Effects of acivicin and PALA, singly and in combination, on de novo pyrimidine biosynthesis.
The inhibitory activities of two oncolytic amino acid analogs, acivicin and N-(phosphonacetyl)-L-aspartate, on pyrimidine biosynthesis have been examined in a murine tumor line, the Lewis lung carcinoma. Acivicin, an antimetabolite elaborated by Streptomyces sviceus, inhibits a spectrum of L-glutamine utilizing enzymes including carbamoyl phosphate synthetase II, the inaugurating enzyme of de novo pyrimidine biosynthesis. Profound inhibition of carbamoyl phosphate synthetase II activity by acivicin is demonstrated in vitro as well as in vivo. N-(Phosphonacetyl)-L-aspartate, a rationally-designed transition-state analog of the reaction catalyzed by L-aspartate transcarbamylase, the second enzyme of the pathway, is a potent and specific inhibitor of L-aspartate transcarbamylase. Both agents, at therapeutic doses, exert marked inhibitions of their respective target enzymes and impede flux through the pathway as monitored by inhibition of pyrazofurin-provoked accumulation of orotate and orotidine. Additionally, synergistic effects are observed when acivicin and N-(phosphonacetyl)-L-aspartate are used in combination, both in terms of biochemical and therapeutic endpoints. The salient features of the actions of these drugs on pyrimidine biosynthesis in the Lewis lung carcinoma are summarized in Table 6. Comparison of the effects of acivicin with those of N-(phosphonacetyl)-L-aspartate suggest divergent actions on nucleotide biosynthesis. In spite of its pronounced sensitivity to acivicin, carbamoyl phosphate synthetase II appears not to be a critical target for the antineoplastic activity of this drug.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000378:metabolism; D002460:Cell Line; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000378:metabolism; D009696:Nucleic Acids / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D009963:Orotic Acid / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D011743:Pyrimidines / Q000096:biosynthesis*
D000964:Antimetabolites, Antineoplastic; D007555:Isoxazoles; D009696:Nucleic Acids; D009943:Organophosphorus Compounds; D010080:Oxazoles; D011743:Pyrimidines; D001224:Aspartic Acid; D009963:Orotic Acid; C013195:sparfosic acid; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid; C006303:acivicin