Modulation of the metabolism and pharmacokinetics of 1-beta-D-arabinofuranosylcytosine by 1-beta-D-arabinofuranosyluracil in leukemic mice.
The interaction between high concentrations of 1-beta-D-arabinofuranosyluracil (HiCAU) and 1-beta-D-arabinofuranosylcytosine (ara-C) was investigated in vivo with emphasis on cell kinetics, pharmacokinetics, and drug metabolism. Mice bearing L5178Y leukemia were given a 48-h s.c. infusion of high-dose ara-U (HiDAU) to achieve a plasma level of 0.5 to 1 mM. A total dose of 7.35 g/kg/day for 2 days was nontoxic; the mean survival of control (saline treated) leukemic mice was 12.2 +/- 1.8 days and 11.7 +/- 2.0 days for the HiDAU-treated leukemic mice. Using flow cytometry, cell cycle progression of L5178Y ascites cells was monitored during HiDAU infusion. At 48 h, the proliferative index (PI) percentage of the leukemic cells is significantly different (P less than 0.001) in HiDAU-treated leukemic mice (mean = 50.8) versus control (mean = 45.6). A higher PI percentage is associated with accumulation of cells in S phase. This effect was highly variable in the ara-U-treated mice, and the ara-U "perturbed" group was defined as those mice whose cells had an increase in the PI to greater than or equal to 50%. The higher PI percentage in HiDAU-treated mice correlated with HiCAU in ascites fluid, leukemic cells, and kidney of perturbed mice. HiCAU in the "ara-U-perturbed" group altered the plasma pharmacokinetics of high-dose ara-C (HiDAC, 1 g/kg), increased the cellular metabolism of ara-C to 1-beta-D-arabinofuranosylcytidine triphosphate (ara-CTP) (3-fold), and increased ara-C-DNA synthesis (3-fold). In mice bearing the L5178Y leukemia, a 48-h infusion of ara-U followed by a 24-h s.c. infusion of 40 mg/kg resulted in a 260% increase in life span and seven 90-day survivors among 16 treated mice. In contrast, ara-U or ara-C alone had a negligible therapeutic effect. ara-U-induced alterations in the systemic pharmacokinetics of ara-C are the result of inhibition of cytidine deaminase activity by HiCAU in liver and kidneys. This results in a decrease in ara-C catabolism and prolongs the plasma half-life of ara-C. The dual alteration of the pharmacokinetics of ara-C and cytokinetics of the leukemia cells by HiCAU results in enhanced survival of leukemic mice. These results may help explain the clinical utility of HiDAC treatment programs for patients with acute leukemia.
Chandrasekaran
B
B
Cancer Center of Wake Forest University, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103.
Capizzi
R L
RL
Kute
T E
TE
Morgan
T
T
Dimling
J
J
D000818:Animals; D001086:Arabinofuranosyluracil / Q000494:pharmacology*; D003561:Cytarabine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D007940:Leukemia L5178 / Q000188:drug therapy / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014529:Uridine / Q000031:analogs & derivatives*
D003561:Cytarabine; D001086:Arabinofuranosyluracil; D003564:Cytidine Deaminase; D014529:Uridine