Minimum dose of fludarabine for the maximal modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during therapy.
1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP). To determine the lowest dose of fludarabine needed for modulation of ara-C metabolism, the present study administered fludarabine at a test dose (15 mg/m2 over 30 min) followed by 2 g/m2 ara-C infused over 4 h. The next day, the fludarabine/ara-C couplet was repeated but with a standard dose (30 mg/m2) of fludarabine. There was a dose-dependent accumulation of F-ara-ATP in circulating leukemia blasts; the median peak concentrations were 33 and 41 microM with 15 and 30 mg/m2 of fludarabine, respectively. These intracellular levels of F-ara-ATP effectively increased ara-CTP accumulation to similar levels. To further titrate the dose of fludarabine, the next cohort of patients (n = 4) initially received fludarabine test doses of 7.5 or 5 mg/m2, followed by the 30 mg/m2 dose of fludarabine on the next day; each dose was infused 4 h prior to 2 g/m2 of ara-C. The peak levels of F-ara-ATP at 7.5 and 5 mg/m2 fludarabine were between 3 and 39 microM. The AML blasts that achieved >/=10 microM intracellular F-ara-ATP accumulated ara-CTP similar to the levels achieved after 30 mg/m2 of fludarabine. However, <10 microM intracellular F-ara-ATP resulted in less ara-CTP accumulation compared to that observed after the conventional dose of fludarabine. These data suggest that the modulation of the ara-CTP accumulation by fludarabine is dependent on the cellular concentration of F-ara-ATP, and that 15 mg/m2 fludarabine infused over 30 min consistently produces cellular F-ara-ATP levels that maximize ara-CTP accumulation in AML blasts. These findings point to the feasibility of intensifying the fludarabine-ara-C regimen by using fludarabine as a 15 mg/m2/dose twice daily with intermediate-dose ara-C.
Gandhi
V
V
Departments of Clinical Investigation and Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Estey
E
E
Du
M
M
Keating
M J
MJ
Plunkett
W
W
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001088:Arabinonucleotides / Q000493:pharmacokinetics; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D013997:Time Factors; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D001088:Arabinonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016179:Granulocyte Colony-Stimulating Factor; C034957:2-fluoro-araATP; D014740:Vidarabine; C024352:fludarabine