SYNERGISTIC ANTITUMOR EFFECT OF RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA WITH MELPHALAN IN ISOLATED LIMB PERFUSION IN THE RAT

The efficacy of isolated limb perfusion (ILP) for 'in-transit' metasta ses from malignant melanoma and irresectable soft tissue sarcoma has b een improved considerably by the addition of tumour necrosis factor (T NF) alpha. A rat sarcoma tumour model was, therefore, developed to eva luate the effects of TNF-alpha, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non-immunog enic BN 175 sarcoma ILPs were performed with perfusate only, TNF-alpha , melphalan alone, or in combination when tumours had grown to approxi mately 1.5 cm in diameter. All rats treated with sham perfusion or per fusion with 50 mu g TNF-alpha showed progressive disease. After perfus ion with 40 mu g melphalan no change in tumour diameter was observed i n any rats at 4 days. After a combined perfusion with 40 mu g melphala n 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.