Collateral sensitivity to N-(phosphonacetyl)-L-aspartic acid in a line of P388 leukemia cells selected for resistance to L-(alpha S, 5S)-alpha-amino-3- chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin).
Administration of N-(phosphonacetyl)-L-aspartic acid (PALA) is ineffective in treating mice bearing the parent P388 leukemia line; however, such treatment becomes highly effective when a cell line, P388/ACIA, derived from P388/0 was selected for resistance to another antimetabolite, acivicin. The observed phenomenon of collateral sensitivity is associated with a significantly higher inhibition of the specific activity of carbamyl phosphate synthetase II, pyrimidine nucleoside kinases, adenine phosphoribosyl transferase, and hypoxanthine phosphoribosyl transferase in the PALA-sensitive line, P388/ACIA. Twenty-four hr following administration of PALA, 200 mg/kg, the 10% lethal dose i.p. to tumor-bearing mice, the intracellular concentrations of uridine triphosphate and cytidine triphosphate were decreased in the P388/ACIA, PALA-sensitive cells, whereas no significant change in the corresponding nucleotide pool sizes was observed in P388/0, PALA-resistant line. Moreover, the purine nucleotide pool demonstrated a significant expansion of adenosine triphosphate and guanosine triphosphate only in the P388/ACIA line following a similar treatment with PALA. It is proposed that the imbalance in the generation of pyrimidine and purine nucleoside triphosphate pools may explain the observed collateral sensitivity to PALA in P388/ACIA leukemia line.
D000228:Adenine Phosphoribosyltransferase / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001221:Aspartate Carbamoyltransferase / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000378:metabolism; D004351:Drug Resistance; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use*; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D011687:Purines / Q000096:biosynthesis; D011743:Pyrimidines / Q000096:biosynthesis
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D007555:Isoxazoles; D009943:Organophosphorus Compounds; D010080:Oxazoles; D011687:Purines; D011743:Pyrimidines; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D000228:Adenine Phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D010746:Phosphonoacetic Acid; C006303:acivicin