title: Progressive resistance to doxorubicin in mouse leukemia L1210 cells with multidrug resistance phenotype: reductions in drug-induced topoisomerase II-mediated DNA cleavage.
abstract: Cells selected for resistance to doxorubicin (DOX) express the multidrug resistance (MDR) phenotype, and resistance has been suggested to be due primarily to enhanced cellular efflux of drug. A progressively DOX-resistant (10- and 40-fold) L1210 mouse leukemia model system, which does not exhibit enhanced DOX efflux as a primary mechanism of resistance, was found to display the MDR phenotype, based on overexpression of P-glycoprotein in western blots and cross-resistance to vinca alkaloids. Cross-resistance to another topoisomerase II inhibitor, etoposide (VP-16), was similar to that of DOX (10- and 40-fold), whereas resistance to N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide (m-AMSA) was 5-fold lower. In contrast, no cross-resistance to camptothecin, an inhibitor of topoisomerase I, was observed. Topoisomerase II decatenation activity in nuclear extracts from 10- and 40-fold DOX-resistant cells was 2- and 4-fold lower, respectively, when compared to sensitive cells. In these cells, however, marked reductions in m-AMSA- and VP-16-induced topoisomerase II mediated DNA cleavage were found to exceed decreases in the catalytic activity of the enzyme. Results from this study demonstrated that, in progressively DOX-resistant L1210 mouse leukemia cells with the MDR phenotype, a better relation existed between the degree of resistance and reduced VP-16- and m-AMSA-induced topoisomerase II mediated DNA cleavage, than between increases in P-glycoprotein and concomitant reduction in DOX accumulation.
authors.affiliation: Research Institute, Cleveland Clinic Foundation, OH 44195.
authors.forename: R
authors.initials: R
authors.lastname: Ganapathi
authors.forename: D
authors.initials: D
authors.lastname: Grabowski
authors.forename: J
authors.initials: J
authors.lastname: Ford
authors.forename: C
authors.initials: C
authors.lastname: Heiss
authors.forename: D
authors.initials: D
authors.lastname: Kerrigan
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D007939:Leukemia L1210 / Q000201:enzymology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000302:isolation & purification; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010641:Phenotype; D013539:Simian virus 40; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004279:DNA, Viral; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D000677:Amsacrine; D005047:Etoposide; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II