REVERSAL BY CYTIDINE OF CYCLOPENTENYL CYTOSINE-INDUCED TOXICITY IN MICE WITHOUT COMPROMISE OF ANTITUMOR-ACTIVITY

Among nine compounds surveyed, cytidine was found to be the most effec tive in reversing the antiproliferative effects of cyclopentenyl cytos ine (CPEC) on human T-lymphoblasts (MOLT-4) in culture. Cytidine, at c oncentrations of 1-25 mu M, enabled cells to maintain normal logarithm ic growth when added up to 12 hr after exposure to a 200 nM concentrat ion of the oncolytic nucleoside, CPEC. The most abundant CPEC metaboli te, CPEC-5'-triphosphate, is a potent [K-1 approximate to 6 mu M] inhi bitor of CTP synthetase (EC 6.3.4.2). accumulation of this inhibitor r esulted in a depletion of CTP levels to 17% of their original cellular concentration. Exogenous cytidine reversed CPEC-induced cellular cyto toxicity by suppressing the formation of CPEC-5'-triphosphate by 70%, and by partially replenishing intracellular CTP to at least 60-70% of its original concentration. In vivo, cytidine (500 mg/kg) administered intraperitoneally 4 hr after each daily dose of CPEC (LD(10)-LD(100)) for 9 days reduced the toxicity and abolished the lethality of CPEC t o non-tumored mice. Of greater practical importance is the finding tha t, under these experimental conditions, cytidine did not curtail the a ntineoplastic properties of CPEC in L1210 tumor-bearing mice. Moreover , the concentration range over which CPEC exhibited antineoplastic act ivity was extended with cytidine administration.