Pharmacology of Combination Chemotherapy of Cytosine Arabinoside (Ara-C) and Uracil Arabinoside (Ara-U) or Tetrahydrouridine (THU) against Murine Leukemia L1210/0 in Tumor-Bearing Mice

Abstract

Deamination of cytosine arabinoside (ara-C) by cytidine deaminase (Cyt DA) is the main mode of the inactivation of this drug in vivo. Tetrahydrouridine (THU) and the deamination product, uracil arabinoside (ara-U) are potent inhibitors of Cyt DA. We investigated whether ara- U or THU pretreatments can protect ara-C frorn excessive deamination in tumor- (L1210) bearing mice. In order to determine this, plasma concentrations of ara-C, ara-U, and the intracellular levels of ara-CTP, the active anabolite of ara-C, were assayed. The control peak plasma levels of ara-C and ara-U were 3.3 and 0.78 mM and they were eliminated with a half life (t_½) of 1.26 and 1.43 hours, respectively. One hour pretreatment with a nontoxic dose of ara-U (single dose of 300 mg/kg intraperitoneally), resulted in increased ara-C levels by 5.9-fold, while ara-U increased 14.3 fold in comparison with controls. A 24-hour (every 8 hours) pretreatment with ara-U increased ara-C plasma levels by 3.0-fold and it was eliminated with a t_½ of 1.21 hours. One hour pretreatment with THU (single dose 25 mg/kg intraperitoneally) enhanced ara-C plasma levels by 5.3-fold. In control LI. 210I0 acid extracts, ara-CTP peaked at 2 hours and reached 2030 ± 85 μM; ara-CTP was eliminated with a t_½ 1.47 hours. The ara-CTP cellular concentrations after 1- and 24-hour pretreatments were 1875 ± 534 and 2624 ±429 μM at 4 hours; the t_½ were 2.20 and 1.44 hours, respectively. The THU pretreatment resulted in a peak concentration of ara-CTP of 2208 ± 366 μM at 2 hours and was eliminated with a t_½ of 2.54 hours. We concluded that all pretreatments increased both the peak plasma ara-C concentrations and the area under the plasma concentration-time curve (AUC). One hour ar a-U pretreatment did not enhance the peak ara-CTP cellular concentration, but did extend the t_½. The 24-hour ara-U and the 1-hour THU pretreatments increased, to some extent, the cellular ara-CTP concentrations, but these differences were not statistically significant. THU pretreatment increased the time the peak occurred and the t_½ of ara-CTP. The area under the cellular ara-CTP concentration-time curve (AUC) in L1210 cells was either the same or increased by a small amount after the pretreatments. No increase in life span (%ILS) was observed after in vivo efficacy experiments in L1210/0 leukemia-bearing mice treated with identical regimens. Thus ara-U and THU pretreatments increase plasma ara-C concentrations, but do not significantly affect the intracellular (tumor) ara-CTP concentrations or the antitumor effect of the combination regimens.