REDUCED DRUG ACCUMULATION IN MULTIPLY DRUG-RESISTANT HUMAN-KB CARCINOMA CELL-LINES

Abstract

Human KB cells with increasing resistance to colchicine and other chemotherapeutic agents were isolated in 4 sequential steps. The characterization of drug uptake in the parent and 4 mutant cell lines is described. 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 4 mutants. Drug efflux occurred rapidly, and differences among the various cell lines could be detected within the 1st min. 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. In this human epithelial cell, the development of resistance to multiple drugs is complex, with changes in drug uptake, accumulation and efflux.