Initial studies on the mechanism of action of a new oncolytic thiazole nucleoside, 2-β-d-ribofuranosylthiazole-4-carboxamide NSC 286193)

摘要: Studies on the mechanism of action a new oncolytic nucleoside, 2-β-d-ribofuranosylthiazole-4-carboxamide, have been undertaken using P388 murine leukemia cells growing in culture. The title compound was cytotoxic at micromolar levels, but number simple substitutions both ring and sugar moieties nullified cytotoxicity. Cytofluorimetric analysis revealed that drug arrests “S phase” cell cycle. At antiproliferative concentrations, agent inhibited synthesis RNA DNA. macromolecular incorporation preformed pyrimidines, including thymidine, by but, among purines, this effect extended only to members adenine family and, fact, utilization guanine its congeners reproducibly stimulated. When an examination made ability comprehensive series purines pyrimidines overcome inhibition thymidine provoked exposure thiazole guanines were notably effective, xanthosine also shown be active antidote. Confirmation producing state deprivation provided high performance liquid chromatography (HPLC) acid-soluble extracts: time-dependent fall concentrations GMP GTP ensued upon drug; other hand, IMP increased ∼15-fold. Pursuant these findings, enzymologic steps unique biosynthesis nucleotides exposed drug. No prominent synthetase could demonstrated vitro or culture, specific activity dehydrogenase underwent substantial reductions cases. HPLC analyses extracts cultures supralethal evidence modest anabolism 5′-monophosphate products; chemically synthesized sample 2-β-d-ribofuranosylthiazole-4-carboxamide-5′-monophosphate twenty times more potent than parent nucleoside inhibiting dehydrogenase. On kinetic analysis, non-competitive with as variable substrate.