A rat extremity soft tissue sarcoma model for the study of systemic treatment with Stealth® liposome-encapsulated tumor necrosis factor-α and cytotoxic agents

In this review possible treatment procedures of solid tumors with cytotoxic agents in combination with Tumor Necrosis Factor alpha (TNF-α) is discussed. Emphasis is put on isolated perfusion treatment of tumors localized in extremities and the possibility of replacing the isolated setting by liposomal encapsulation of agents. Clinical studies demonstrated high response rates and limb salvage percentages in patients treated by an isolated limb perfusion (ILP) with TNF-α in combination with melphalan for sarcomas and melanomas confined to extremities. ILP studies performed in rats demonstrated that antitumor activities of both melphalan and doxorubicin are potentiated by TNF-α. However, treatment of tumors localized in other parts of the body (e.g. organs) is much more difficult as complete isolation is often impossible to achieve or because of severe toxicity to the perfused tissue. For treatment of these tumors or systemic disease (i.e. metastasis involving several sites) systemic administration is warranted. In the case of TNF-α this is not likely to be successful as this agent is very toxic, allowing systemic dosages to be administered which are 50-fold below the concentration needed for effective combination therapy. The rat tumor models discussed for studies on ILP or systemic treatment of solid tumors closely resemble the clinical setting, and as the tumors are implanted in the hind legs ILP is incorporated as positive control. The syngeneic tumors are non-immunogenic and highly vascularized and as the rats are completely immunocompetent allow interaction studies between host immune system and treatment. Here we discuss the possible use of liposome-encapsulated TNF-α and cytotoxic agents. The liposomes used are so-called Stealth® or long circulating liposomes which have a prolonged blood residence time and tend to localize in high percentages in tumors. Results obtained with combination of liposomal TNF-α (TNF-SL) and doxorubicin (DOX-SL®) in sarcoma-bearing rats is discussed.