Abstract
The problem of multidrug resistance has been extensively studied over the past two decades by using multidrug-resistant (MDR) cell lines derived in vitro by stepwise selection. These cells, obtained after exposure to increasing concentrations of a single cytotoxic drug, display a characteristic pattern of cross-resistance to other drugs, unrelated in structure or intracellular targets, to which they have not been previously exposed. A large body of published biochemical data describing the phenotypic expression of MDR in cultured cells exists and is reviewed in detail in other chapters of this volume. One obvious common character of these cytotoxic compounds is that they are small, hydrophobic molecules that appear to enter the cell by passive diffusion across the membrane. In general, the onset of drug resistance is linked to a decrease in the level of intracellular accumulation of drug molecules in these cells. This decreased rate is dependent upon the production of ATP in drug-resistant cells, since deoxyglucose or sodium azide treatments of these cells restore the normal rate of accumulation observed in drug-sensitive cells (Danø, 1973; Ling and Thompson, 1974; Skovsgaard, 1978). The level of various proteins has been found to fluctuate in drug-resistant cells; however, the overproduction of a heterogeneous group of high-molecular-weight membrane glycoproteins, termed P-glycoprotein, has been the most consistent phenotypic marker of MDR in cultured cells (Juliano and Ling, 1976). The relationship between these overproduced proteins and drug resistance is not clear, however. A genetic approach may represent the systematic tool necessary to characterize the mechanistic basis of drug resistance.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Arceci, R. J., Croop, J. M., Horwitz, S. B., and Housman, D. E., 1988, The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus, Proc. Natl. Acad. Sci. USA 85:4350–4354.
Beck, W. T., Mueller, T. J., and Tanzer, L. R., 1979, Altered surface membrane glycoproteins in Vinca alkaloid-resistant human leukemic lymphoblasts, Cancer Res. 39:2070–2076.
Bhalla, K., Hindenburg, A., Taub, R. N., and Grant, S., 1985, Isolation and characterization of anthracycline-resistant human leukemic cell line, Cancer Res. 45:3657–3662.
Cornwell, M. M., Safa, A. R., Felsted, R., Gottesman, M. M., and Pastan, I., 1986, Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150–170 kDa protein detected by photoaffinity labelling, Proc. Natl. Acad. Sci. USA, 83:3847–3850.
Cornwell, M. M., Tsuruo, T., Gottesman, M. M., and Pastan, I., 1987, ATP-binding properties of P-glycoprotein from multidrug-resistant KB cells, FASEB J. 1:51–54.
Croop, J. M., Raymond, M., Haber, D., Devault, A., Arceci, R. J., Gros, P., and Housman, D. E., 1989, The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues, Mol. Cell. Biol. 9:1346–1350.
Danø, K., 1973, Active outward transport of daunomycin in resistant Erlich ascites tumor cells, Biochim. Biophys. Acta 323:446–483.
Deuchars, K. L., Du, R., Naik, M., Evernden-Porelle, D., Kartner, N., Van der Bliek, A. M., and Ling, V, 1987, Expression of hamster P-glycoprotein and multidrug resistaned in DNA-mediated transformants of mouse LTA cells, Mol. Cell. Biol. 7:718–724.
Devault, A., and Gros, P., 1990, Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities, Mol. Cell. Biol. 10:1652–1663.
Felmlee, T., Pellett, S., and Welch, R. A., 1985, Nucleotide sequence of an Escherichia coli chromosomal hemolysin, J. Bacteriol. 163:94–105.
Gerlach, J. H., Endicott, J. A., Juranka, P. F., Henderson, G., Sarangi, F., Deuchars, K. L., and Ling, V, 1986, Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance, Nature 324:485–489.
Greenberger, L. M., Williams, S. S., and Horowitz, S. B., 1987, Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins, J. Biol. Chem. 262:13685–13689.
Gros, P., Croop, J., Varshavsky, A., and Housman, D. E., 1986a, Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells, Proc. Natl. Acad. Sci. USA 83:337–341.
Gros, P., Ben Neriah, Y., Croop, J., and Housman, D. E., 1986b, Isolation and expression of a complementary DNA that confers multidrug resistance, Nature 323:728–731.
Gros, P., Fallows, D. A., Croop, J., and Housman, D. E., 1986c, Chromosome-mediated gene transfer of multidrug resistance, Mol. Cell. Biol. 6:3785–3790.
Gros, P., Croop, J., and Housman, D. E., 1986d, Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins, Cell 47:371–390.
Gros, P., Raymond, M., Bell, J., and Housman, D. E., 1988, Cloning and characterization of a second member of the mouse mdr gene family, Mol Cell. Biol. 8:2770–2778.
Grand, S. H., Patil, S. R., Shah, H. D., Pauw, P. G., and Stadler, J. R., 1983, Correlation of unstable multidrug cross-resistance in Chinese hamster ovary cells with a homogeneously staining region on chromosome 1, Mol. Cell. Biol. 3:1634–1641.
Guild, B. C, Mulligan, R. C. Gros, P., and Housman, D. E., 1988, Retroviral transfer of a murine cDNA for multidrug resistance confers pleiotropic drug resistance to cells without prior drug selection, Proc. Natl. Acad. Sci. USA 85:1595–1599.
Hsu, S. I., Lothstein, L., and Horwitz, S. B., 1989, Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells, J. Biol. Chem. 264:12053–12062.
Juliano, R. L., and Ling, V., 1976, A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta 455:152–162.
Kuo, T., Pathak, S., Ramagli, L., Rodrigues, L., and Hsu, T. C., 1982, Vincristine-resistant Chinese hamster ovary cells, in: Gene Amplification (R. T. Schimke, ed.), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., pp. 53–62.
Ling, V., and Thompson, L. H., 1974, Reduced permeability in CHO cells as a mechanism of resistance to colchicine, J. Cell. Physiol. 83:103–111.
Martinsson, T., and Levan, G., 1987, Localization of the multidrug resistance-associated 170 kDa P-glycoprotein gene to mouse chromosome 5 and to homogeneously staining regions in multidrug-resistant mouse cells by in situ hybridization, Cytogenet. Cell Genet. 45:99–101.
Raymond, M., Rose, E., Housman, D. E., and Gros, P., 1990, Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells, Mol. Cell. Biol. 10:1642–1651.
Riordan, J. R., Deuchars, K., Kartner, N., Alon, N., Trent, J., and Ling, V., 1985, Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines, Nature 316:817–819.
Roninson, I. B., 1983, Detection and mapping of homologous, repeated and amplified DNA sequences by DNA renaturation in agarose gels, Nucleic Acids Res. 11:5413–5423.
Roninson, I. B., Abelson, H., Housman, D. E., Howell, N., and Varshavsky, A., 1984, Amplification of specific DNA sequences correlates with multidrug resistance in Chinese hamster cells, Nature 309:626–628.
Safa, A. R., Glover, C. J., Meyers, M. B., Biedler, J. L., and Felsted, R. L., 1986, Vinblastine photoaffinity labeling of a high molecular weight surface membrane glycoprotein specific for multidrug-resistant cells, J. Biol. Chem. 261:6137–6140.
Schurr, E., Raymond, M., Bell, J. C, and Gros, P., 1989, Characterization of the multidrug resistance protein expressed in cell clones stably transfected with the mouse mdr1 cDNA, Cancer Res. 49:2729–2734.
Shen, D.-W., Fojo, A., Chin, J. E., Roninson, I. B., Richert, N., Pastan, I., and Gottesman, M. M., 1986a, Human multidrug-resistant cell lines: Increased mdr1 expression can precede gene amplification, Science 232:643–645.
Shen, D.-W., Fojo, A., Roninson, I. B., Chin, J. E., Soffir, R., Pastan, I., and Gottesman, M. M., 1986b, Multidrug resistance in DNA-mediated transformants is linked to transfer of the human mdr1 gene, Mol. Cell. Biol. 6:4039–4045.
Skovsgaard, T., 1978, Mechanism of cross-resistance between vincristine and daunorubicin in Ehrlich ascites tumor cells, Cancer Res. 38:4722–4727.
Ueda, K., Cornwell, M. M., Gottesman, M. M., Pastan, I., Roninson, I. B., Ling, V., and Riordan, J. R., 1986, The mdr1 gene, responsible for multidrug resistance, codes for P-glycoprotein, Biochem. Biophys. Res. Commun. 141:956–962.
Walker, J. E., Daraste, M., Runswick, M. J., and Gay, N. J., 1982, Distantly related sequences in the alpha and beta subunits of ATP synthetase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMRO J 1:945–951.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Springer Science+Business Media New York
About this chapter
Cite this chapter
Gros, P., Raymond, M., Housman, D. (1991). Cloning and Characterization of Mouse mdr Genes. In: Roninson, I.B. (eds) Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3794-6_3
Download citation
DOI: https://doi.org/10.1007/978-1-4615-3794-6_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6691-1
Online ISBN: 978-1-4615-3794-6
eBook Packages: Springer Book Archive