Abstract
To study tumor therapeutic treatment modalities, whether from a clinical, preclinical, or fundamental point of view, the use of clinically relevant animal models is indispensable. Particularly when the treatment comprises a multitargeted approach, (e.g., both tumor cells and endothelial cells are targeted), the in vitro data will be of very limited value. Well-chosen animal models will provide conclusive data on the activity of the drug in the complex in vivo setting. Moreover, when the treatment targets the stromal compartment of the tumor rather than the tumor cells directly, insight into the mechanism of action is only possible when studied in vivo. This approach is of great importance for studies on the use of tumor necrosis factor-α (TNFα) in solid tumor therapy. Although TNFα has shown activity toward tumor cells in vitro directly, we and others have demonstrated that an important activity of this cytokine is directed toward the tumor vasculature. To elucidate the working mechanism of TNFα and to test possible treatment modalities, the animal models described here are crucial. In this chapter we will describe the use of specific animal models for efficacy studies, such as isolated limb perfusion and isolated liver perfusion in the rat.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285.
Kerbel, R. and Folkman, J. (2002) Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2, 727–739.
ten Hagen, T. L. M., Eggermont, A. M. M., and Lejeune, F. J. (2001) TNFα is here to stay—revisited. Trends Immunol. 22, 127–129.
Creech, O. J., Krementz, E. T., Ryan, R. F., and Winblad, J. N. (1958) Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann. Surg. 148, 616–632.
Benckhuijsen, C., Kroon, B. B., Van Geel, A. N., and Wieberdink, J. (1988) Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur. J. Surg. Oncol. 14, 157–163.
Thompson, J. F. and Gianoutsos, M. P. (1992) Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J. Surg. 16, 227–233.
Klaase, J. M., Kroon, B. B., Van Geel, A. N., Eggermont, A. M., and Franklin, H. R. (1993) Systemic leakage during isolated limb perfusion for melanoma. Br. J. Surg. 80, 1124–1126.
Wieberdink, J., Benckhuysen, C., Braat, R. P., van Slooten, E. A., and Olthuis, G. A. (1982) Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur. J. Cancer Clin. Oncol. 18, 905–910.
Eggermont, A. M. M. (1996) Treatment of melanoma in-transit metastases confined to the limb. Cancer Surv. 26, 335–349.
OmLor, G., Gross, G., Ecker, K. W., Burger, I., and Feifel, G. (1992) Optimization of isolated hyperthermic limb perfusion. World J. Surg. 16, 1117–1119.
de Wilt, J. H. W., Manusama, E. R., van Tiel, S. T., Van Ijken, M. G. A., ten Hagen, T. L. M., and Eggermont, A. M. M. (1999) Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats. Br. J. Cancer 80, 161–166.
Manusama, E. R., Nooijen, P. T. G. A., Stavast, J., Durante, N. M. C., Marquet, R. L., and Eggermont, A. M. M. (1996) Synergistic antitumour effect of recombinant human tumour necrosis factor alpha 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., and Eggermont, A. M. M. (1996) Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach. Eur. J. Surg. Oncol. 22, 152–157.
Van Der Veen, A. H., Seynhaeve, A. L. B., Breurs, J., Nooijen, P. T. G. A., Marquet, R. L., and Eggermont, A. M. M. (1999) In vivo isolated kidney perfusion with TNF-alpha in tumour bearing rats. Br. J. Cancer 79, 433–439.
Van Ijken, M. G. A., van Etten, B., de Wilt, J. H. W., van Tiel, S. T., ten Hagen, T. L. M., and Eggermont, A. M. M. (2000) Tumor necrosis factor-alpha augments tumor effects in isolated hepatic perfusion with melphalan in a rat sarcoma model. J. Immunother. 23, 449–455.
van Etten, B., de Vries, M. R., Van Ijken, M. G. A., Lans, T. E., Guetens, G., Ambagtsheer, G., et al. (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.
van Etten, B., ten Hagen, T. L. M., de Vries, M. R., Ambagtsheer, G., Huet, T., and Eggermont, A. M. M. (2002) Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras. Br. J. Cancer 86, 436–442.
Tjaden, U. R. and de Bruijn, E. A. (1990) Chromatographic analysis of anticancer drugs. J. Chromatogr. 531, 235–294.
Mayer, L. D., Tai, L. C. L., Ko, D. S. C., Masin, D., Ginsberg, R. S., Cullis, P. R., et al. (1989) Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 49, 5922–5930.
Gabizon, A., Shmeeda, H., and Barenholz, Y. (2003) Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42, 419–436.
Gabizon, A. and Papahadjopoulos, D. (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc. Natl. Acad. Sci. USA 85, 6949–6953.
Lienard, D., Ewalenko, P., Delmotte, J. J., Renard, N., and 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.
Lejeune, F. J., Lienard, D., Leyvraz, S., and Mirimanoff, R. O. (1993) Regional therapy of melanoma. Eur. J. Cancer 29A, 606–612.
Hill, S., Fawcett, W. J., Sheldon, J., Soni, N., Williams, T., and Thomas, J. M. (1993) Low-dose tumour necrosis factor alpha and melphalan in hyperthermic isolated limb perfusion. Br. J. Surg. 80, 995–997.
Vaglini, M., Belli, F., Ammatuna, M., Inglese, M. G., Manzi, R., Prada, A., et al. (1994) Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan. Cancer 73, 483–492.
Eggermont, A. M. M., Schraffordt Koops, H., Lienard, D., Kroon, B. B. R., Van Geel, A. N., Hoekstra, H. J., et al. (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.
Fraker, D. L., Alexander, H. R., Andrich, M., and Rosenberg, S. A. (1996) Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J. Clin. Oncol. 14, 479–489.
Lienard, D., Eggermont, A. M., Koops, H. S., Kroon, B., Towse, G., Hiemstra, S., et al. (1999) Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res. 9, 491–502.
Stehlin, J. S., Jr., de Ipolyi, P. D., Giovanella, B. C., Gutierrez, A. E., and Anderson, R. F. (1975) Soft tissue sarcomas of the extremity. Multidisciplinary therapy employing hyperthermic perfusion. Am. J. Surg. 130, 643–646.
Krementz, E. T., Carter, R. D., Sutherland, C. M., and Hutton, I. (1977) Chemotherapy of sarcomas of the limbs by regional perfusion. Ann. Surg. 185, 555–564.
Klaase, J. M., Kroon, B. B., Benckhuijsen, C., Van Geel, A. N., Albus-Lutter, C. E., and Wieberdink, J. (1989) Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer 64, 616–621.
Rossi, C. R., Vecchiato, A., Foletto, M., Nitti, D., Ninfo, V., Fornasiero, A. X. S. G., et al. (1994) Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas. Cancer 73, 2140–2146.
Di Filippo, F., Calabro, A. M., Cavallari, A., Carlini, S., Buttini, G. L. X. M. F., Cavaliere, F., et al. (1988) The role of hyperthermic perfusion as a first step in the treatment of soft tissue sarcoma of the extremities. World J. Surg. 12, 332–339.
Eggermont, A. M. M., Lienard, D., Schraffordt Koops, H., Rosenkaimer, F., and Lejeune, F. J. (1993) Treatment of irresectable soft tissue sarcomas of the limbs by isolation perfusion with high dose TNF-alpha in combination with interferon-gamma and melphalan. In Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance (Fiers, W. and Buurman, W. A., eds), Karger, Basel, pp. 239–243.
Eggermont, A. M. M., Schraffordt Koops, H., Klausner, J. M., Kroon, B. B. R., Schlag, P. M., Lienard, D., et al. (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.
Nooijen, P. T. G. A., Manusama, E. R., Eggermont, A. M. M., Schalkwijk, L., Stavast, J., Marquet, R. L., et al. (1996) Synergistic effects of TNF-alpha and melphalan in an isolated limb perfusion model of rat sarcoma: a histopathological, immunohistochemical and electron microscopical study. Br. J. Cancer 74, 1908–1915.
Van Der Veen, A. H., de Wilt, J. H. W., Eggermont, A. M. M., van Tiel, S. T., Seynhaeve, A. L. B., and ten Hagen, T. L. M. (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.
Rossi, C. R., Foletto, M., Di Filippo, F., Vaglini, M., Anza, M., Azzarelli, A., et al. (1999) Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion. Cancer 86, 1742–1749.
Manusama, E. R., de Wilt, J. H. W., ten Hagen, T. L. M., Marquet, R. L., and Eggermont, A. M. M. (1999) Toxicity and anti-tumor activity of interferon gamma alone and in combination with TNF alpha and melphalan in isolated limb perfusion in the BN175 sarcoma tumor model in rats. Oncol. Rep. 6, 173–177.
Seynhaeve, A. L. B., de Wilt, J. H. W., van Tiel, S. T., Eggermont, A. M. M., and ten Hagen, T. L. M. (2002) Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity. Br. J. Cancer 86, 1174–1179.
de Wilt, J. H., Manusama, E. R., van Etten, B., van Tiel, S. T., Jorna, A. S., Seynhaeve, A. L., et al. (2000) Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions. Br. J. Cancer 83, 1176–1182.
de Wilt, J. H. W., ten Hagen, T. L. M., de Boeck, G., van Tiel, S. T., de Bruijn, E. A., and Eggermont, A. M. M. (2000) Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br. J. Cancer 82, 1000–1003.
Kristensen, C. A., Nozue, M., Boucher, Y., and Jain, R. K. (1996) Reduction of interstitial fluid pressure after TNF-alpha treatment of three human melanoma xenografts. Br. J. Cancer 74, 533–536.
ten Hagen, T. L. M., Van Der Veen, A. H., Nooijen, P. T. G. A., van Tiel, S. T., Seynhaeve, A. L. B., and Eggermont, A. M. M. (2000) Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth liposomal doxorubicin (DOXIL) in soft tissue sarcoma-bearing rats. Int. J. Cancer 87, 829–837.
ten Hagen, T. L. M., Seynhaeve, A. L. B., van Tiel, S. T., Ruiter, D. J., and Eggermont, A. M. M. (2002) Pegylated liposomal tumor necrosis factor-alpha results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil) in soft tissue sarcoma-bearing rats. Int. J Cancer 97, 115–120.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Humana Press Inc.
About this protocol
Cite this protocol
ten Hagen, T.L.M., Eggermont, A.M.M. (2004). Tumor Vascular Therapy With TNF. In: Corti, A., Ghezzi, P. (eds) Tumor Necrosis Factor. Methods in Molecular Medicine™, vol 98. Humana Press. https://doi.org/10.1385/1-59259-771-8:227
Download citation
DOI: https://doi.org/10.1385/1-59259-771-8:227
Publisher Name: Humana Press
Print ISBN: 978-1-58829-223-0
Online ISBN: 978-1-59259-771-0
eBook Packages: Springer Protocols