Since the purification of Tumor Necrosis Factor-a (TNF-a) in the mid 1980's the anti-tumor capacity of TNF-a has received considerable attention. Acute softening of the tumor, hemorrhagic necrosis and occlusion of the neovasculature led to tumor necrosis. The mechanism behind this process was not well understood, until recently. The initial enthusiasm of the anti-tumor capacity of TNF-a in rodent tumor models was tempered by the severe toxicity encountered in clinical phase IIII trials. Only 1/50 to 1120 of the dose required for anti-tumor effect in human xenograft tumor models in mice, can be administered in man. In 1992 Lejeune et al combined TNF-a, melphalan and Interferon y (IFN-y) to achieve impressive results in anticancer therapy. The combination proved to be very successfill in the isolated perfusion setting in the treatment of extensively metastasized melanoma patients. Complete response (CR) rates of 80-90 % were achieved. In isolated limb perfusion (ILP) the concentration gap between animal studies and clinical trials could be overcome. Investigations were expanded to other forms of cancer, and Eggennont et al proved the same regimen to be as successful in locally advanced extremity soft tissue sarcomas, with a limb salvage percentage of over 80 %, followed by a much easier and less mutilating resection of the tumor remnants. Currently, TNF-a based isolated limb perfusion has become the standard of treatment for patients with multiple in transit melanoma metastases or non-resectable extremity sarcomas. This led to the approval and registration of TNF-a in Europe for clinical use in patients with locally advanced extremity soft tissue sarcomas treated by ILP with TNF-a and melphalan (BeromunĀ®). Angiographic studies revealed that the main target of TNF-a was the tumor associated vasculature (TAV). The immediate reaction and softening of the tumor in ILP treated patients were associated with selective occlusion of the TAV. Blood flow decreased and metabolic activity in tumors was arrested. Morphological and immunohistochemical studies of tumor biopsies from patients after TNF -a based ILP showed early damage to the TAV, as shown by perivascular release of von Willebrand Factor (vWF). Whether damage to the vascular endothelium equally plays a pivotal role is a matter of debate.

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Dutch Cancer Society (KWF), Erasmus Stichting Heelkundig Kankeronderzoek, Wetenschappelijk Fonds Catharina Ziekenhuis, Alza Parmaceuticals, Lipoid GMbH, Boehringer lngelheim, Mathys Nederland, Ethicon/Johnson&Johnson, Tyco Healthcare, Smith&Nephew, Bosman and Rx Medical
A.M.M. Eggermont (Alexander)
Erasmus University Rotterdam
Erasmus MC: University Medical Center Rotterdam

van der Veen, A. H. (2000, June 8). Tumor necrosis factor-a and tumor targeting : regional and systemic administration of TNF-a in the rat for treatment of solid tumors. Retrieved from