Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines.
Human KB cells with increasing resistance to colchicine and other chemotherapeutic agents have been isolated in four sequential steps. This report describes the characterization of drug uptake in the parent and four mutant cell lines. Drug uptake in these cell lines occurred via a nonsaturable process. In general, drug accumulation decreased with increasing drug resistance; this relationship was seen best with colchicine, vincristine, vinblastine, and daunomycin and, to a lesser extent, with actinomycin D. The accumulation of dexamethasone, an agent to which all lines were equally sensitive, was similar for the parent and the four mutants. Drug efflux occurred rapidly, and differences among the various cell lines could be detected within the first minute. In the more resistant lines, a greater percentage of the drug was released more rapidly, although the absolute amount of drug released was less. Verapamil partially reversed the multiple drug-resistance phenotype by increasing the initial rate of uptake and accumulation of drugs in the resistant cell lines without an apparent effect on drug efflux. The results suggest that, in this human epithelial cell, the development of resistance to multiple drugs is complex, with changes in drug uptake, accumulation, and efflux.
D000970:Antineoplastic Agents / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells; D009369:Neoplasms / Q000378:metabolism*; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D014700:Verapamil