Pegylated liposomal tumor necrosis factor-alpha results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil (R)) in soft tissue sarcoma-bearing rats

Previously we reported that encapsulation of tumor necrosis factor-alpha (T NF) in pegylated (STEALTH (R)) liposomes (TNF-PEGL) dramatically improved c irculation times of the protein and augmented accumulation in tumor tissue. We and others have demonstrated enhanced antitumor activity of doxorubicin or melphalan by free TNF when used in ig doses in an isolated limb perfusi on setting. In the present study the antitumor activity of TNF-PEGL was stu died in combination with liposomal chemotherapy. BN rats with subcutaneous BN175 sarcomas (8-12 mm diameter) received no treatment or pegylated liposo mal doxorubicin (Doxil (R)) alone or in combination with various doses of T NF-PEGL (15-200 mug/kg), The evaluated endpoints were tumor response and to xicity of the treatment regimens. Here we demonstrate that TNF-PEGL at a do se of 15 mug/kg markedly augments the antitumor activity of liposomal doxor ubicin, without resulting in the increased toxic side effects observed with free TNF at doses resulting in a similar enhancement of the antitumor effe cts. Even at a TNF dose of 200 mug/kg TNF, repeated administration of TNF-P EGL did not result in severe weight loss or cause diarrhea. Repeated dosing of free TNF at this dose resulted in severe, life-threatening weight loss and occurrence of diarrhea in all animals. These results indicate that pegy lated liposomal encapsulation may be effective in systemic application of T NF for combined treatment with liposomal chemotherapy of advanced solid tum ors. (C) 2002 Wiley-Liss, Inc.