Control of enzymic programs and nucleotide pattern in cancer cells by acivicin and tiazofurin.
The mechanism of action of acivicin and tiazofurin was compared in hepatoma 3924A. The results were evaluated by assessing the impact of these drugs on primary targets, the activities of key enzymes, and on secondary and tertiary targets, the concentrations of pools of ribonucleotides and deoxyribonucleotides. The action of acivicin entails inhibition and inactivation of the key enzymes of glutamine utilization in the biosynthesis of purines and pyrimidines. As a result, the GTP and CTP pools were markedly depleted, whereas those of ATP and UTP were unaffected. Acivicin also markedly decreased the concentrations of all 4 deoxynucleoside triphosphates. The nucleotide pools returned to normal or near normal range within 2 to 3 days after a single acivicin injection. The pharmacologic targets of acivicin in anticancer chemotherapy include prominently the activities of glutamine-utilizing enzymes and the pools of GTP and CTP and all 4 dNTP's. These biochemical targets also serve as indicators of acivicin action in cancer cells. The action of tiazofurin in hepatoma cells entails the primary target, IMP dehydrogenase. The subsequent effects include marked enlargement of IMP and PRPP pools and depletion of the pools of GDP and GTP. The increased IMP concentration selectively inhibited the activities of hypoxanthine-guanine phosphoribosyltransferase, but did not affect that of adenine phosphoribosyltransferase. The markedly decreased GTP pool de-inhibited the activity of AMP deaminase which permitted the channeling of AMP to IMP. An important indicator of tiazofurin action is the prolonged depletion of dGTP pools and similar but less pronounced declines in the pools of dCTP and dATP. In contrast, dTTP pools were increased. The crucial biochemical targets and indicators of tiazofurin action in sensitive cancer cells include inhibition of IMP dehydrogenase, a decrease in the concentrations of GDP, GTP, dGTP, dCTP, dATP and marked rise in the pools of IMP, PRPP and dTTP. Measurements of the molecular targets and indicators of drug action should be helpful in identifying cancer cells and tissues sensitive or resistant to the action of acivicin or tiazofurin. Identification of the targets and indicators should also be helpful in the design of frequency of administration of the drugs in combatting animal and human neoplasia.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007555:Isoxazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D010428:Pentosephosphates / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007555:Isoxazoles; D009711:Nucleotides; D010080:Oxazoles; D010428:Pentosephosphates; D012263:Ribonucleosides; D012254:Ribavirin; D010754:Phosphoribosyl Pyrophosphate; D007168:IMP Dehydrogenase; D010430:Pentosyltransferases; C022484:purine phosphoribosyltransferase; C006303:acivicin; C033706:tiazofurin