Enhanced effect of an L-glutamine antagonist, L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, by Acinetobacter L-glutaminase-L-asparaginase.
The effect of L-glutamine and L-asparagine depletion by Acinetobacter L-glutaminase-L-asparaginase on the toxicity and antitumor activity of L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (NSC-163501) was tested in mice. The LD50 of six daily doses of NSC-163501 in BDF1 female mice decreased from 7.5 to 0.3 mg/kg/day by combination treatment with the enzyme. Enzyme therapy also decreased the dose of NSC-163501 needed for maximal prolongation of survival in these mice inoculated with L1210 leukemia. Nevertheless, the combination did not prolong survival in L1210-bearing mice beyond that of higher doses of NSC-163501 alone. In contrast, the combination of enzyme plus NSC-163501 inhibited the growth of established sc implanted Ehrlich ascites carcinoma in ICRf male mice much more than either agent alone. Treatment with Acinetobacter L-glutaminase-L-asparaginase decreased the L-asparagine and L-glutamine levels in acid extracts of the Ehrlich tumor. NSC-163501 did not affect the amide levels or alter the decrease produced by enzyme therapy.
D000150:Acinetobacter / Q000201:enzymology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001215:Asparaginase / Q000008:administration & dosage*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005972:Glutaminase / Q000008:administration & dosage*; D005973:Glutamine / Q000037:antagonists & inhibitors*; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D007555:Isoxazoles / Q000008:administration & dosage* / Q000633:toxicity; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000008:administration & dosage*
D000596:Amino Acids; D007555:Isoxazoles; D010080:Oxazoles; D005973:Glutamine; D001215:Asparaginase; D005972:Glutaminase; D005998:Glycine