Maytansine-resistant mutants of Chinese hamster ovary cells with an alteration in alpha-tubulin.
Mutant clones of Chinese hamster ovary cells resistant to killing by the Vinca alkaloid maytansine have been isolated using a single-step procedure. These mutants are threefold more resistant to killing by the drug than the wild-type parent. The majority of the clones (30 to 34) probably contain alterations in membrane permeability based on their cross-resistance to an unrelated drug, puromycin. Two of the four puromycin-sensitive clones were found to contain "extra" spots which migrated close to alpha-tubulin on two-dimensional gels. The "extra" spots were shown to be electrophoretic variants of alpha-tubulin with an identical two-dimensional tryptic peptide map to that of the wild-type alpha-tubulin. The alpha-tubulin mutants were cross-resistant to other microtubule disrupting drugs such as griseofulvin, vinblastine, and colcemid, but were more sensitive to the microtubule-stabilizing agent taxol than the wild-type parental cells. Mutant--wild-type hybrids were found to be resistant to levels of maytansine intermediate between the lethal doses for mutant and wild-type cells. A possible explanation for the drug resistance of these mutants is discussed.
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance; D005260:Female; D008453:Maytansine / Q000494:pharmacology*; D009154:Mutation; D010053:Ovary; D010078:Oxazines / Q000494:pharmacology*; D010446:Peptide Fragments / Q000032:analysis; D011506:Proteins / Q000302:isolation & purification; D011691:Puromycin / Q000494:pharmacology; D014404:Tubulin / Q000235:genetics* / Q000302:isolation & purification
D010078:Oxazines; D010446:Peptide Fragments; D011506:Proteins; D014404:Tubulin; D008453:Maytansine; D011691:Puromycin