Synergistic activity of purine metabolism inhibitors in cultured human tumor cells.
Cytotoxic effects of 3-deazaguanosine (3-DGUO) result from the inhibition of DNA synthesis and incorporation of the drug into DNA. Synergistic antiproliferative effects of a combination of 3-deazaguanosine and 2-beta-D-ribofuranosylthiazole-4-carboxamide, a potent inhibitor of inosine monophosphate dehydrogenase, was observed in human tumor cells. Inosine reversed the antiproliferative effects of the 3-deazaguanosine but not 2-beta-D-ribofuranosylthiazole-4-carboxamide. 3-Deazaguanosine monophosphate was shown to inhibit the activity of the de novo purine synthesis enzyme, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide transformylase. The data suggested a cytotoxic effect of 3-DGUO associated with the inhibition of de novo purine synthesis by drug nucleotides, an effect which may account for the synergistic action noted.
D015092:3-Deazauridine / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007288:Inosine / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism*; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D015092:3-Deazauridine; D012254:Ribavirin; D007288:Inosine; C033706:tiazofurin