Salvage capacity of hepatoma 3924A and action of dipyridamole (original) (raw)

Abstract

Experimental and clinical studies revealed that marked inhibition of de novo pathways of purine and pyrimidine metabolism by antimetabolites failed to produce lasting remissions in neoplastic diseases. In elucidating the mechanism of action of the anti-glutamine agent, acivicin, we observed that after injection of this drug in hepatoma-bearing rats the activities of glutamine utilizing enzymes of de novo purine and pyrimidine biosynthesis were markedly decreased in the tumor (1, 2). However, the concentrations of only GTP and CTP declined, whereas those of ATP and UTP did not (1, 2). The protection of the adenylate and uridylate pools was tentatively attributed to the contribution of the salvage pathways (1). To test this hypothesis, we compared in liver and hepatomas the activities of the key enzymes of de novo pathways (ribonucleotide reductase, carbamoyl-phosphate synthetase II, CTP synthetase, amidophosphoribosyitransferase, IMP dehydrogenase with those of salvage enzymes (uridine-cytidine, deoxycytidine and thymidine kinases; adenine and hypoxanthine-guanine phosphoribosyltransferases). The results showed that in liver the activities of the enzymes of salvage pathways were orders of magnitude higher in both purine and pyrimidine metabolism than those of de novo synthesis. In hepatomas in pyrimidine metabolism the activities of the de novo and the salvage enzymes were elevated and the increase was transformation-and progression-linked. In contrast, in purine metabolism, the de novo enzyme activities were elevated, but the activities of the salvage enzymes did not show a transformation-or progression-linked alteration.

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