Liposome-Encapsulated Tumor Necrosis Factor-α Enhances the Effects of Radiation Against Human Colon Tumor Xenografts

Abstract

Recent reports have shown that tumor necrosis factor-α (TNF-α) can augment the effects of radiation against certain tumor types. However, the high concentrations of intravenous infusion of TNF-α needed to cause tumor regression can induce many systemic side effects. The aims of this study were to determine if TNF-α encapsulated in sterically stabilized (Stealth^®, ALZA Corporation, Mountain View, CA), PEGylated liposomes (SL) augments the antitumor effects of radiation and to compare its efficacy and possible toxicity with free TNF-α in the LS174T human colon tumor xenograft model. Nude mice were injected subcutaneously (s.c.) with LS174T cells and treated intravenously (i.v.) with Stealth-liposomal TNF-α (SL-TNF-α) with and without radiation or TNF-α with or without radiation when tumor size was ∼ 200 mm³. In phase 1, a significant decrease (p = 0.047) in tumor growth was observed with radiation at day 21 but not with SL-TNF-α or free TNF-α alone. By the end of phase 1 (day 27) with continued treatments, the SL-TNF-α plus radiation group had significantly smaller tumors (p = 0.044) than those in the free TNF-α plus radiation group. In phase 2, where a similar tumor growth reduction pattern was observed, the addition of TNF-α to radiation, either as free protein or within SL, increased lymphocyte activation and natural killer (NK) cell numbers in both blood and spleen. The effect was generally more pronounced with SL-TNF-α. Systemic toxicity, based on hematologic analyses and body weight, was absent or minimal. Collectively, the data show that pretreatment with SL-TNF-α can enhance more effectively, and possibly more safely, the effects of radiation against human colon tumor xenografts than can free TNF-α and that the increased antitumor action may involve upregulation of lymphocytes.