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Genetic, Biochemical, and Cross-Resistance Studies with Mutants of Chinese Hamster Ovary Cells Resistant to the Anticancer Drugs, VM-26 and VP16-213¹

Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

The effects of the anticancer drugs 4'-demethylepipodophyllotoxin thenylidene ß-D-glucoside and 4'-demethylepipodophyllotoxin ethylidene ß-D-glucoside on the growth and viability of Chinese hamster ovary cells have been examined. Stable mutants which are from 4- to 12-fold more resistant to these drugs (Vpm^R mutants) are obtained in a single selection step in Chinese hamster ovary cells at a frequency of between 0.2 x 10^-6 and 0.5 x 10^-6. However, treatment of cells with the mutagen ethyl methanesulfonate (300 µg/ml for 20 hr) increased the frequency of resistant mutants by about 20- to 30-fold in different experiments. The two Vpm^R mutants which have been studied in detail exhibited significantly increased cross-resistance to a number of anticancer drugs and other compounds, including actinomycin D, Adriamycin, bruceantin, chromomycin A₃, colchicine, daunomycin, ellipticine, ethidium bromide, 5-fluorouracil, ftorafur, mithramycin, puromycin, and vinblastine. However, the level of resistance of these mutants towards several podophyllotoxin derivatives (namely, podophyllotoxin, 4'-demethylepipodophyllotoxin, and podophyllotoxin ß-D-glucoside) and a number of other anticancer drugs, namely, 9-ß-D-arabinofuranosyladenine, chlorambucil, hexamethylmelamine, hydroxyurea, maytansine, methotrexate, methylglyoxal (bis)guanylhydrazone, mitomycin C, and taxol, was found to be unaltered. Interestingly, the sensitivity of the above mutant cell lines toward a number of other anticancer drugs, namely, bleomycin, cis-diamminedichloroplatinum(II), and 1-ß-D-arabinofuranosylcytosine, was found to be enhanced in comparison to the parental cells. The mutant cell lines showed reduced uptake of [³H]daunomycin in comparison to the sensitive cells, and this result, together with the cross-resistance of the mutants to unrelated drugs, indicates that the genetic lesion in these mutants is most probably affecting the membrane permeability of various drugs. In cell hybrids formed between the resistant and the sensitive cells, the drug-resistant phenotype of both of the above mutants behaved in a codominant manner. The results of these studies are discussed in relation to the mechanism of action of 4'-demethylepipodophyllotoxin thenylidene ß-D-glucoside and 4'-demethylepipodophyllotoxin ethylidene ß-D-glucoside.

¹ Work supported by a research grant from the Medical Research Council and the National Cancer Institute of Canada.

Received 7/23/82. Accepted 12/10/82.

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