Biochemical modulation of arabinosylcytosine for therapy of leukemias.
Analysis of different ribonucleotide reductase inhibitors to modulate arabinosylcytosine (ara-C) metabolism suggested that pretreatment with arabinosyl-2-fluoroadenine (F-ara-A) significantly potentiated the rate of ara-CTP (5'-triphosphate of ara-C) accumulation in both quiescent lymphocytes (p = 0.046) and in cycling blasts (p = 0.017). In vitro incubations of freshly isolated leukemia cells from patients with chronic (n = 7) or acute (n = 5) leukemias with F-ara-A, increased the rate of ara-CTP accumulation by a median of 1.5 or 1.7-fold, respectively, when subsequently incubated with ara-C. The objective of the present investigation was to test the hypothesis that ara-C can be biochemically modulated during therapy of leukemias. To test the biochemical modulation of ara-C in the clinical setting, we designed two protocols to administer fludarabine (clinical formulation of F-ara-A) and ara-C in a pharmacologically directed sequence for patients with chronic lymphocytic leukemia (CLL) refractory to conventional fludarabine therapy or for patients with acute myelogenous leukemia (AML) in relapse. Comparison of ara-CTP pharmacokinetics demonstrated a significant increase in the area under concentration curve (AUC) of ara-CTP both in CLL (median 1.5-fold) and AML cells (median 1.8-fold) after fludarabine infusion. Analyses of different processes involved in the metabolism of ara-CTP indicated that the increase in AUC was due to potentiation of the rate of ara-CTP accumulation. These studies demonstrate that protocols designed on biochemical and pharmacological rationales modulate ara-C metabolism during therapies.
Gandhi
V
V
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Estey
E
E
Keating
M J
MJ
Plunkett
W
W
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D003561:Cytarabine / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D014740:Vidarabine; C024352:fludarabine