Studies on the mode of action of 3-deazapyrimidines—1: Metabolism of 3-deazauridine and 3-deazacytidine in microbial and tumor cells

Abstract

The pyrimidine analogs 3-deazauridine and 3-deazacytidine are effective inhibitors of the growth of various microbial and tumor cell lines in culture, and of some experimental tumors in vivo. As part of a study on their modes of action, the metabolic conversion of the analogs by intact Escherichia coli, leukemia L-1210 and Ehrlich ascites carcinoma cells, or by cell-free extracts derived from these or from Streptococcus faecium cells, was examined. Neither analog underwent cleavage of its glycosidic bond in the bacterial or tumor cell extracts, which catalyzed the cleavage of uridine but not of cytidine. Deazacytidine was not deaminated by extracts of E.coli, which effected the rapid deamination of cytidine. Both analogs were phosphorylated to the nucleoside triphosphate stage, as determined with Ehrlich ascites extracts, and Ehrlich ascites, L-1210 and E. coli cells. The possible formation of 2′-deoxyribonucleoside phosphate derivatives was examined with 3-deazacytidine, and a 2′-deoxyribonucleotide derivative of this analog was found in the acid-soluble fraction of E. coli cells. Neither 3-deazauridine nor 3-deazacytidine was incorporated into the RNA or DNA of Ehrlich ascites cells in vivo.