An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene

Kyunghee Choi, Chang jie Chen, Michael Kriegler, Igor B. Roninson

Research output: Contribution to journalArticle

370 Scopus citations

Abstract

Multidrug resistance in human cells results from increased expression of the mdr1 (P-glycoprotein) gene, Although the same gene is activated in cells selected with different drugs, multidrug-resistant cell lines can be preferentially resistant to their selecting agent. The mdr1 cDNA sequence from vinblastine-selected KB cells, which are uniformly resistant to different lipophilic drugs, was compared with the corresponding sequence from colchicine-selected KB cells preferentially resistant to colchicine. These sequences differ at three positions, resulting in a single amino acid change in P-glycoprotein. These differences result from mutations that occured during colchicine selection. The appearance of these mutations coincides with the emergence of preferential resistance to colchicine. We have constructed biologically active mdr1 cDNA clones that express either wild-type or mutant P-glycoprotein. Multidrug-resistant transfectants obtained with the mutant sequence were characterized by increased relative resistance to colchicine compared with transfectants obtained with wild-type sequence. mdr1 mutations are therefore responsible for preferential resistance to colchicine in multidrug-resistant KB cells.

Original languageEnglish
Pages (from-to)519-529
Number of pages11
JournalCell
Volume53
Issue number4
DOIs
StatePublished - May 20 1988
Externally publishedYes

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