A cisplatin-resistant murine leukemia cell line exhibits increased topoisomerase II activity.
cis-Dichlorodiammineplatinum(II) (CDDP) resistance in L1210/10 murine leukemia cells is multifactorial and involves decreased drug uptake, increased glutathione content, and enhanced DNA repair activity. We show here that 0.35 M NaCl nuclear extracts from L1210/10 cells possess an approximately 3-fold increase in DNA topoisomerase II activity, compared with parental L1210 cells, as measured by decatenation of kinetoplast DNA. No difference in topoisomerase I activity is observed between the two cell lines. Immunoblot analysis of topoisomerase II protein in resistant and sensitive cells suggests that the observed differences in topoisomerase II activity cannot be explained by differences in the level of protein expressed. L1210/10 cells are 2.5-fold more sensitive than L1210 cells to the cytotoxic effects of the topoisomerase II inhibitor 4'-(9-acridylamino)methane-sulfon-m-anisidide. Sequential treatment with 4'-(9-acridyl-amino)methanesulfon-m-anisidide and CDDP leads to an additive cytotoxic effect of the two drugs in sensitive L1210 cells, as determined by colony formation in semi-solid medium. In contrast, the same treatment leads to a supra-additive effect in L1210/10 cells, which strongly suggests a role for topoisomerase II in the CDDP resistance of this cell line.
Barret
J M
JM
Laboratoire de Pharmacologie et de Toxicologie Fondamentales du CNRS, Toulouse, France.
Calsou
P
P
Larsen
A K
AK
Salles
B
B
D000595:Amino Acid Sequence; D000677:Amsacrine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004260:DNA Repair / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D018105:DNA, Kinetoplast / Q000187:drug effects* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007364:Intercalating Agents / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D007939:Leukemia L1210 / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured
D018105:DNA, Kinetoplast; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D007364:Intercalating Agents; D000677:Amsacrine; C033073:4'-(9-acridinylamino)methanesulfon-o-anisidide; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D005978:Glutathione; D002945:Cisplatin