SELECTION AND CHARACTERIZATION OF CHINESE-HAMSTER OVARY CELL MUTANTS RESISTANT TO MELPHALAN (L-PHENYLALANINE MUSTARD)

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (2) , 393-400
Abstract
Melphalan (Alkeran) is an alkylating agent commonly used in the treatment of multiple myeloma and other neoplasia. Melphalan-resistant (MelR) Chinese hamster ovary cells were isolated in vitro. Stably resistant clones were observed with a frequency of about 10-7 after a single drug exposure. Two clones, MelR1 and MelR6 were studied in detail; their phenotypes were compared to a colchicine-resistant membrane permeability mutant (CHRC5) isolated previously by Ling and Thompson which was cross-resistant to melphalan. The MelR clones were cross-resistant to the nitrogen mustard class of alkylating agents, e.g., melphalan, nitrogen mustard and chlorambucil, but not to alkylating agents, e.g., methanesulfonic acid:ethyl ester or mitomycin C. The MelR clones differed from CHRC5 in their lack of cross-resistance to puromycin and adriamycin. Studies with [14C]melphalan showed CHRC5, but not the MelR clones, to be defective in drug accumulation into whole cells. The mechanism of melphalan resistance in CHRC5 is attributed to reduced drug accumulation due to a plasma membrane alteration. In the MelR clones, investigation of drug distribution into cell subfractions revealed reduced accumulation into the nucleus compared to the parental cell line. The mechanism of resistance in the MelR cells probably results from a nuclear alteration(s) specific to a subclass of alkylating agents.