Enzyme targets of antiglutamine agents in cancer chemotherapy.
The modes of action of azaserine and acivicin were compared. 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. It was observed that both drugs act as competitive inhibitors for glutamine-utilizing enzymes involved in the biosynthesis of purines and pyrimidines, but in addition acivicin exerts a direct inactivating effect (probably by alkylation) on the enzymes. The different tissues examined displayed varying sensitivity to the drugs which may be attributed in part at least to the tissue glutamine content. Acivicin markedly depleted the CTP pools, but ATP and UTP were unaffected. It also decreased the concentration of all 4 deoxynucleoside triphosphates. These biochemical targets serve as indicators of acivicin action in cancer cells and should also be helpful in the design of combination chemotherapy. On the basis of the biochemical action of acivicin, actinomycin and dipyridamole were selected for testing in combination chemotherapy. Both drugs acted synergistically with acivicin.
D000818:Animals; D000878:Anthranilate Synthase; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001377:Azaserine / Q000494:pharmacology*; D004357:Drug Synergism; D005973:Glutamine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D019884:Nitrogenous Group Transferases; D010080:Oxazoles / Q000494:pharmacology*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D051381:Rats; D012265:Ribonucleotides / Q000378:metabolism; D014166:Transferases / Q000037:antagonists & inhibitors
D000903:Antibiotics, Antineoplastic; D007555:Isoxazoles; D010080:Oxazoles; D012265:Ribonucleotides; D005973:Glutamine; D010754:Phosphoribosyl Pyrophosphate; D001377:Azaserine; D014166:Transferases; D019884:Nitrogenous Group Transferases; D000878:Anthranilate Synthase; C020655:anthranilate synthase, glutamine amidotransferase subunit; C006303:acivicin