TY - JOUR
T1 - An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene
AU - Choi, Kyunghee
AU - Chen, Chang jie
AU - Kriegler, Michael
AU - Roninson, Igor B.
N1 - Funding Information:
We wish to thank M. M. Gottesman and I. Pastan for providing multidrug-resistant KB cell lines, L. Sha and R. Kaplan for excellent technical assistance, B. Morse for help with clone constructions, and C. F. Perez and K. Noonan for helpful discussions. This work was supported by Public Health Service grant CA40333 from the National Cancer Institute and by a grant from Cetus Corporation.
PY - 1988/5/20
Y1 - 1988/5/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0024292717&partnerID=8YFLogxK
U2 - 10.1016/0092-8674(88)90568-5
DO - 10.1016/0092-8674(88)90568-5
M3 - Article
C2 - 2897240
AN - SCOPUS:0024292717
SN - 0092-8674
VL - 53
SP - 519
EP - 529
JO - Cell
JF - Cell
IS - 4
ER -