Modulation of arabinosylcytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: implications for combination therapy.
Our previous studies indicated that K562 cells loaded with arabinosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) accumulated arabinosylcytosine 5'-triphosphate (ara-CTP) at a threefold higher rate compared to the control cells. In the present study lymphocytes were obtained from patients with chronic lymphocytic leukemia before and after F-ara-A monophosphate therapy. The rate of ara-CTP accumulation after in vitro ara-C incubation was compared in lymphocytes obtained prior to therapy without any other manipulation, after ex vivo F-ara-ATP (100 mumol/L) treatment, and after in vivo F-ara-A monophosphate therapy. Lymphocytes showed a 2.2-fold (n = 23) and 1.7-fold (n = 23) median increase in the cellular concentration of ara-CTP after an ex vivo incubation with 100 mumol/L F-ara-A and 20 to 24 hours after the first dose (25 or 30 mg/m2) of F-ara-A monophosphate in vivo treatment, respectively. Although the rates of F-ara-ATP and ara-CTP accumulation varied among patients, a relationship was observed in individuals between the cellular concentration of F-ara-ATP at the beginning of the ara-C incubation and ara-CTP accumulation. These studies strongly suggest that a protocol designed to administer F-ara-A monophosphate prior to ara-C infusion will augment ara-CTP accumulation by leukemia cells.
Gandhi
V
V
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Nowak
B
B
Keating
M J
MJ
Plunkett
W
W
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001088:Arabinonucleotides / Q000378:metabolism* / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004341:Drug Evaluation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use*
D001088:Arabinonucleotides; D003561:Cytarabine; D001084:Vidarabine Phosphate; D001085:Arabinofuranosylcytosine Triphosphate; C042382:fludarabine phosphate