In vivo isolated kidney perfusion with tumour necrosis factor alpha (TNF-alpha) in tumour-bearing rats

Isolated perfusion of the extremities with high-dose tumour necrosis factor alpha (TNF-alpha) plus melphalan leads to dramatic tumour response in pati ents with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determi ne whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfu sion. We studied the feasibility of a perfusion with TNF-alpha and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 mu g TNF-alpha. Higher doses appeared to induce renal failure and a secondary cytokine release wi th fatal respiratory and septic shock-like symptoms. In vitro, the combinat ion of TNF-alpha and melphalan did not result in a synergistic growth-inhib iting effect on CC 531 colon adenocarcinoma cells, whereas an additive effe ct was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfus ion, with TNF-alpha alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidne y to perfusion with TNF-alpha, the minimal threshold concentration of TNF-a lpha to exert its anti-tumour effects was not reached. The applicability of TNF-alpha in isolated kidney perfusion for human tumours seems, therefore, questionable.