M. Gutman et al., SYNERGISM OF TUMOR-NECROSIS-FACTOR-ALPHA AND MELPHALAN IN SYSTEMIC AND REGIONAL ADMINISTRATION - ANIMAL STUDY, Invasion & metastasis, 17(4), 1998, pp. 169-175
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.