The role of methionine in methotrexate-sensitive and methotrexate-resistant mouse leukemia L1210 cells.
A mouse L1210 leukemia cell line was made 25-fold resistant to methotrexate (MTX) and had altered methionine transport and metabolism. L1210 cells resistant to methotrexate also had a 50-fold decrease in the exogenous methionine requirement for optimal cell growth compared to the parent cells. This change in methionine requirement was associated with differences in methionine metabolism between MTX-sensitive and MTX-resistant cell lines. Analysis of amino acid transport systems revealed different Kt and Vmax properties of methionine and nonmetbolizable amino acid analogues. There was a greater than twofold decrease in the initial sodium-dependent uptake of methionine in the resistant cells. Amino acid competition experiments revealed altered substrate specificities in the resistant cells. The cellular alterations occurring upon resistance may result from methotrexate-membrane interactions, and have been previously observed in cisplatinum-resistant cells. Thus modulation of methionine metabolism may provide the biochemical basis for MTX and cisplatinum collateral resistance.
D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D005493:Folic Acid Antagonists; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000378:metabolism / Q000502:physiology*; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D012964:Sodium / Q000494:pharmacology
D005493:Folic Acid Antagonists; D009363:Neoplasm Proteins; D012964:Sodium; D008715:Methionine; D002945:Cisplatin; D008727:Methotrexate