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

The efficacy of isolated limb perfusion (ILP) for 'in-transit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF-alpha, 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-alpha, 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 mu g TNF-alpha showed progressive disease. After perfusion with 40 mu g melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 mu g melphalan and 50 mu g TNF-alpha complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF-alpha and melphalan was not observed in vitro.