Skip to main content
SpringerLink
Log in

Drug resistance in rat colon cancer cell lines is associated with minor changes in susceptibility to cytotoxic cells

  • Original Articles
  • Interleukin-2, Adherent Lymphokine-Activated Killer, Natural Killer, Multidrug Resistance, Cisplatin Resistance
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The development of resistance to anticancer drugs urges the search for different treatment modalities. Several investigators have reported the concomitant development of drug resistance and resistance to natural killer (NK), lymphokine-activated killer (LAK) or monocyte/macrophage cell lysis, while others described unchanged or even increased susceptibility. We investigated this subject in the rat colon carcinoma cell line, CC531-PAR, which is intrinsically multidrug-resistant (MDR), and in three sublines derived from this parental cell line: a cell line with an increased MDR phenotype (CC531-COL), a revertant line from CC531-COL (CC531-REV), which demonstrates enhanced sensitivity to anticancer drugs of the MDR phenotype, and an independently developed cisplatin-resistant line (CC531-CIS). In a 4-h51Cr-release assay we found no difference in susceptibility to NK cell lysis. No significant differences in lysability by adherent LAK (aLAK) cells were observed in a 4-h assay. In a prolonged 20-h51Cr-release assay an enhanced sensitivity to aLAK-cell-mediated lysis was observed in the revertant, P-glycoprotein-negative cell line and in the cisplatin-resistant cell line (CC531-CIS). None of the cell lines was completely resistant to lysis by aLAK cells. Therefore, a role for immunotherapy in the treatment of drug-resistant tumors remains a realistic option.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ades EW, Bosse D, Pruckler J (1990) Potentiation of human natural killer cell activity by recombinant interleukin-2 towards multidrugresistant human epidermoid carcinoma. Pathobiology 58: 84

    PubMed  Google Scholar 

  2. Andrews PA, Howell SB (1990) Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells 2: 35

    PubMed  Google Scholar 

  3. Allavena P, Grandi M, D'Incalci M, Geri O, Giuliani FC, Mantovani A (1987) Human tumor cell lines with pleiotropic drug resistance are efficiently killed by interleukin-2 activated killer cells and by activated monocytes. Int J Cancer 40: 104

    PubMed  Google Scholar 

  4. Allavena P, Damia G, Colombo T, Maggioni D, D'Incalci M, Mantovani A (1989) Lymphokine-activated killer (LAK) and monocytemediated cytotoxicity on tumor cell lines resistant to antitumor agents. Cell Immunol 120: 250

    PubMed  Google Scholar 

  5. Allavena P, Peccatori F, Maggioni D, Pirovano P, Mantovani A (1989) Killing of tumor cells with pleiotropic drug resistance by OK432-activated effector cells. Immunopharmacol Immunotoxicol 11: 257

    PubMed  Google Scholar 

  6. Benoist H, Madoulet C, Jardillier J-C, Desplaces A (1985) Adriamycin induced resistance of sensitive K 562 cells to natural killer lymphocyte attack. Cancer Immunol Immunother 20: 122

    PubMed  Google Scholar 

  7. Bolhuis RL, Sturm E, Braakman E (1991) T cell targeting in cancer therapy. Cancer Immunol Immunother 34: 1

    PubMed  Google Scholar 

  8. Eggermont AMM, Marquet RL, De Bruin RWF, Jeekel J (1986) Effects of the interferon-inducer ABPP on colon cancer in rats: importance of tumor load and tumor site. Cancer Immunol Immunother 22: 217

    PubMed  Google Scholar 

  9. FitzGerald DJ, Willingham MC, Cardarelli CO, Hamada H, Tsuruo T, Gottesman MM, Pastan I (1987) A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc Natl Acad Sci USA 84: 4288

    PubMed  Google Scholar 

  10. Gambacorti-Passerini C, Rivoltini L, Supino R, Mariani M, Parmiani G (1988) Differential lysis of melanoma clones by autologous recombinant interleukin 2-activated lymphocytes. Relationship with spontaneous resistance to doxorubicin (Dx). Int J Cancer 42: 544

    PubMed  Google Scholar 

  11. Gambacorti-Passerini C, Rivoltini L, Supino R, Rodolfo M, Radrizzani M, Fossati G, Parmiani G (1988) Susceptibility of chemoresistant murine and human tumor cells to lysis by interleukin 2-activated lymphocytes. Cancer Res 48: 2372

    PubMed  Google Scholar 

  12. Gautam SC, Chikkala NF, Lewis I, Grabowski DR, Finke JH, Ganapathi R (1992) Therapeutic efficacy of interleukin-2 activated killer cells against Adriamycin resistant mouse B16-BL6 melanoma. Anticancer Res 12: 921

    PubMed  Google Scholar 

  13. Gheuens EEO, Van Bockstaele DR, Van der Keur M, Tanke HJ, Van Oosterom AT, De Bruijn EA (1991) Flow cytometric double labelling technique for screening of multidrug resistance. Cytometry 12: 636

    PubMed  Google Scholar 

  14. Gheuens EEO, Van der Heyden SAM, Elst HJ, Eggermont AMM, Van Oosterom AT, De Bruijn EA (1993) Multidrug resistance in rat colon carcinoma cell lines CC531, CC531mdr+ and CC531rev, Jpn J Cancer Res (in press)

  15. Goldstein LJ, Galski H, Fojo A, Willingham M, Lai S-L, Gazdar A, Pirker R, Green A, Crist W, Brodeut GM, Lieber M, Cossman J, Gottesman MM, Pastan I (1989) Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81: 116

    PubMed  Google Scholar 

  16. Harker WG, Tom C, McGregor JR, Slade L, Samlowski WE (1990) Human tumor cell line resistance to chemotherapeutic agents does not predict resistance to natural killer or lymphokine-activated killer cell-mediated cytolysis. Cancer Res 50: 5931

    PubMed  Google Scholar 

  17. Julius MH, Simpson E, Herzenberg LA (1973) A rapid method for the isolation of functional thymus derived murine lymphocytes. Eur J Immunol 3: 645

    PubMed  Google Scholar 

  18. Kimmig A, Gekeler V, Neumann M, Frese G, Handgretinger R, Kardos G, Diddens H, Niethammer D (1990) Susceptibility of multidrug-resistant human leukemia cell lines to human interleukin 2-activated killer cells. Cancer Res 50: 6793

    PubMed  Google Scholar 

  19. Los G, Nagel JD, McVie JG (1990) Anti-tumor effect of cisplatin, carboplatin, mitoxantrone, and doxorubicin on peritoneal tumor growth after intraperitoneal and intravenous chemotherapy: a comparative study. Sel Cancer Ther 6: 73

    PubMed  Google Scholar 

  20. Marquet RL, Westbroek DL, Jeekel J (1984) Interferon treatment of a transplantable rat colon adenocarcinoma: importance of tumor site. Int J Cancer 33: 689

    PubMed  Google Scholar 

  21. Marquet RL, IJzermans JNM, De Bruin RWF, Fiers W, Jeekel J (1987) Antitumor activity of recombinant mouse tumor necrosis factor (TNF) on colon cancer in rats is promoted by recombinant rat interferon gamma; toxicity is reduced by indomethacin. Int J Cancer 40: 550

    PubMed  Google Scholar 

  22. Mickisch GH, Pai LH, Gottesman MM, Pastan I (1992) Monoclonal antibody MRK16 reverses the multidrug resistance of multidrug-resistant transgenic mice. Cancer Res 52: 4427

    PubMed  Google Scholar 

  23. Mickisch GH, Pai LH, Siegmund M, Campain J, Gottesman MM, Pastan I (1993)Pseudomonas exotoxin conjugated to monoclonal antibody MRK16 specifically kills multidrug resistant cells in cultured renal carcinomas and in MDR-transgenic mice. J Urol 149: 174

    PubMed  Google Scholar 

  24. Mizutani Y, Banovida B, Nio Y, Yoshida O (1993) Enhanced susceptibility ofcis-diamminedichloroplatinum-treated K562 cells to lysis by peripheral blood lymphocytes and lymphokine activated killer cells. Cancer 71: 1313

    PubMed  Google Scholar 

  25. Ohtsu A, Sasaki Y, Tamura T, Fujiwara Y, Ohe Y, Minato K, Nakagawa K, Bungo M, Saijo N (1989) Inhibition of colony formation of drug-resistant human tumor cell lines by combinations of interleukin-2-activated killer cells and antitumor drugs. Jpn J Cancer Res 80: 265

    PubMed  Google Scholar 

  26. Pastan I, Gottesman M (1987) Multiple-drug resistance in human cancer. N Engl J Med 316: 1388

    PubMed  Google Scholar 

  27. Prehn RT, Main JW (1957) Immunity to methylcholanthrene induced sarcomas. J Natl Cancer Inst 18: 769

    PubMed  Google Scholar 

  28. Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS (1981) Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol 1: 51

    PubMed  Google Scholar 

  29. Rivoltini L, Gambacorti-Passerini C, Supino R, Parmiani G (1989) Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance. Int J Cancer 43: 880

    PubMed  Google Scholar 

  30. Rivoltini L, Colombo MP, Supino R, Ballinari D, Tsuruo T, Parmiani G (1990) Modulation of multidrug resistance by verapamil ormdrl anti-sense oligodeoxynucleotide does not change the high susceptibility to lymphokine-activated killers inmdr-resistant human carcinoma (LoVo) line. Int J Cancer 46: 727

    PubMed  Google Scholar 

  31. Rivoltini L, Cattoretti G, Arienti F, Mastroianni A, Melani C, Colombo MP, Parmiani G (1991) The high lysability by LAK cells of colon-carcinoma cells resistant to doxorubicin is associated with a high expression of ICAM-1, LFA-3, NCA and a less-differentiated phenotype. Int J Cancer 47: 746

    PubMed  Google Scholar 

  32. Rosenberg SA (1991) Immunotherapy and gene therapy of cancer. Cancer Res 51: 5074s

  33. Safrit JT, Bonavida B (1992) Hierarchy of in vitro sensitivity and resistance of tumor cells to cytotoxic effector cells, cytokines, drugs and toxins. (1992) Cancer Immunol Immunother 34: 321

    PubMed  Google Scholar 

  34. Savas B, Cole SPC, Akoglu TF, Pross HF (1992) P-glycoprotein-mediated multidrug resistance and cytotoxic effector cells. Nat Immun 11: 177

    PubMed  Google Scholar 

  35. Scheper RJ, Dalton WS, Grogan TM, Schlosser A, Bellamy WT, Taylor CW, Scuderi P, Spier C (1991) Altered expression of P-glycoprotein and cellular adhesion molecules on human multi-drug-resistant tumor cells does not affect their susceptibility to NK- and LAK-mediated cytotoxicity. Int J Cancer 48: 562

    PubMed  Google Scholar 

  36. Scheringa M, IJzermans JNM, Jeekel J, Marquet RL (1990) The antitumour activity of the interferon inducer bropirimine is partially mediated by endogenous tumour necrosis factor-α. Cancer Immunol Immunother 32: 251

    PubMed  Google Scholar 

  37. Treichel RS, Olken S (1992) The relationship between multi-drug resistance and resistance to natural-killer-cell and lymphokine-activated killer-cell lysis in human leukemic cell lines. Int J Cancer 50: 305

    PubMed  Google Scholar 

  38. Van de Vric W, Gheuens EEO, Durante NMC, De Bruijn EA, Marquet RL, Van Oosterom AT, Eggermont AMM (1993) In vitro and in vivo chemosensitizing effect of cyclosporin-A on an intrinsic multidrug resistant rat colon tumour. J Cancer Res Clin Oncol 119: 609

    PubMed  Google Scholar 

  39. Van Dijk J, Tsuruo T, Segal DM, Bolhuis RLH, Colognola R, Van de Griend RJ, Fleuren GJ, Warnaar SO (1989) Bispecific antibodies reactive with the multidrug-resistance-related glycoprotein and CD3 induce lysis of multidrug-resistant tumor cells. Int J Cancer 44: 738

    PubMed  Google Scholar 

  40. Vujanovic NL, Herberman RB, Maghazachi AA, Hiserodt JC (1988) Lymphokine-activated killer cells in rats III. A simple method for the purification of large granular lymphocytes and their rapid expansion and conversion into lymphokine-activated killer cells. J Exp Med 167: 15

    PubMed  Google Scholar 

  41. Wood WJ, Lotzovà E (1989) Adriamycin-induced resistance to natural killer (NK)-mediated cytotoxicity. Cancer 64: 396

    PubMed  Google Scholar 

  42. Woods G, Lund LA, Naik M, Ling V, Ochi A (1988) Resistance of multidrug-resistant lines to natural killer-like cell-mediated cytotoxicity. FASEB J 2: 2791

    PubMed  Google Scholar 

  43. Yanovich S, Hall RE, Weinert C (1986) Resistance to natural killer cell-mediated cytolysis by a pleiotropic drug-resistant human erythroleukemia (K562-R) cell line. Cancer Res 46: 4511

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Rotterdam Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands

    Wim Van de Vrie & Alexander M. M. Eggermont

  2. Laboratory for Experimental Surgery, Erasmus University, PO Box 1738, 3000 DR, Rotterdam, The Netherlands

    Wim Van de Vrie, Amelie M. Bijma & Richard L. Marquet

  3. Laboratory of Cancer Research and Clinical Oncology, Antwerp University, B-2610, Wilrijk, Belgium

    Sylke A. M. Van der Heyden, Eric E. O. Gheuens, Ernst A. De Bruijn & Allan T. Van Oosterom

Authors
  1. Wim Van de Vrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylke A. M. Van der Heyden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric E. O. Gheuens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amelie M. Bijma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ernst A. De Bruijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard L. Marquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Allan T. Van Oosterom
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexander M. M. Eggermont
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van de Vrie, W., Van der Heyden, S.A.M., Gheuens, E.E.O. et al. Drug resistance in rat colon cancer cell lines is associated with minor changes in susceptibility to cytotoxic cells. Cancer Immunol Immunother 37, 337–342 (1993). https://doi.org/10.1007/BF01518457

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01518457

Key words

Search

Navigation