Lung Carcinoma Cell Line Cleavage Activity in an Adriamycin-resistant Human Small Cell Reduced DNA Topoisomerase II Activity and Drug-induced DNA

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resist ant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the V, 170,000 Pglycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed crossresistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfonm-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was twoto threefold reduced in both cellular and nuclear extracts from GLCt/ADR. Topo I activities appeared similar in extracts from GLC/ADR and the parental sensitive cell line ((.!(,). The slight in crease in doubling time from IS to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and /n-AMSA-induced DNA cleavage was 5fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. There fore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage