MDR 1 activation is the predominant resistance mechanism selected by vinblastine in MES-SA cells.
Single-step selection with vinblastine was performed in populations of the human sarcoma cell line MES-SA, to assess cellular mechanisms of resistance to the drug and mutation rates via fluctuation analysis. At a stringent selection with 20 nM vinblastine, resulting in 5-6 logs of cell killing, the mutation rate was 7 x 10(-7)per cell generation. Analysis of variance supported the hypothesis of spontaneous mutations conferring vinblastine resistance, rather than induction of adaptive response elements. Surviving clones displayed a stable multidrug resistance phenotype over a 3-month period. All propagated clones demonstrated high levels of resistance to vinblastine and paclitaxel, and lower cross-resistance to doxorubicin and etoposide. Activation of MDR 1 gene expression and P-glycoprotein function was demonstrable in all clones. No elevation was found in the expression of the mrp gene, the LRP-56 major vault protein and beta-tubulin isotypes (M40, beta4, 5beta, and beta9) in these mutants. We conclude that initial-step resistant mechanism in these vinblastine-selected mutants commonly arises from a stochastic mutation event with activation of the MDR 1 gene.
Chen
G K
GK
Oncology Division, Department of Medicine, and the Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305-5151, USA.
Durán
G E
GE
Mangili
A
A
Beketic-Oreskovic
L
L
Sikic
B I
BI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000235:genetics; D014747:Vinblastine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D012333:RNA, Messenger; D020112:Rhodamine 123; D014316:Tritium; D020394:Vault Ribonucleoprotein Particles; D014747:Vinblastine; D000099187:Major Vault Protein; C070272:valspodar