Ischemia promotes the antitumor effect of tumor necrosis factor alpha (TNFα) in isolated limb perfusion in the rat

Isolated limb perfusion with recombinant human tumor necrosis factor a (rHuTNFα) in combination with cytostatic agents has led to a major improvement in the treatment of in transit metastases of melanoma stage III in the extremities and to limb salvage in patients with irresectable sarcoma. In order to investigate which factors enhance TNFα antitumor effects we performed isolated limb perfusion in rats with the non-immunogenic BN 175 sarcoma. We applied two different models to determine whether TNFα response is enhanced under ischemic conditions or not. In the ischemic model (model I) we found in all rHuTNFα (100 μg) perfused extremities (n=9) regression of tumor. There were 3 partial remissions and 6 complete remissions. No cure was obtained by this therapy. After 3-11 days recurrences were observed at the edge of the former tumor. In sham perfused limbs no regression was seen (n=6). In the second model in which the perfusate is oxygenated adequately, we found no tumor response after rHuTNFα (100 μg) perfusion (n=7). In sham perfused limbs again no response was seen (n=5). Histologic assessment of rHuTNFα treated tumors revealed hemorrhagic necrosis in the centre of the tumor, characteristic for TNFα and this was not found in sham treated tumors. These data show evidence that ischemia promotes TNFα antitumor effects.