Skip to main content
SpringerLink
Log in

Hierarchy of in vitro sensitivity and resistance of tumor cells to cytotoxic effector cells, cytokines, drugs and toxins

  • Original articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

Drug resistance of tumor cells has led to the development of other therapeutic modalities including biological response modifiers, lymphokine-activated killer cells (LAK), and cytokines alone and in combination. The premise of these alternative modalities is that drug resistance can be overcome by other cytotoxic agents or cytotoxic effector cells. However, the relationship between tumor cell sensitivity to these different agents and the cytotoxicity caused by drugs is not known or well understood. Thus, understanding the relationship between these different systems of tumor cell cytotoxicity is essential for optimal therapeutic intervention. To this end, we compared the tumor cell cytotoxicity mediated by recombinant tumor necrosis factor (rTNF), cytotoxic effector cells (natural killer cells, monocytes, LAK cells), chemotherapeutic drugs, and microbial toxins. Human tumor cell lines sensitive and resistant to rTNF or drugs were used to evaluate the effectiveness of the other cytotoxic modalities. Sensitivity was considered as tumor cell cytotoxicity above 15% while resistance refers to that below 10%. Cell lines tested consisted of several histological types such as brain, lung, colon and ovarian tumors. In our experiments, cell lines made resistant to rTNF by coculture were also relatively resistant to unactivated monocytes and their supernatants. These lines were sensitive to all other methods tested including activated monocytes, natural killer and LAK cells, drugs, and toxins. The tumor lines naturally resistant to rTNF were found to have various degrees of sensitivity and resistance to these other systems. Upon the analysis of our data, a pattern emerged that suggested a hierarchy of sensitivity and resistance of the tumor cells to the cytotoxic mechanisms explored. From a majority of cell lines resistant to rTNF to a minority of lines resistant to LAK, we found an interesting gradation of sensitivity and/or resistance to the other cytotoxic modalities employed. The hypothesis of an underlying common mechanism of action within these systems is discussed.

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. Barton RL, Briggs SL, Koppel GA (1991) Monoclonal antibody drug targeting. Drugs News and Perspectives 4: 73–88

    Google Scholar 

  2. Bonavida B, Wright SC (1987) Multistage model of NK cell mediated cytotoxicity involving NKCF as soluable cytotoxic mediators. Adv Can Res 49: 169–187

    Google Scholar 

  3. Bonavida B, Tsuchitani T, Safrit J, Zighelboim J (1989) Mechanism of target cell lysis by cytotoxic cells, factors, and drugs. In: Tapiero H, Robert J, and Lampidis TJ (eds) Anti cancer drugs. Colloque INSERM. Libbey Eurotext, London, pp 113–128

    Google Scholar 

  4. Brunda MJ, Davatelis V (1985) Augmentation of NK cell activity by recombinant IL-2 and recombinant IFNs. In: Herberman R (ed) Mechanisms of cytotoxicity by NK cells. Academic Press, New York, pp 397–407

    Google Scholar 

  5. Capel ID, Leach D, Dorrel HM (1983) Vitamin E retards the lipoperoxidation resulting from anticancer drug administration. Anticancer Res 3: 59–62

    PubMed  Google Scholar 

  6. Carson DA, Seto S, Wasson DB, Carrera CJ (1986) DNA strand breaks, NAD metabolism, and programmed cell death. Exp Cell Res 164: 273–281

    PubMed  Google Scholar 

  7. Carswell EA, Old LJ, Kassel R, Green S, Fiore N, Williams B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72: 3666–3670

    PubMed  Google Scholar 

  8. Chang MP, Bramhall J, Graves S, Bonavida B, Wisnieski B (1989) Internucleosomal DNA cleavage precedes diptheria toxin-induced cytolysis. J Biol Chem 264: 15 261–15 267

    Google Scholar 

  9. Decker T, Lohmann-Matthes M, Gifford GE (1987) Cell associated tumor necrosis factor (TNF) as a killing mechanism of activated cytotoxic macrophages. J Immunol 138: 957–962

    PubMed  Google Scholar 

  10. Dennert G, Podack E (1983) Cytolysis by H-2 specific T killer cells. J Exp Med 157: 1483–1493

    PubMed  Google Scholar 

  11. Duke RC, Cohen J, Chervenak R (1986) Differences in target cell DNA fragmentation induced by mouse CTL and NK cells. J Immunol 137: 1442–1448

    PubMed  Google Scholar 

  12. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine activated killer cell phenomenon. Lysis of NK resistant fresh and solid tumor cells by IL-2 activated autologous human PBL. J Exp Med 155: 1823–1841

    PubMed  Google Scholar 

  13. Hiserodt JC, Chambers WH (1985) Role of soluble cytotoxic factors in lymphkine activated killer cell mediated cytotoxicity. Ann NY Acad Sci 532: 395–404

    Google Scholar 

  14. Ichinose Y, Bakouche O, Tsao JY, Fidler IJ (1988) Tumor necrosis factor and IL-1 associated with plasma membranes of activated human monocytes lyse monokine-sensitive but not monokine-resistant tumor cells whereas viable activated monocytes lyse both. J Immunol 141: 512–518

    PubMed  Google Scholar 

  15. Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988) A novel form of TNF/Cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53: 45–53

    PubMed  Google Scholar 

  16. Lichtenstein A, Berek JS, Bast RC, Spina C, Hacker N, Knapp RC, Zighelboim J (1984) Activation of peritoneal lymphocyte cytotoxicity in patients with ovarian cancer by intraperitoneal treatment withCornebacterium parvum. J Biol Response Modif 3: 371–376

    Google Scholar 

  17. Matthews N, Neale ML, Jackson SK, Stark JM (1987) Tumor cell killing by tumor necrosis factor: inhibition by anaerobic conditions, free radical scavengers, and inhibitors of arachitanate metabolism. Immunology 62: 153–155

    PubMed  Google Scholar 

  18. Nathan CF, Silverstein SC, Bruckner LH, Cohn ZA (1979) Extracellular cytolysis by activated macrophages and granulocytes: II. Hydrogen peroxides as mediators of cytotoxicity. J Exp Med 149: 100–113

    PubMed  Google Scholar 

  19. Paya CV, Kenmotsu N, Schoon RA, Liebson PJ (1988) Tumor necrosis factor and lymphotoxin secretion by human NK cells leads to antiviral cytotoxicity. J Immunol 141: 1989–1995

    PubMed  Google Scholar 

  20. Pennica DGE, Haflick JS, Sesburg PH, Denynck R, Palladino MA, Kohr WJ, Aggarwaal BB, Goeddel DV (1984) Human tumor necrosis factor: precursor, structure, expression and homology to lymphotoxin. Nature 312: 724–728

    PubMed  Google Scholar 

  21. Philip R, Epstein LB (1986) Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, γ-interferon and interleukin-1. Nature 323: 86–89

    PubMed  Google Scholar 

  22. Rosenberg SA, Lotze MJ (1986) Cancer immunotherapy using IL-2 and IL-2 activated lymphocytes. Annu Rev Immunol 4: 681–709

    PubMed  Google Scholar 

  23. Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor infiltrating lymphocytes. Science 233: 1318–1320

    PubMed  Google Scholar 

  24. Salmon SE, Soehnlen B, Dalton WS, Meltzer P, Scuderi P (1989) Effects of tumor necrosis factor on sensitive and multidrug resistant human leukemia and myeloma cell lines. Blood 74: 1723–1727

    PubMed  Google Scholar 

  25. Schmid DS, Honung R, McGrath KM, Paul N, Ruddle NH (1987) Target cell DNA fragmentation is mediated by lymphotoxin and TNF. Lymphokine Res 6: 195–202

    PubMed  Google Scholar 

  26. Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E, Kufe DW (1988) Recombinant human tumor necrosis factor administered as a five day continuous infusion in cancer patients: phase 1 toxicity and effects on lipid metabolism. J Clin Oncol 6: 344–350

    PubMed  Google Scholar 

  27. Suzukate K, Vistica BP, Vistica DT (1982) Reduction in glutathione content of L-PAM-resistant L1210 cells confers drug sensitivity. Biochem Pharmacol 31: 121–124

    PubMed  Google Scholar 

  28. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickle J, Vanarsdell JN, Yamamoto R, Mark DF (1985) Molecular cloning of the complementary DNA for tumor necrosis factor. Science 228: 149–154

    PubMed  Google Scholar 

  29. Wong GHW, Elwell JH, Oberley LW, Goeddel DV (1989) Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58: 923–931

    PubMed  Google Scholar 

  30. Wright SC, Bonavida B (1987) Studies on the mechanism of natural killer cell mediated cytotoxicity: IX. Functional comparison of human natural killer cytotoxic factors with recombinant lymphotoxin and tumor necrosis factor. J Immunol 138: 1791–1797

    PubMed  Google Scholar 

  31. Yoshie O, Tada K, Ishida N (1986) Binding and crosslinking of 125I-labelled recombinant human tumor necrosis factor to cell surface receptors. J Biochem (Tokyo) 100: 531–591

    Google Scholar 

  32. Zighelboim J, Nio Y, Berek JS, Bonavida B (1988) Immunologic control of ovarian cancer. Nat Immun Cell Growth Regul 7: 216–225

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, UCLA School of Medicine and the Jonsson Comprehensive Cancer Center, University of California, 90 024, Los Angeles, CA, USA

    Jeffrey T. Safrit & Benjamin Bonavida

Authors
  1. Jeffrey T. Safrit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin Bonavida
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by grant CA43 121 from the Department of Health and Human services, NIH, and NRSA clinical and fundamental immunology training grant A107 126, NIH (J. S.), and in part by a grant from the Concern Foundation, Los Angeles and a gift from the Boiron Foundation

Rights and permissions

Reprints and permissions

About this article

Cite this article

Safrit, J.T., Bonavida, B. Hierarchy of in vitro sensitivity and resistance of tumor cells to cytotoxic effector cells, cytokines, drugs and toxins. Cancer Immunol Immunother 34, 321–328 (1992). https://doi.org/10.1007/BF01741553

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01741553

Key words

Search

Navigation