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

Tumor necrosis factor-α 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-α 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 mutiple melanoma in-transit metastases confined to the limb. This achievement may herald the development of new applications of TNF-α 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-α, which can be given systemically, to enhance the antitumor potency of formulated drugs (such as liposomal doxorubicin) by increasing solid tumor targeting.