Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate.
Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006157:Guanosine Monophosphate / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology; D007941:Leukemia P388 / Q000378:metabolism* / Q000473:pathology; D007942:Leukemia, Experimental / Q000378:metabolism*; D015122:Mercaptopurine / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011687:Purines / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D007093:Imidazoles; D011687:Purines; C028138:5-carbamoyl-1H-imidazol-4-yl-piperonylate; D006157:Guanosine Monophosphate; D015122:Mercaptopurine; D007041:Hypoxanthine Phosphoribosyltransferase; C033758:4-carbamoylimidazolium 5-olate