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The extended-MDR phenotype

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Abstract

Cellular models have made a significant contribution to our understanding of the molecular mechanisms of resistance to chemotherapeutic drugs. However the vast majority of these models involve cell sublines with high levels of resistance generated by continuous exposure to high drug doses, and although the majority express a multidrug resistance (MDR) phenotype, they fall short of the broader drug cross resistance that is characteristic of cancers which no longer respond to treatment. Several studies have reported cell sublines which not only have the MDR phenotype and are resistant to ‘natural product’ lipophilic drugs, but they are also resistant to alkylating agents and antimetabolites. A common feature of these sublines is they were generated by treatment with low, clinically relevant levels of drug given intermittently. The term extended-MDR has been used to describe this type of broad drug cross resistance. Here we review those factors that promote the development of extended-MDR, the characteristics of extended-MDR sublines and the possible resistance mechanisms involved.

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References

  • Barnouin K, Leier I, Jedlitschky G, PourtierManzanedo A, Konig J, Lehmann WD and Keppler D (1997) Multidrug resistance protein-mediated transport of chlorambucil and melphalan conjugated to glutathione. Brit J Cancer 77: 201-209.

    Google Scholar 

  • Batist G, Torres-Garcia S, Demuys J, Greene D, Lehnert S, Rochon MandPanasci L (1989) Enhanced DNA cross-link removal: The apparent mechanism of resistance in a clinically relevant melphalan resistant human breast cancer cell line. Mol Pharmacol 36: 224-230.

    CAS  Google Scholar 

  • Bielack SS, Kallenbach K, Looft G, Erttmann R and Winkler K (1995) Structurally modified anthracyclines retain activity in a cell line with simultaneous typical and atypical multidrug resistance. Anticancer Res 15: 1279-1284.

    CAS  Google Scholar 

  • Boege F (1996) Analysis of eukaryotic DNA topoisomerases and topoisomerase-directed drug effects. Eur J Clin Chem Clin Biochem 34: 873-888.

    CAS  Google Scholar 

  • Chao CC (1995) Lack of elevated drug efflux in adriamycin-resistant immunoblastic B lymphoma cells with mdr1 overexpression.

  • Chao CCK (1996) Cross-resistance to cis-diamminedi-chloroplatinum (ii) of a multidrug-resistant lymphoma cell line associated with decreased drug accumulation and enhanced DNA repair. Eur J Pharmacol 305: 213-222.

    Article  CAS  Google Scholar 

  • Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM and Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258: 1650-1654.

    CAS  Google Scholar 

  • Davey RA, Su GM, Hargrave RM, Harvie RM, Baguley BC and Davey MW (1997) The potential of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide to circumvent three multidrug-resistance phenotypes in vitro. Cancer Chemother Pharmacol 39: 424-430.

    Article  CAS  Google Scholar 

  • Davey R, Longhurst T, Davey M, Belov L, Harvie R, Hancox D and Wheeler H (1995) Drug resistance mechanisms and MRP expression in response to epirubicin treatment in a human leukaemia cell line. Leuk Res 19: 275-282.

    Article  CAS  Google Scholar 

  • Endicott JA and Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137-171.

    Article  CAS  Google Scholar 

  • Gazdar A, Carney D, Russell E, Sims H, Baylin S, BunnJr P, Guccion J and Minna J (1980) Establishment of continuous, clonable cultures of small-cell carcinoma of the lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 40: 3502-3507.

    CAS  Google Scholar 

  • Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA and Pastan I (1995) Genetic analysis of the multidrug transporter. Annu Rev Genet 29: 607-649.

    Article  CAS  Google Scholar 

  • Hamaguchi K, Godwin AK, Yakushiji M, O'Dwyer PJ, Ozols RF and Hamilton TC (1993) Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. Cancer Res 53: 5225-5232.

    CAS  Google Scholar 

  • Hannun YA (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89: 1845-1853.

    CAS  Google Scholar 

  • Ishikawa T, Bao JJ, Yamane Y, Akimaru K, Frindrich K, Wright CD and Kuo MT (1996) Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 271: 14981-14988.

    Article  CAS  Google Scholar 

  • Kavallaris M (1997) The role of multidrug resistance-associated protein (MRP) expression in multidrug resistance. Anti-Cancer Drugs 8: 17-25.

    CAS  Google Scholar 

  • Kellen JA (1994) Molecular interrelationships in multidrug resistance. Anticancer Res 14: 433-435.

    CAS  Google Scholar 

  • Keppler D and Konig J (1997) Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. FASEB 11: 509-516.

    CAS  Google Scholar 

  • Kool M, DeHaas M, Scheffer GL, Scheper RJ, Van Eijk MJT, Juijn JA, Baas F and Borst P (1997) Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57: 3537-3543.

    CAS  Google Scholar 

  • List AF, Spier CM, Cline A, Doll DC, Garewal H, Morgan R and Sandberg AA (1991) Expression of the multidrug resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype. Brit J Haematol 78: 28-34.

    CAS  Google Scholar 

  • Little C, Nau M, Carney D, Gazdar A and Minna J (1983) Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306: 194-196.

    Article  CAS  Google Scholar 

  • Loe DW, Deeley RG and Cole SPC (1996) Biology of the multidrug resistance-associated protein, MRP. Eur J Cancer 32A: 945-957.

    Article  CAS  Google Scholar 

  • Marks DC, Belov L, Davey MW, Davey RA and Kidman AD (1992) The MTT cell viability assay for cytotoxicity testing in multidrug-resistant human leukemic cells. Leukemia Res 16: 1165-1173.

    Article  CAS  Google Scholar 

  • Marks DC, Davey MW, Davey RA, and Kidman AD (1993) Differentiation and multidrug resistance in response to drug treatment in the K562 human leukaemia cell line. Brit J Haematol 84: 83-89.

    CAS  Google Scholar 

  • Marks DC, Su GMI, Davey RA and Davey MW (1996) Extended multidrug resistance in haemopoietic cells. Brit J Haematol 95: 587-595.

    Article  CAS  Google Scholar 

  • Masanek U, Stammler G and Volm M (1997) Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin. Anti-Cancer Drugs 8: 189-198.

    CAS  Google Scholar 

  • Mattern J and Volm M (1995) Resistance mechanisms in human lung cancer. Invasion and Metastasis 15: 81-94.

    CAS  Google Scholar 

  • Mellish KJ, Barnard CF, Kelland LR and Harrap KR (1994) Circumvention of acquired tetraplatin resistance in a human ovarian carcinoma cell line by a novel trans platinum complex, JM335 [trans ammine (cyclohexylamine) dichloro dihydroxo platinum (IV)]. Int J Cancer 59: 65-70.

    CAS  Google Scholar 

  • O'Brien ML and Tew KD (1996) Glutathione and related enzymes in multidrug resistance. Eur J Cancer 32A: 967-978.

    Google Scholar 

  • Roy SN and Horwitz SB (1985) A phosphoglycoprotein associated with taxol resistance in J774.2 cells. Cancer Res 45: 3856-3863.

    CAS  Google Scholar 

  • Shen HX, Paul S, Breuninger LM, Ciaccio PJ, Laing NM, Helt M, Tew KD and Kruh GD (1996) Cellular and in vitro transport of glutathione conjugates by MRP. Biochemistry 35: 5719-5725.

    Article  CAS  Google Scholar 

  • Su GM, Davey MW, Davey RA and Kidman AD (1994) Development of extended multidrug resistance in HL60 promyelocytic leukaemia cells. Brit J Haematol 88: 566-574.

    CAS  Google Scholar 

  • Su GM, Davey MW and Davey RA (1998) Induction of broad drug resistance in small cell lung cancer cells and its reversal by paclitaxel. Int J Cancer 76: 702-708.

    Article  CAS  Google Scholar 

  • Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S and Kuwano M (1996) A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res 56: 4124-4129.

    CAS  Google Scholar 

  • Tew KD (1994) Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 54: 4313-4320.

    CAS  Google Scholar 

  • Tjuljandin SA, Doig RG, Sobol MM, Watson DM, Sheridan WP, Morstyn G, Mihaly G and Green MD (1990) Pharmacokinetics and toxicity of two schedules of high dose epirubicin. Cancer Res 50: 5095-5101.

    CAS  Google Scholar 

  • Yang LY, Trujillo JM, Siciliano MJ, Kido Y, Siddik ZH and Su YZ (1993) Distinct P-glycoprotein expression in two subclones simultaneously selected from a human colon carcinoma cell line by cis-diamminedichloroplatinum (II). Int J Cancer 53: 478-485.

    CAS  Google Scholar 

  • Yang XW and Page M (1995) P-glycoprotein expression in ovarian cancer cell line following treatment with cisplatin. Oncol Res 7: 619-624.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Clinical Oncology Department, Royal North Shore Hospital, Bill Walsh Cancer Research Laboratories, St. Leonards, 2065, Australia.

    Ross Davey

  2. Cell and Molecular Biology Department, University of Technology, Sydney, Gore Hill, 2065, Australia.

    Mary Davey

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  1. Ross Davey
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  2. Mary Davey
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Davey, R., Davey, M. The extended-MDR phenotype. Cytotechnology 27, 237–247 (1998). https://doi.org/10.1023/A:1008081208312

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