Decreased 6-mercaptopurine retention by two resistant variants of mouse neuroblastoma with normal hypoxanthine-guanine-phospho-ribosyltransferase activities.
In an effort to propose more effective chemotherapeutic regimens for the treatment of neuroblastoma, we have characterized mouse, neuroblastoma variants whose growth in tisue culture are resistant to antimetabolites. We report the partial characterization of two lines resistant to 6-mercaptopurine (6-MP). Concentrations of drug required to inhibit their growth rates 50% are 110- and 575-fold higher, respectively, than that inhibiting the sensitive parental clone. Unlike most 6-MP-resistant cell lines described previously, both neuroblastoma populations display normal activities of hypoxanthine-guanine phosphoribosyltransferase but greatly reduced accumulation of 14-C-labeled 6-MP. Drug accumulation was inhibited by adenine, blocked by dinitrophenol but not ouabain and strongly temperature dependent suggesting a need for cytoplasmic phosphoribosylation. Possible mechanisms for this reduction in 6-MP retention are discussed. Importantly, eight clones isolated in 6-MP-free media from the 110-fold resistant population of cells demonstrated quantitatively identical growth inhibition at all drug concentrations tested suggesting that the original 110-fold resistant neuroblastoma population was homogenous with respect to its mechanisms of resistance.
D000818:Animals; D002460:Cell Line; D004351:Drug Resistance; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D015122:Mercaptopurine / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology* / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013997:Time Factors
D015122:Mercaptopurine; D013762:Tetrahydrofolate Dehydrogenase; D007041:Hypoxanthine Phosphoribosyltransferase