Cytidine as an antidote to CPEC: It has been observed that cytidine, given intraperitoneally at a dose of 500mg/kg 4 hours after a range of doses of cyclopentenyl cytosine (CPEC, LD10-LD90) does not diminish the antineoplastic activity of CPEC against the subcutaneous L1210 tumor, but does appear to minimize the toxicity of the agent such that its therapeutic index is increased. Studies in non tumor-bearing mice confirm that cytidine given after CPEC, virtually abrogates the lethal actions of this Phase I clinical drug. Resistance to CPEC: Resistance to CPEC has been developed in vitro by both chemical mutagenesis and growth of initially sensitive cells in the presence of incremental concentrations of the drug. Resistant murine lymphoblasts and human myeloblasts so developed exhibit increased activity of CTP synthase and the gene encoding it along with marked elevations of most cytidine nucleotides. Additionally, intact human myeloblasts exhibit lower than normal activity of uridine/- cytidine kinase, the enzyme which inaugurates the phosphorylation of CPEC.
