Abstract
Hamster cells grown in culture may, like human and mouse cells, develop multidrug resistance (MDR) when exposed to certain cytotoxic chemotherapeutic agents. Several phenotypic features that are characteristic of MDR have been described; these include (1) resistance to many structurally and functionally unrelated drugs that have different cellular targets and modes of action; (2) reversal of MDR by certain agents, including verapamil and cyclosporin A; and (3) reduced intracellular drug accumulation relative to that of drug-sensitive cells. In this report we show that the introduction and overexpression of the hamster pgp1 cDNA confers to otherwise drug-sensitive cells an MDR phenotype with these features. Moreover, pgp1 transfectants showed varying degrees of resistance to anthracycline analogues, indicating that structural analogues of commonly used anticancer agents are capable of circumventing drug resistance conferred by pgp.
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Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JS, Struhl K (eds) (1989) Current protocols in molecular biology. Greene, New York, pp 1.7.1, 4.0.1, 9.1.1
Azzaria M, Schurr E, Gros P (1989) Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance. Mol Cell Biol 9: 5289
Biedler JL, Riehm H (1970) Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radio-autographic, and cytogenetic studies. Cancer Res 30: 1174
Chen C-J, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells Cell 47: 381
Croop J, Guild B, Gros P, Housman D (1987) Genetics of multidrug resistance: relationship of cloned gene to the complete multidrug resistant phenotype. Cancer Res 47: 5982
Devault A, 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
Devine SE, Ling V, Melera PW (1992) Amino acid substitutions in the sixth transmembrane domain of P-glycoprotein alter multidrug resistance. Proc Natl Acad Sci USA 89: 4564
Devine SE, Hussain A, Davide JP, Melera PW (1988) Full-length and alternatively spliced pgp1 transcripts in Chinese hamster lung cells. J Biol Chem 266: 4545
Dhir R, Gros P (1992) Functional analysis of chimeric proteins constructed by exchanging homologous domains of two P-glycoproteins conferring distinct drug resistance profiles, Biochemistry 31: 6103
Endicott JA, Sarangi F, Ling V (1991) Complete cDNA sequences encoding the Chinese hamster P-glycoprotein gene family. DNA Sequences 2: 89
Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137
Freshney RI (1983) Culture of animal cells, a manual of basic technique. Alan Liss, New York, p 129
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62: 385
Greenberger LM, Williams SS, Horwitz SB (1987) Biosyntheses of heterogeneous forms of multidrug resistance-associated glycoproteins. J Biol Chem 262: 13685
Gros P, Ben Neriah Y, Croop J, Housman DE (1986) Isolation and expression of a complementary DNA that confers multidrug resistance. Nature 323: 728
Gros P, Raymond M, Bell J, Housman D (1988) Cloning and characterization of a second member of the mouse mdr gene family. Mol Cell Biol 8: 2770
Gros P, Croop J, Roninson I, Varshavsky A, Housman DE (1986) Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells. Proc Natl Acad Sci USA 83: 337
Gros P, Croop J, Housman D (1986) Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47: 371
Hammond JR, Johnstone RM, Gros P (1989) Enhanced efflux of [3H]vinblastine from Chinese hamster ovary cells transfected with a full-length complementary DNA clone for the mdr1 gene. Cancer Res 49: 3867
Howell N, Belli TA, Zaczkiewicz H, Belli JA (1984) High level, unstable Adriamycin resistance in a Chinese hamster mutant cell line with double minute chromosomes. Cancer Res 44: 4023
Hussain A, Lewis D, Yu M, Melera PW (1992) Construction of a dominant selectable marker using a novel dihydrofolate reductase. Gene 112: 179
Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455: 152
Kartner N, Ling V (1989) Multidrug resistance in cancer. Sci Am 260: 44
Kartner N, Evernden-Porelle D, Bradley G, Ling V (1985) Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 316: 820
Ling V, Thompson LH (1974) Reduced permeability in CHO cells ad a mechanism of resistance to colchicine. J Cell Physiol 83: 103
Melera PW, Biedler JL (1991) Molecular and cytogenetic analysis of multidrug resistance-associated gene amplification in Chinese hamster, mouse sarcoma, and human neuroblastoma cell. In: IB Roninson (ed) Molecular and cellular biology of multidrug resistance in tumor cells. Plenum, New York, p 117
Pastan I, Gottesman MM, Ueda K, Lovelace E, Rutherford AV, Willingham MC (1987) A retrovirus carrying an mdr1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA 85: 4486
Pastan I, Gottesman MM (1991) Multidrug resistance. Annu Rev Med 42: 277
Peterson RHF, Meyers MB, Spengler BA, Biedler JL (1983) Alteration of plasma membrane glycopeptides and gangliosides of Chinese hamster cells accompanying resistance to daunorubicin and vincristine. Cancer Res 43: 222
Riehm H, Biedler JL (1971) Cellular resistance to daunomycin in Chinese hamster cells in vitro. Cancer Res 31: 409
Riordan JR, Deuchars K, Kartner N, Alon N, Trent J, Ling V (1985) Amplification of P-glycoprotein in multidrug-resistant mammalian cell lines. Nature 316: 817
Riordan JR, Ling V (1979) Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J Biol Chem 254: 12701
Ripamonti M, Pezzoni G, Pesenti E, Pastori A, Farao M, Bargiotti A, Suaroto A, Spreafico F, Grandi M (1992) In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells. Br J Cancer 65: 703
Roninson IB, Abelson HT, Housman DE, Howell N, Varshavsky A (1984) Amplification of specific DNA sequences correlates with multi-drug resistance in Chinese hamster cells. Nature 309: 626
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning, a laboratory manual, 2nd edn. Cold Spring Harbor Press, Cold Spring Harbor, New York, p 1.53
Scotto KW, Biedler JL, Melera PW (1986) Amplification and expression of genes associated with multidrug resistance in mammalian cells. Science 232: 751
Shen D-W, Fojo A, Chin JE, Roninson IB, Pastan I, Gottesman MM (1986) Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232: 643
Subak-Sharpe H (1965) Biochemically marked variants of the Syrian hamster fibroblast cell line BHK21 and its derivatives. Exp Cell Res 38: 106
Tsuruo T (1991) Reversal of multidrug resistance by calcium channel blockers and other agents. In: Roninson IB (ed) Molecular and cellular biology of multidrug resistance in tumor cells. Plenum, New York, p 349
Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human mdr1 gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 84: 3004
Van der Bliek AM, Van der Velde-Koerts T, Ling V, Borst P (1986) Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line. Mol Cell Biol 6: 1671
Van der Bliek AM, Kooiman PM, Schneider C, Borst P (1988) Sequence of mdr3 cDNA encoding a human P-glycoprotein. Gene 71: 401
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Present address: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Devine, S.E., Melera, P.W. Functional studies with a full-length P-glycoprotein cDNA encoded by the Hamster pgp1 gene. Cancer Chemother. Pharmacol. 33, 465–471 (1994). https://doi.org/10.1007/BF00686502
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DOI: https://doi.org/10.1007/BF00686502