Mechanism of resistance of a variant of P388 leukemia to L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin).
Acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; NSC 163501] is a fermentation-derived amino acid antibiotic antagonistic to L-glutamine which exhibits potent oncolytic properties. We have developed a variant of P388 leukemia resistant to acivicin (P388/ACIA) and compared its properties with those of the parent line (P388/S). An examination of the enzymes utilizing L-glutamine revealed that the basal specific activities of L-asparagine synthetase and L-glutaminase were 1-to 3-fold higher in the parent line. The activities of carbamoyl phosphate synthetase II, L-asparagine synthetase, formylglycinamide ribonucleotide amidotransferase, and guanosine monophosphate synthetase were about equally inhibited in the two cell lines, while there was a partial inhibition of 5-phosphoribosyl-1-pyrophosphate amidotransferase, fructose-6-phosphate amidotransferase, and L-glutaminase activities, found only in the sensitive line. Cytidine triphosphate synthetase activity was not inhibited in either line. There was no difference in the dose response or restitution of L-glutamine utilizing enzyme activities between the two lines. Acivicin treatment produced a 2- to 3-fold augmentation of the L-glutamine pools only in the sensitive line. Drug injection induced increased 5-phosphoribosyl-1-pyrophosphate levels in both lines. Acivicin perturbed guanosine nucleotide pools only in the sensitive line, indicating that the primary mechanism of action of acivicin in P388 leukemia may be directed at guanosine monophosphate synthetase. Transport studies demonstrated a restricted uptake of acivicin by the resistant cells. These studies suggest that the transport of acivicin and L-glutamine plays an important role in determining the sensitivity or resistance to acivicin in these tumors.
Jayaram
H N
HN
Ardalan
B
B
Deas
M
M
Johnson
R K
RK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D004351:Drug Resistance; D014644:Genetic Variation; D005973:Glutamine / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use*; D007700:Kinetics; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010080:Oxazoles / Q000627:therapeutic use*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D007555:Isoxazoles; D010080:Oxazoles; D005973:Glutamine; D010754:Phosphoribosyl Pyrophosphate; C006303:acivicin