Synergistic antitumour effect of recombinant human tumour necrosis factor a with melphalan in isolated limb perfusion in the rat

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Abstract
The efficacy of isolated limb perfusion (ILP) for ‘intransit’ metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) α. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF‐α, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non‐immunogenic BN 175 sarcoma ILPs were performed with perfusate only, TNF‐α, melphalan alone, or in combination when tumours had grown to approximately 1·5 cm in diameter. All rats treated with sham perfusion or perfusion with 50 μg TNF‐α showed progressive disease. After perfusion with 40 μg melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 μg melphalan and 50 μg TNF‐α complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF‐α and melphalan was not observed in vitro.