This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Elliott, E. M. Articles by Ling, V. Search for Related Content PubMed PubMed Citation Articles by Elliott, E. M. Articles by Ling, V.

Selection and Characterization of Chinese Hamster Ovary Cell Mutants Resistant to Melphalan (L-Phenylalanine Mustard)¹

The Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M4X 1K9

Melphalan (Alkeran) is an alkylating agent commonly used in the treatment of multiple myeloma and other neoplasia. We have isolated melphalan-resistant (Mel^R) Chinese hamster ovary cells in vitro. Stably resistant clones were observed with a frequency of about 10^-7 after a single drug exposure. Two clones, Mel^R1 and Mel^R6, were studied in detail, and their phenotypes were compared to a colchicine-resistant membrane permeability mutant (CH^RC5) isolated previously by Ling and Thompson (J. Cell Physiol., 83: 103–116, 1974), which was cross-resistant to melphalan.

The Mel^R cones were cross-resistant to the nitrogen mustard class of alkylating agents, such as melphalan, nitrogen mustard, and chlorambucil, but not to alkylating agents, such as methanesulfonic acid:ethyl ester or mitomycin C. The Mel^R clones differed from CH^RC5 in their lack of cross-resistance to puromycin and Adriamycin. Studies with [¹⁴C]melphalan showed CH^RC5, but not the Mel^R clones, to be defective in drug accumulation into whole cells. The mechanism of melphalan resistance in CH^RC5 is attributed to reduced drug accumulation due to a plasma membrane alteration. In the Mel^R clones, investigation of drug distribution into cell subfractions revealed reduced accumulation into the nucleus compared to the parental cell line. We therefore propose that the mechanism of resistance in the Mel^R cells results from a nuclear alteration(s) specific to a subclass of alkylating agents.

¹ This work was supported by the National Cancer Institute of Canada and the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Department of Medical Biophysics, University of Toronto, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9.

Received 8/ 6/80. Accepted 10/29/80.