MDR 1 Activation Is the Predominant Resistance Mechanism Selected by Vinblastine in MES-SA Cells

Br J Cancer. 2000 Oct;83(7):892-8. doi: 10.1054/bjoc.2000.1371.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cyclosporins / pharmacology
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Etoposide / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, MDR / genetics*
  • Humans
  • Multidrug Resistance-Associated Proteins
  • Mutation
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Paclitaxel / pharmacology
  • Phenotype
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rhodamine 123 / pharmacokinetics
  • Sarcoma / drug therapy
  • Sarcoma / genetics
  • Sarcoma / metabolism
  • Tritium
  • Tumor Cells, Cultured
  • Uterine Neoplasms / drug therapy
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / metabolism
  • Vault Ribonucleoprotein Particles / biosynthesis
  • Vault Ribonucleoprotein Particles / genetics
  • Vinblastine / pharmacokinetics
  • Vinblastine / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents, Phytogenic
  • Cyclosporins
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Vault Ribonucleoprotein Particles
  • major vault protein
  • Tritium
  • Rhodamine 123
  • Vinblastine
  • Etoposide
  • Paclitaxel
  • valspodar