSF treatment decreased the ara-CTP AUC; the AUC values were altered only slightly in a fourth patient. Studies of these patients' blasts incubated in vitro with ara-C before and after clinical infusion of GM-CSF revealed similar ara-CTP accumulation patterns. Together, these studies suggest that 2-4 days of GM-CSF administration does not increase the accumulation of ara-CTP in the circulating blasts from patients in the blastic phase of chronic myelogenous leukemia.
Gandhi
V
V
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Du
M
M
Kantarjian
H M
HM
Plunkett
W
W
D001085:Arabinofuranosylcytosine Triphosphate / Q000493:pharmacokinetics*; D001752:Blast Crisis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D003561:Cytarabine / Q000627:therapeutic use*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D004359:Drug Therapy, Combination; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D014407:Tumor Cells, Cultured / Q000378:metabolism
D003845:Deoxycytosine Nucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C024107:2'-deoxycytidine 5'-triphosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor