Multidrug resistance phenotype of human BRO melanoma cells transfected with a wild-type human mdr1 complementary DNA

Cancer Res. 1990 Mar 15;50(6):1779-85.

Abstract

We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated from normal human liver into human BRO melanoma cells to study the drug-resistant phenotype produced by the exclusive overexpression of normal human mdr1 P-glycoprotein. The drug resistance pattern of mdr1-transfected clones includes relatively high resistance to gramicidin D (about 300-fold), vincristine (about 100-fold), and actinomycin D (about 100-fold) and a lower degree of resistance to doxorubicin (about 10-fold), VP16-213 (about 10-fold), and colchicine (about 6-fold). The transfectants did not exhibit resistance to trimetrexate, cis-platinum, mitomycin C, 1-beta-D-arabinofuranosylcytosine, bleomycin, G418, or magainin-2-amide; they were slightly more sensitive to verapamil (2-fold) but not to Triton X-100. As in other multidrug-resistant cell lines, resistance to vincristine could be reversed by verapamil and, more effectively, by cyclosporin A. Chloroquine only marginally increased drug sensitivity in mdr1-transfected cells. Gramicidin D resistance was also reversed by verapamil, suggesting that the mechanism of resistance to this polypeptide antibiotic is similar to that of other drugs transported by P-glycoprotein. Thus, expression of the wild-type mdr1 complementary DNA induces a drug-resistant phenotype similar to that induced by mdr1 complementary DNAs isolated from drug-resistant cell lines with relatively low colchicine resistance. As other cell lines may display a different pattern of drug resistance, it is clear that other resistance mechanisms or cell type-specific factors may modulate the resistance. mdr1-transfected cell lines provide a convenient tool for the identification of P-glycoprotein-mediated phenomena.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents / pharmacology*
  • Biological Transport
  • Cell Division / drug effects
  • Cell Line
  • Cell Membrane / metabolism
  • DNA / genetics
  • Daunorubicin / metabolism
  • Drug Resistance / genetics*
  • Humans
  • Kinetics
  • Melanoma
  • Membrane Glycoproteins / genetics*
  • Nucleic Acid Hybridization
  • Phenotype
  • Transfection*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects*
  • Tumor Cells, Cultured / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Membrane Glycoproteins
  • DNA
  • Daunorubicin