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Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion

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Abstract

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

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Reference

  1. Lienard D, Lejeune FJ, Ewalenko P (1992) In transit metastases of malignant melanoma treated by high dose rTNF alpha in combination with interferon-gamma and melphalan in isolation perfusion. World J Surg 16:234–240

    Article  PubMed  CAS  Google Scholar 

  2. Eggermont AM, Schraffordt KH, Lienard D, Kroon BB, van Geel AN, Hoekstra HJ, Lejeune FJ (1996) Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 14:2653–2665

    PubMed  CAS  Google Scholar 

  3. Eggermont AM, Schraffordt KH, Klausner JM, Kroon BB, Schlag PM, Lienard D, van Geel AN, Hoekstra HJ, Meller I, Nieweg OE, Kettelhack C, Ben-Ari G, Pector JC, Lejeune FJ (1996) Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 224:756–764

    Article  PubMed  CAS  Google Scholar 

  4. Olieman AF, Lienard D, Eggermont AM, Kroon BB, Lejeune FJ, Hoekstra HJ, Koops HS (1999) Hyperthermic isolated limb perfusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities: a multicenter study. Arch Surg 134:303–307

    Article  PubMed  CAS  Google Scholar 

  5. Eggermont AM, de Wilt JH, ten Hagen TL (2003) Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol 4:429–437

    Article  PubMed  Google Scholar 

  6. de Wilt JH, ten Hagen TL, de Boeck G, van Tiel ST, de Bruijn EA, Eggermont AM (2000) Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 82:1000–1003

    Article  PubMed  Google Scholar 

  7. de Wilt JH, Manusama ER, van Tiel ST, van IJken MG, ten Hagen TL, Eggermont AM (1999). Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats. Br J Cancer 80:161–166

    Article  PubMed  Google Scholar 

  8. van der Veen AH, de Wilt JH, Eggermont AM, van Tiel ST, Seynhaeve AL, ten Hagen TL (2000) TNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects. Br J Cancer 82:973–980

    Article  PubMed  Google Scholar 

  9. van Etten B, de Vries MR, van IJken MG, Lans TE, Guetens G, Ambagtsheer G, van Tiel ST, de Boeck G, de Bruijn EA, Eggermont AM, ten Hagen TL (2003) Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-alpha-based isolated hepatic perfusion. Br J Cancer 88:314–319

    Article  PubMed  CAS  Google Scholar 

  10. van Ijken MGA, van Etten B, de Wilt JHW, van Tiel ST, ten Hagen TLM, Eggermont AMM (2000) TNF-alpha augments anti-tumor efficacy in isolated hepatic perfusion with melphalan in a rat sarcoma model. J Immunother 23:449–455

    Article  PubMed  Google Scholar 

  11. Garrison JC (1990) Histamine, bradykinin, 5-hydroxytryptamine and their antagonists. In: Gilman AG, Rall TW, Nie AS, Taylor P (eds) The pharmacological basis of therapeutics. 8th edn, Pergamon, Elmsford, pp 575–599

    Google Scholar 

  12. Brunstein F, Hoving S, Seynhaeve AL, van Tiel ST, Guetens G, de Bruijn EA, Eggermont AM, ten Hagen TL (2004) Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion—preclinical studies. J Natl Cancer Inst 96:1603–1610

    PubMed  CAS  Google Scholar 

  13. Epstein AL, Mizokami MM, Li J, Hu P, Khawli LA (2003) Identification of a protein fragment of interleukin 2 responsible for vasopermeability. J Natl Cancer Inst 95:741–749

    PubMed  CAS  Google Scholar 

  14. Siegel JP, Puri RK (1991) Interleukin-2 toxicity. J Clin Oncol 9(4):694–704

    PubMed  CAS  Google Scholar 

  15. Hoving S, Brunstein F, aan de Wiel Ambagtsheer G, van Tiel ST, de Boeck G, de Bruijn EA, Eggermont AM, ten Hagen TL (2005) Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats. Cancer Res 65:4300–4308

    Article  PubMed  CAS  Google Scholar 

  16. Winkelhake JL, Gauny SS (1990) Human recombinant interleukin-2 as an experimental therapeutic. Pharmacol Rev 42(1):1–28

    PubMed  CAS  Google Scholar 

  17. Naredi P (2002) Histamine as an adjunct to immunotherapy. Semin Oncol 29:31–34

    Article  PubMed  CAS  Google Scholar 

  18. Hellstrand K (2002) Histamine in cancer immunotherapy: a preclinical background. Semin Oncol 29:35–40

    Article  PubMed  CAS  Google Scholar 

  19. Kort WJ, Zondervan PE, Hulsman LO, Weijma IM, Westbroek DL (1984) Incidence of spontaneous tumors in a group of retired breeder female brown Norway rats. J Natl Cancer Inst 72:709–713

    PubMed  CAS  Google Scholar 

  20. de Boeck G, van Cauwenberghe K, Eggermont AM, van Oosterom AT, de Bruijn EA (1997) Determination of melphalan and hydrolysis products in body fluids by GC–MS. J High Res Chromatogr 20:697–700

    Article  Google Scholar 

  21. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112

    Article  PubMed  CAS  Google Scholar 

  22. Jaffe EA, Nachman RL, Becker CG, Minick R (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52:2745–2756

    Article  PubMed  CAS  Google Scholar 

  23. Asea A, Hermodsson S, Hellstrand K (1996) Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol 43:9–15

    Article  PubMed  CAS  Google Scholar 

  24. Azuma Y, Shinohara M, Wang PL, Hidaka A, Ohura K (2001) Histamine inhibits chemotaxis, phagocytosis, superoxide anion production, and the production of TNFalpha and IL-12 by macrophages via H2-receptors. Int Immunopharmacol 1:1867–1875

    Article  PubMed  CAS  Google Scholar 

  25. Hayley S, Kelly O, Anisman H (2002) Murine tumor necrosis factor-alpha sensitizes plasma corticosterone activity and the manifestation of shock: modulation by histamine. J Neuroimmunol 131:60–69

    Article  PubMed  CAS  Google Scholar 

  26. Wang J, Al-Lamki RS, Zhang H, Kirkiles-Smith N, Gaeta ML, Thiru S, Pober JS, Bradley JR (2005) Histamine antagonizes tumor necrosis factor (TNF) signaling by stimulating TNF receptor shedding from the cell surface and Golgi storage pool. J Biol Chem 278:21751–21760

    Article  CAS  Google Scholar 

  27. Oosterling SJ, van der Bij GJ, Meijer GA, Tuk CW, van Garderen E, van Rooijen N, Meijer S, van der Sijp JRM, Beelen RHJ, van Egmond M (2005) Macrophages direct tumour histology and clinical outcome in a colon cancer model. J Pathol 207:147–155

    Article  PubMed  Google Scholar 

  28. Klimp AH, de Vries EGE, Scherphof GL, Daemen T (2002) A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol 44:143–161

    Article  CAS  Google Scholar 

  29. Agarwala SS, Sabbagh MH (2001) Histamine dihydrochloride: inhibiting oxidants and synergising IL-2 mediated immune activation in the tumour microenvironment. Expert Opin Biol Ther 1(5):869–879

    Article  PubMed  CAS  Google Scholar 

  30. Epstein AL, Mizokami MM, Li J, Hu P, Khawli LA (2003) Identification of a protein fragment of Interleukin-2 responsible for vasopermeability. J Natl Cancer Inst 95:741–749

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Maxim Pharmaceuticals Inc., San Diego, CA for kindly providing histamine dihydrochloride and Chiron, Amsterdam, the Netherlands for kindly providing IL-2 for this study.

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Authors and Affiliations

  1. Department of Surgical Oncology, Erasmus MC, Laboratory of Experimental Surgical Oncology, Daniel den Hoed Cancer Centre, Room Ee 0175, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands

    Flavia Brunstein, Saske Hoving, Gisela aan de Wiel-Ambagtsheer, Alexander M. M. Eggermont & Timo L. M. ten Hagen

  2. Department of Experimental Oncology, University of Leuven, Leuven, Belgium

    Ernst A. de Bruijn & Gunther Guetens

  3. Lab Experimental Oncology (LEO), University of Leuven, Leuven, Belgium

    Gunther Guetens

  4. Departments of Chemistry and Oncology, University of Antwerp, Antwerp, Belgium

    Gunther Guetens

Authors
  1. Flavia Brunstein
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  2. Saske Hoving
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  3. Gisela aan de Wiel-Ambagtsheer
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  4. Ernst A. de Bruijn
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  5. Gunther Guetens
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  6. Alexander M. M. Eggermont
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  7. Timo L. M. ten Hagen
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Correspondence to Flavia Brunstein.

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Brunstein, F., Hoving, S., aan de Wiel-Ambagtsheer, G. et al. Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion. Cancer Immunol Immunother 56, 573–580 (2007). https://doi.org/10.1007/s00262-006-0206-y

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  • DOI: https://doi.org/10.1007/s00262-006-0206-y

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