Clinical Immunotherapeutics

, Volume 5, Issue 2, pp 91–95 | Cite as

Reversal of Tumour Drug Resistance with Monoclonal Antibodies

Prospects and Problems
  • Mikihiko Naito
  • Takashi Tsuruo
Leading Article


Emergence of drug resistance is a major problem in cancer chemotherapy. P-glycoprotein, a product of the MDR1 gene, plays an important role in multidrug resistance. Since P-glycoprotein is expressed on the tumour cell surface, therapeutic application of monoclonal antibodies (mAbs) against P-glycoprotein has been considered. Anti-P-glycoprotein mAbs enhance immune responses against multidrug-resistant tumours expressing P-glycoprotein, and also inhibit the transport function of P-glycoprotein. Accordingly, selective elimination of multidrug-resistant tumours has been demonstrated in vitro and in vivo. Although there remain many questions to be solved, selective targeting of multidrug-resistant tumours by anti-P-glycoprotein mAbs is a promising strategy for overcoming multidrug resistance.


Adis International Limited Multidrug Resistance Vinca Alkaloid Anti Tumour Drug Multidrug Transporter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 1989; 58: 137–71PubMedCrossRefGoogle Scholar
  2. 2.
    Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427PubMedCrossRefGoogle Scholar
  3. 3.
    Tsuruo T. Mechanism of multidrug resistance and implications for therapy. Jpn J Cancer Res 1988; 79: 285–96PubMedCrossRefGoogle Scholar
  4. 4.
    Tsuruo T. Reversal of multidrug resistance by calcium channel blokers and other agents. In: Roninson IB, editor. Molecular and cellular biology of multidrug resistance in tumor cells. New York: Plenum Publishing Co., 1991: 349–72CrossRefGoogle Scholar
  5. 5.
    Dalton WS, Grogan TM, Meltzer PS, et al. Drug-resistance in multiple myeloma and non-Hodgkin’s lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 1989; 7: 415–24PubMedGoogle Scholar
  6. 6.
    Miller TP, Grogan TM, Dalton WS, et al. P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 1991; 9: 17–24PubMedGoogle Scholar
  7. 7.
    Sonneveld P, Durie BGM, Lokhorst HM, et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. Lancet 1992; 340: 255–9PubMedCrossRefGoogle Scholar
  8. 8.
    Kartner N, Everden-Porelle D, Bradley G, et al. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 1985; 316: 820–3PubMedCrossRefGoogle Scholar
  9. 9.
    Scheper RJ, Bulte JWM, Brakkee JG, et al. Monoclonal antibody JSB-1 detects a highly conserved epitope on the P-glycoprotein associated with multidrug resistance. Int J Cancer 1988; 42: 389–94PubMedCrossRefGoogle Scholar
  10. 10.
    Hamada H, Tsuruo T. Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. Proc Natl Acad Sci USA 1986; 83: 7785–9PubMedCrossRefGoogle Scholar
  11. 11.
    Meyers MB, Rittman-Graner L, O’Brien JP, et al. Characterization of monoclonal antibodies recognizing an Mr 180,000 P-glycoprotein in multidrug-resistant human tumor cells. Cancer Res 1989; 49: 3209–14PubMedGoogle Scholar
  12. 12.
    Merchetner EB, Roninson IB. Efficient inhibition of P-glycoprotein mediated multidrug resistance with a monoclonal antibody. Proc Natl Acad Sci USA 1992; 89: 5824–8CrossRefGoogle Scholar
  13. 13.
    Arceci RJ, Stieglitz K, Brass J, et al. Monoclonal antibody to an external epitope of the human mdr1 P-glycoprotein. Cancer Res 1993; 53: 310–7PubMedGoogle Scholar
  14. 14.
    Schinkel AH, Arceci RJ, Smit JJM, et al. Binding properties of monoclonal antibodies recognizing external epitopes of the human MDR1 P-glycoprotein. Int J Cancer 1993; 55: 478–84PubMedCrossRefGoogle Scholar
  15. 15.
    Aihara M, Aihara Y, Schmidt-Wolf G, et al. A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy. Blood 1991; 77: 2079–84PubMedGoogle Scholar
  16. 16.
    Cenciarelli C, Currier SJ, Willingham MC, et al. Characterization by somatic cell genetics of a monoclonal antibody to the MDR1 gene product (P-glycoprotein): determination of P-glycoprotein expression in multi-drug-resistant KB and CEM cell variants. Int J Cancer 1991; 47: 533–43PubMedCrossRefGoogle Scholar
  17. 17.
    Tsuruo T, Hamada H, Sato S, et al. Inhibition of multidrug-resistant human tumor growth in athymic mice by anti-P-glycoprotein monoclonal antibodies. Jpn J Cancer Res 1989; 80: 627–31PubMedCrossRefGoogle Scholar
  18. 18.
    Heike Y, Hamada H, Inamura N, et al. Monoclonal anti-P-glycoprotein antibody-dependent killing of multidrug-resistant tumor cells by human mononuclear cells. Jpn J Cancer Res 1990; 81: 1155–61PubMedCrossRefGoogle Scholar
  19. 19.
    Iwahashi T, Okochi E, Ariyoshi K, et al. Specific targeting and killing activities of anti-P-glycoprotein monoclonal antibody MRK-16 directed against intrinsically multidrug-resistant human colorectal carcinoma cell lines in nude mouse model. Cancer Res 1993; 53: 5475–82PubMedGoogle Scholar
  20. 20.
    Naito M, Tsuge H, Kuroko C, et al. Enhancement of cellular accumulation of cyclosporin A by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multi-drug resistance. J Natl Cancer Inst 1993; 85: 311–6PubMedCrossRefGoogle Scholar
  21. 21.
    Naito M, Tsuge H, Kuroko C, et al. Enhancement of reversing effect of cyclosporin Aon vincristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16. Jpn J Cancer Res 1993; 84: 489–92PubMedCrossRefGoogle Scholar
  22. 22.
    Broxterman HJ, Kuiper CM, Schuurhuis GJ, et al. Increase of daunorubicin and vincristine accumulation in multidrug resistant human ovarian carcinoma cells by a monoclonal antibody reacting with P-glycoprotein. Biochem Pharmacol 1988; 37: 2389–93PubMedCrossRefGoogle Scholar
  23. 23.
    Pearson JW, Fogler WE, Volker K, et al. Reversal of drug resistance in a human colon cancer xenograft expressing MDR1 complementary DNA by in vivo administration of MRK 16 monoclonal antibody. J Natl Cancer Inst 1991; 83: 1386–91PubMedCrossRefGoogle Scholar
  24. 24.
    Rittmann-Grauer LS, Yong MA, Sanders V, et al. Reversal of vinca alkaloid resistance by anti-P-glycoprotein monoclonal antibody HYB-241 in a human tumor xenograft. Cancer Res 1992; 52: 1810–6PubMedGoogle Scholar
  25. 25.
    Kulkarni SS, Wang Z, Spitzer G, et al. Elimination of drug resistant myeloma tumor cells lines by monoclonal anti-P-glycoprotein antibody and rabbit complement. Blood 1989; 74: 2244–51PubMedGoogle Scholar
  26. 26.
    FitzGerald DJ, Willingham MC, Cardarelli CO, et al. A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc Natl Acad Sci USA 1987; 84: 4288–92PubMedCrossRefGoogle Scholar
  27. 27.
    Dinota A, Tazzari PL, Michieli M, et al. In vitro bone marrow purging of multidrug-resistant cells with a mouse monoclonal antibody directed against Mr 170,000 glycoprotein and a saporin-conjugated anti-mouse antibody. Cancer Res 1990; 50: 4291–4PubMedGoogle Scholar
  28. 28.
    Padmanabhan R, Tsuruo T, Kane SE, et al. Magnetic-affinity cell sorting of human multidrug-resistant cells. J Natl Cancer Inst 1991; 83: 565–9PubMedCrossRefGoogle Scholar
  29. 29.
    Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735–8PubMedCrossRefGoogle Scholar
  30. 30.
    Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 695–8PubMedCrossRefGoogle Scholar
  31. 31.
    Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 1991; 66: 85–94PubMedCrossRefGoogle Scholar
  32. 32.
    Tatsuta T, Naito M, Oh-hara T, et al. Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 1992; 267: 20383–91PubMedGoogle Scholar
  33. 33.
    Shirai A, Naito M, Tatsuta T, et al. Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein. Biochim Biophys Acta 1994; 1222: 400–4PubMedCrossRefGoogle Scholar
  34. 34.
    Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr 1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502PubMedCrossRefGoogle Scholar
  35. 35.
    Hamada H, Miura K, Ariyoshi K, et al. Mouse-human chimeric antibody against the multidrug transporter P-glycoprotein. Cancer Res 1990; 50: 3167–71PubMedGoogle Scholar
  36. 36.
    Ariyoshi K, Hamada H, Naito M, et al. Mouse-human chimeric antibody MH171 against the multidrug transporter P-glycoprotein. Jpn J Cancer Res 1992; 83: 515–21PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Mikihiko Naito
    • 1
  • Takashi Tsuruo
    • 1
    • 2
  1. 1.Institute of Molecular and Cellular BiosciencesThe University of TokyoBunkyo-ku, TokyoJapan
  2. 2.Cancer Chemotherapy CenterJapanese Foundation for Cancer ResearchTokyoJapan

Personalised recommendations