An overview on the use of TNF-alpha: our experience with regional administration and developments towards new opportunities for systemic application.

Tumor necrosis factor-alpha is a multifunctional cytokine and its potential as antitumor agent has been extensively investigated for the treatment of cancer: Initial enthusiasm was tempered when systemic treatment with TNF-alpha was found to cause severe toxic side effects in phase I/II studies. Other applications were sought and a revival of the drug was its application in combination with the cytotoxic drug melphalan in isolated limb perfusion (ILP). Here we discuss the pre-clinical and clinical studies which led to the success in treatment of patients with irresectable extremity soft tissue sarcoma and multiple melanoma in-transit metastases confined to the limb. This achievement may herald the development of new applications of TNF-alpha in isolated organ perfusion settings. An extension of its use may be found in the application of less toxic TNF-mutants or encapsulated in sterically stabilized liposomes. The review concludes with the possible application of low dose TNF-alpha, which can be given systemically, to enhance the anti-tumor potency of formulated drugs (such a liposomal doxorubicin) by increasing solid tumor targeting.