Summary
Isolated perfusion of the extremities with high-dose tumour necrosis factor α (TNF-α) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-α and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 μg TNF-α. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-α and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-α alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-α, the minimal threshold concentration of TNF-α to exert its anti-tumour effects was not reached. The applicability of TNF-α in isolated kidney perfusion for human tumours seems, therefore, questionable.
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References
Affres, H., Perez, J., Hagege, J., Fouqueray, B., Kornprobst, M., Ardaillou, R. & Baud, L. (1991). Desferrioxamine regulates tumor necrosis factor release in mesangial cells. Kidney Int 39: 822–830.
Asbach, H. W. & Bersch, W. (1980). The effect of in situ isolated perfusion of experimental renal tumors with cytotoxic agents in high concentration. Urol Int 35: 112–124.
Asher, A., Mule, J. J., Reichert, C. M., Shiloni, E. & Rosenberg, S. A. (1987). Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo. J Immunol 138: 963–974.
Baud, L. & Ardaillou, R. (1995). Tumor necrosis factor in renal injury. Miner Electrolyte Metab 21: 336–341.
Borel Rinkes, I. H. M., de Vries, M. R., Jonker, A. M., Swaak, T. J. G., Hack, C. E., Nooijen, PTGA, Wiggers, T. & Eggermont, A. M. M. (1997). Isolated hepatic perfusion in the pig with TNF-α with and without melphalan. Br J Cancer 75: 1447–1453.
Brouckaert, P. G. G., Leroux-Rouls, G. G., Guisez, Y., Tavernier, J. & Fiers, W. (1986). In vivo anti tumor activity of recombinant human and murine TNF, alone and in combination with murine IFN-gamma on a syngeneic murine melanoma. Int J Cancer 38: 763–769.
Dealtry, G. B., Naylor, M. S., Fiers, W. & Balkwill, F. R. (1987). The effect of recombinant human tumor necrosis factor on growth and macromolecular synthesis of human epithelial cells. Exp Cell Res 170: 428–438.
Eggermont, A. M. M., Liénard, D., Schrafford Koops, H., Rosenkaimer, F. & Lejeune, F. J. (1993). Treatment of irresectable soft tissue sarcomas of the limbs by isolation perfusion with high dose TNFα in combination with interferon-gamma and melphalan. In Tumour Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance, Fiers W, Buurman WA (eds.), pp. 239–243, Karger: Basle
Eggermont, A. M. M., Schraffordt Koops, H., Liénard, D., Kroon, B. B. R., van Geel, A. N., Hoekstra, H. J. & Lejeune, F. J. (1996a). Isolated limb perfusion with high dose tumor necrosis factor-α in combination with Interferon-γ and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 14: 2653–2665.
Eggermont, A. M. M., Schraffordt Koops, H., Klausner, J., Kroon, B. B. R., Schlag, P. M., Liénard, D., Van Geel, A. N., Hoekstra, H. J., Meller, I., Nieweg, O. E., Kettelhack, C., Ben-Ari, G., Pector, J. C. & Lejeune, F. J. (1996b). Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced extremity sarcomas. The cumulative multicenter European experience. Ann Surg 224: 756–765.
Fajardo, L. F., Kwan, H. H., Kowalski, J., Prionas, S. D. & Allison, A. C. (1992). Dual role of tumor necrosis factor-α in angiogenesis. Am J Pathol 140: 539–544.
Feinberg, B., Kurzrock, R., Talpaz, M., Blick, M., Saks, S. & Gutterman, J. U. (1988). A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol 6: 1328–1334.
Fine, L. G. (1986). The biology of renal hypertrophy. Kidney Int 29: 619–634.
Fraker, D. L., Alexander, H. R. & Thom, A. K. (1994). Use of tumor necrosis factor in isolated hepatic perfusion. Circulatory Shock 44: 45–50.
Gaskill, H. V. (1988). Continuous infusion of tumor necrosis factor: mechanisms of toxicity in the rat. J Surg Res 44: 664–671.
Hieber, U. & Heim, M. E. (1994). Tumor necrosis factor for the treatment of malignancies. Oncology 51: 142–153.
Kahky, M. P., Daniel, C. O., Cruz, A. B. & Gaskill, H. V. (1990). Portal infusion of tumor necrosis factor increases mortality in rats. J Surg Res 49: 138–145.
Kallinowski, F., Schaeffer, C., Tyler, G. & Vaupel, P. (1989). In vivo targets of recombinant human tumor necrosis factor-α: blood flow, oxygen consumption and growth of isotransplanted art tumors. Br J Cancer 60: 555–560.
Kramer, S. M. & Carver, M. E. (1986). Serum-free in vivo bioassay for the detection of tumor necrosis factor. J Immunol Methods 93: 201–206.
Lejeune, F. J., Liénard, D., Leyvraz, S. & Mirimanoff, R. O. (1993). Regional therapy of melanoma. Eur J Cancer 29A: 606–612.
Liénard, D., Ewalenko, P., Delmotte, J. J., Renard, N. & Lejeune, F. J. (1992). High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 10: 52–60.
Liénard, D., Eggermont, A. M. M., Schraffordt Koops, H., Kroon, B. B., Rosenkaimer, F., Autier, P. & Lejeune, F. J. (1994). Isolated perfusion of the limb with high-dose tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study. Melanoma Res 4: 21–26.
Maessen, J. G., Greve, J. W. M. & Buurman, W. A. (1991). Increased sensitivity to endotoxemia by tissue necrosis. Surgery 109: 154–159.
Manusama, E. R., Marquet, R. L., Durante, N. M. C. & Eggermont, A. M. M. (1994). Ischemia promotes the antitumour effect of tumor necrosis factor-α (TNFα) in isolated limb perfusion in the rat. Reg Cancer Treat 7: 155–159.
Manusama, E. R., Nooijen, PTGA, Stavast, J., Durante, N. M. C., Marquet, R. L. & Eggermont, A. M. M. (1996a). Synergistic antitumor effect of recombinant human tumor necrosis factor α with melphalan in isolated limb perfusion in the rat. Br J Surg 83: 551–555.
Manusama, E. R., Stavast, J., Durante, N. M. C., Marquet, R. L. & Eggermont, A. M. M. (1996b). Isolated limb perfusion with TNFα and melphalan in a rat osteosarcoma model: a new anti-tumor approach. Eur J Surg Oncol 22: 152–157.
Marquet, R. L., Westbroek, D. L. & Jeekel, J. (1984). Interferon treatment of a transplantable rat colon adenocarcinoma: importance of tumor site. Int J Cancer 33: 689–692.
Nooijen, PTGA, Manusama, E. R., Schalkwijk, L., de Waal, R. M. W., Eggermont, A. M. M. & Ruiter, D. J. (1996). Histopathologic analysis of the synergistic antitumor effects of TNFα and melphalan in an isolated limb perfusion model of rat sarcoma. Br J Cancer 74: 1908–1915.
Pass, H. I., Mew, D. J. Y., Kranda, K. C., Temeck, B. K., Donington, J. S. & Rosenberg, S. A. (1996). Isolated lung perfusion with tumor necrosis factor for pulmonary metastases. Ann Thorac Surg 61: 1609–1617.
Pogrebniak, H. W., Witt, C. J., Terrill, R., Kranda, K., Travis, W. D., Rosenberg, S. A. & Pass, H. I. (1994). Isolated lung perfusion with tumor necrosis factor: a swine model in preparation of human trials. Ann Thorac Surg 57: 1477–1483.
Prehn, R. T. & Main, J. W. (1957). Immunity to methylcholantrene-induced sarcomas. J Natl Cancer Inst 18: 769–778.
Shimomura, K., Manda, T., Mukumoto, S., Kobayashi, K., Nakano, K. & Mori, J. (1988). Recombinant human tumor necrosis factor-α: thrombus formation is a cause of anti-tumour activity. Int J Cancer 41: 243–247.
Sidhu, R. S. & Bollon, A. P. (1993). Tumor necrosis factor activities and cancer therapy – a perspective. Pharm Ther 57: 79–128.
Skehan, P., Storeng, R., Scudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenney, S. & Boyd, M. R. (1990). New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82: 1107–1112.
Spriggs, D. R. & Yates, S. W. (1992). Cancer chemotherapy. Experience with TNF administration in humans. In Tumor Necrosis Factors: The Molecules and their Emerging Role in Medicine, Beutler B (ed.), pp. 383–406, Raven Press: New York
Spriggs, D. R., Sherman, M. L., Michie, H., Arthur, K. A., Imamura, K., Willmore, D., Frei 3rd, E. & Kufe, D. W. (1988). Recombinant human tumor necrosis factor administered as a 24 h intravenous infusion. A phase I and pharmacologic study. J Natl Cancer Inst 80: 1039–1044.
Tipping, P. G., Leong, T. W. & Holdsworth, S. R. (1991). Tumor necrosis factor production by glomerular macrophages in anti-glomerular basement membrane glomerulonephritis in rabbits. Lab Invest 65: 272–279.
Tracey, K. J., Beutler, B., Lowry, S. F., Merryweather, J., Wolpe, S., Milsark, I. W., Hariri, R. J., Fahey, T. J., Zentella, A., Albert, J. D., Shires, G. T. & Cerami, A. (1986). Shock and tissue injury induced by recombinant human cachectin. Science 234: 470–474.
Walther, M. M., Jennings, S. B., Choyke, P. L., Andrich, M., Hurley, K., Marston Linehan, W., Rosenberg, S. A. & Alexander, R. B. (1996). Isolated perfusion of the kidney with tumor necrosis factor for localized renal-cell carcinoma. World J Urol 14: S2–S7.
Watanabe, N., Niitsu, Y., Umeno, H., Sone, H., Neda, H., Yamauchi, N., Maeda, M. & Urushizaki, I. (1988). Toxic effect of TNF on tumor vasculature in mice. Cancer Res 49: 2179–2183.
Weksler, B., Schneider, A., Ng, B. & Burt, M. E. (1993). Isolated single lung perfusion in the rat: an experimental model. J Appl Physiol 74: 2736–2739.
Weksler, B., Blumberg, D., Lenert, J. T., Ng, B., Fong, Y. & Burt, M. E. (1994). Isolated single-lung perfusion with TNF-α in a rat sarcoma lung metastasis model. Ann Thorac Surg 58: 328–332.
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Veen, A., Seynhaeve, A., Breurs, J. et al. In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats. Br J Cancer 79, 433–439 (1999). https://doi.org/10.1038/sj.bjc.6690067
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DOI: https://doi.org/10.1038/sj.bjc.6690067
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