In a previous study we suggested that, in addition to the reduced
Adriamycin accumulation, part of the resistance in an
Adriamycin-resistant 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 Mr 170,000
P-glycoprotein was not overexpressed in GLC4/ADR and that
verapamil did not reverse the
Adriamycin resistance. GLC4/ADR expressed cross-resistance to
teniposide,
etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (
m-AMSA), and
mitoxantrone. Further investigations of the
drug-
Topo II interaction revealed that the decatenation activity of
Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR.
Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced
Topo II activity in GLC4/ADR.
Etoposide and
m-AMSA-induced DNA cleavage was 5-fold 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. Therefore, these results suggest that resistance of GLC4/ADR to
Adriamycin was in part due to the reduced
drug-induced formation of the cleavage complex.