Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine.

Intrinsic and acquired multidrug resistance (MDR) is an important problem in cancer therapy. MDR in human KB carcinoma cells selected for resistance to colchicine, vinblastine, or doxorubicin (former generic name adriamycin) is associated with overexpression of the "MDR1" gene, which encodes P-glycoprotein. We previously have isolated an overlapping set of cDNA clones for the human MDR1 gene from multidrug-resistant KB cells. Here we report the construction of a full-length cDNA for the human MDR1 gene and show that this reconstructed cDNA, when inserted into a retroviral expression vector containing the long terminal repeats of Moloney leukemia virus or Harvey sarcoma virus, functions in mouse NIH 3T3 and human KB cells to confer the complete multidrug-resistance phenotype. These results suggest that the human MDR1 gene may be used as a positive selectable marker to introduce genes into human cells and to transform human cells to multidrug resistance without introducing nonhuman antigens.

[1]  I. Pastan,et al.  The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. , 1987, The Journal of biological chemistry.

[2]  J. Endicott,et al.  Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance , 1986, Nature.

[3]  D. Housman,et al.  Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins , 1986, Cell.

[4]  Michael M. Gottesman,et al.  Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells , 1986, Cell.

[5]  I. Pastan,et al.  Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene , 1986, Molecular and cellular biology.

[6]  D. Housman,et al.  Chromosome-mediated gene transfer of multidrug resistance , 1986, Molecular and cellular biology.

[7]  I. Pastan,et al.  Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. , 1986, Cancer research.

[8]  D. Housman,et al.  Isolation and expression of a complementary DNA that confers multidrug resistance , 1986, Nature.

[9]  T. Tsuruo,et al.  Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Lowy,et al.  Mutational analysis of a ras catalytic domain , 1986, Molecular and cellular biology.

[11]  I. Pastan,et al.  Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. , 1986, The Journal of biological chemistry.

[12]  I. Pastan,et al.  Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[13]  K. Scotto,et al.  Amplification and expression of genes associated with multidrug resistance in mammalian cells. , 1986, Science.

[14]  I. Pastan,et al.  Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. , 1986, Science.

[15]  A. M. van der Bliek,et al.  Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line , 1986, Molecular and cellular biology.

[16]  J. Riordan,et al.  Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines , 1985, Nature.

[17]  I. Pastan,et al.  Amplification of DNA sequences in human multidrug-resistant KB carcinoma cells. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[18]  I. Pastan,et al.  Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. , 1985, Cancer research.

[19]  D. Melton,et al.  Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. , 1984, Nucleic acids research.

[20]  D. Housman,et al.  Amplification of specific DNA sequences correlates with multi-drug resistance in Chinese hamster cells , 1984, Nature.

[21]  J. Riordan,et al.  Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. , 1983, Science.

[22]  T. Tsuruo,et al.  Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. , 1982, Cancer research.

[23]  J. Riordan,et al.  DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression , 1982, Molecular and cellular biology.

[24]  D. Lowy,et al.  Dual evolutionary origin for the rat genetic sequences of Harvey murine sarcoma virus , 1980, Journal of virology.

[25]  R. Johnson,et al.  Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia. , 1979, Cancer research.

[26]  J. Till,et al.  Pleiotropic phenotype of colchicine‐resistant CHO cells: Cross‐resistance and collateral sensitivity , 1976, Journal of cellular physiology.

[27]  I. Pastan,et al.  Expression of a multidrug-resistance gene in human tumors and tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Housman,et al.  Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Riordan,et al.  Genetic and biochemical characterization of multidrug resistance. , 1985, Pharmacology & therapeutics.