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Attenuated Topoisomerase II Content Directly Correlates with a Low Level of Drug Resistance in a Chinese Hamster Ovary Cell Line¹

James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40292

A new multiple drug-resistant Chinese hamster ovary cell line, CHO-SMR₅, has been isolated which demonstrates a direct correlation between reduced cellular topoisomerase II activity (5-fold reduction) and a low level of resistance (3- to 7-fold) to topoisomerase II inhibitors. This cell line, initially selected for resistance to 9-(4,6-O-ethylidene-ß-D-glucopyranosyl)-4'-demethylepipodophyllotoxin, exhibits cross-resistance to other topoisomerase II inhibitors including 4'-(9-acridinylamino)methanesulfon-m-anisidide, doxorubicin, and mitoxantrone. The resistant cells show a 4,5-fold decrease in topoisomerase II by immunoblotting when compared to wild-type cells. Drug uptake studies reveal equivalent equilibrium intracellular concentrations of [³H]9-(4,6-O-ethylidene-ß-D-glucopyranosyl)-4'-demethylepipodophyllotoxin in the resistant and parental cells. The catalytic activity of topoisomerase II (decatenation of kinetoplast DNA) is 5-fold less in the drug-resistant cell line relative to wild-type Chinese hamster ovary cells. Drug-induced DNA damage, measured as either formation of DNA double-strand breaks or covalent DNA-enzyme complexes, is 4-fold less in the resistant cell line. Finally, Northern blot analysis demonstrates a 5-fold reduction in topoisomerase II mRNA isolated from log phase CHO-SMR₅ cells. These findings suggest that a reduced level of topoisomerase II is likely to be the sole mechanism of drug resistance in this novel cell line.

¹ This work was supported by USPHS Grant CA01124 awarded by the National Cancer Institute and by Brown Cancer Center Funds.

² To whom requests for reprints should be addressed, at the James Graham Brown Cancer Center, 529 South Jackson Street, University of Louisville, Louisville, KY 40292.

Received 8/ 6/91. Accepted 10/ 7/91.

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