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.
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 from 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 1/2) 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 1/2 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 L1210/0 acid extracts, ara-CTP peaked at 2 hours and reached 2030 +/- 85 microM; ara-CTP was eliminated with a t 1/2 1.47 hours. The ara-CTP cellular concentrations after 1- and 24-hour pretreatments were 1875 +/- 534 and 2624 +/- 429 microM at 4 hours; the t 1/2 were 2.20 and 1.44 hours, respectively. The THU pretreatment resulted in a peak concentration of ara-CTP of 2208 +/- 366 microM at 2 hours and was eliminated with a t 1/2 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 ara-U pretreatment did not enhance the peak ara-CTP cellular concentration, but did extend the t 1/2. 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 1/2 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Avramis
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Department of Pediatrics, USC School of Medicine, Childrens Hospital of Los Angeles 90027.
Powell
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W
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism*; D003641:Deamination; D007939:Leukemia L1210 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D013767:Tetrahydrouridine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D014529:Uridine / Q000031:analogs & derivatives*
D003561:Cytarabine; D013767:Tetrahydrouridine; D001086:Arabinofuranosyluracil; D014529:Uridine