Toxicity and antitumor activity of interferon gamma alone and in combinations with TNFalpha and melphalan in isolated limb perfusion in the BN175 sarcoma tumor model in rats.

Isolated limb perfusion (ILP) with TNFalpha, melphalan (M), and IFNgamma results in high tumor response rates in patients with soft tissue sarcomas, melanomas and other tumors. IFNgamma can act synergistically in combination with TNFalpha but in clinical studies this has not been fully investigated. In the BN175 rat sarcoma limb perfusion model we investigated the role of IFNgamma. There were 8 different treatment groups: (I) sham ILP (n=9); (II) IFNgamma alone (n=10); (III) TNFalpha 50 microg (n=9); (IV) TNFalpha + IFNgamma (n=6); (V) melphalan (M) 40 microg (n=11); (VI) M + IFNgamma (n=6); (VII) TNFalpha + M (n=27); (VIII) TNFalpha + M + IFNgamma (n=9). Tumor response and hindlimb function were analyzed. In group I-VI no tumor regressions were observed at 5 days after ILP. ILP with TNFalpha + M had highly effective response rate (RR) of 73%; complete response (CR) rate 55%), very similar to RR in patients. Addition of IFNgamma increased the RR by 16% to 89% and the CR rate by 23% to 78%. This difference was not statistically significant. When IFNgamma was added to TNFalpha or TNFalpha + M it increased limb toxicity significantly (p<0.05 and p<0.005). Since such regional toxicity has not been observed in patients while similar increases in tumor response rates have been reported with IFNgamma it is of importance to define the role of IFNgamma in the clinical setting.