TNF and manipulation of the tumor cell-stromal interface: "ways to make chemotherapy effective".

Growth of solid tumors depends largely on the development of a functional vasculature, which has been the focus in anti-tumor therapy since Folkman in 1971 proposed that prohibiting the formation of new vessels could inhibit tumor growth. The recognition of the tumor vascular bed as an important target led to the development of 3 vascular-targeted strategies. I) The anti-angiogenesis strategy that prevents the formation of new blood vessels and normalizes the remaining vessels. II) Applying vasculo-destructive agents to induce apoptosis in the endothelium of the tumor-associated vasculature that results in vascular collapse and tumor necrosis. III) Promoting further abnormalization of the already abnormal features of the tumor-associated vasculature with vaso-active agents to enhance vessel permeability. Tumor necrosis factor alpha (TNF) is a very promising vaso-active agent because of its anti-tumor effects but its severe systemic toxicity is a major drawback. Therefore a new setting, in which the optimal therapeutic benefit of TNF could be exploited, needed to be found. Through an isolated perfusion high dose of TNF can be administered in the blood circulation of the tumor-bearing extremity or organ. Alternatively, systemically low doses can be safely administered for several times. Importantly, TNF has no anti-tumor effect by itself and the combination with a conventional chemotherapeutic drug that targets the tumor cell is a prerequisite for a good tumor response. In this dual approach, TNF enhances intratumoral accumulation of the chemotherapeutic drug resulting in an impressive tumor response.