Liposome-encapsulated tumor necrosis factor-alpha enhances the effects of radiation against human colon tumor xenografts

Recent reports have shown that tumor necrosis factor-alpha (TNF-alpha) can augment the effects of radiation against certain tumor types. However, the high concentrations of intravenous infusion of TNF-alpha needed to cause tu mor regression can induce many systemic side effects. The aims of this stud y were to determine if TNF-alpha encapsulated in sterically stabilized (Ste alth(R), ALZA Corporation, Mountain View, CA), PEGylated liposomes (SL) aug ments the antitumor effects of radiation and to compare its efficacy and po ssible toxicity with free TNF-alpha in the LS174T human colon tumor xenogra ft model. Nude mice were injected subcutaneously (s.c.) with LS174T cells a nd treated intravenously (i.v.) with Stealth-liposomal TNF-alpha (SL-TNF-al pha) with and without radiation or TNF-alpha with or without radiation when tumor size was similar to 200 mm(3). In phase 1, a significant decrease (p =0.047) in tumor growth was observed with radiation at day 21 but not with SL-TNF-alpha or free TNF-alpha alone. By the end of phase 1 (day 27) with c ontinued treatments, the SL-TNF-alpha plus radiation group had significantl y smaller tumors (p=0.044) than those in the free TNF-alpha plus radiation group. In phase 2, where a similar tumor growth reduction pattern was obser ved, the addition of TNF-alpha to radiation, either as free protein or with in SL, increased lymphocyte activation and natural killer (NK) cell numbers in both blood and spleen. The effect was generally more pronounced with SL -TNF-alpha. Systemic toxicity, based on hematologic analyses and body weigh t, was absent or minimal. Collectively, the data show that pretreatment wit h SL-TNF-alpha can enhance more effectively, and possibly more safely, the effects of radiation against human colon tumor xenografts than can free TNF -alpha and that the increased antitumor action may involve upregulation of lymphocytes.