SYNERGISM OF TUMOR-NECROSIS-FACTOR-ALPHA AND MELPHALAN IN SYSTEMIC AND REGIONAL ADMINISTRATION - ANIMAL STUDY

Tumor necrosis factor (TNF) is a highly cytotoxic cytokine. However, d ue to its severe side effects, the only clinical situation allowing it s administration in humans is isolated limb perfusion (ILP). Early stu dies have shown that TNF alone is of limited efficacy even at high dos es via ILP, and that a chemotherapeutic agent needs to be added. The m ost commonly used drug in this setting is melphalan which is considere d to be synergistic with TNF. However, since melphalan has not been co mmonly used in sarcoma, we believed that confirmation of its synergist ic effect with TNF in an experimental sarcoma model could prove valuab le for future drug choice. B16F10 melanoma and CT26 colon carcinoma ce lls were injected subcutaneously (s.c.) into mice, while GF fibrosarco ma cells were injected s.c. into the hindleg of Wistar rats. The anima ls were then divided into four treatment groups: TNF alone, melphalan alone, TNF and melphalan, and 0.9% NaCl controls. Mice were treated wi th intraperitoneal injections and rats by ILP. TNF dosage was 20 mu g for mice and 200 mu g for rats. Melphalan was given at 5-10 mg/kg for both mice and rats. Results showed synergism of TNF and melphalan in b oth modes of therapy. In the systemic administration groups (mice carr ying B16F10 and CT26 tumors), tumors increased in size in all but the combined TNF-melphalan group. In the regional delivery groups (rats ca rrying GF sarcoma cells treated via ILP), there was a 16% decrease in tumor volume in rats treated with TNF alone, a 29% decrease in rats tr eated with melphalan, and a 75% decrease in the combined TNF-melphalan group. In conclusion, TNF and melphalan proved to be highly synergist ic in both systemic and regional delivery. This fact makes melphalan a n adequate choice for TNF perfusion in advanced limb malignancies.