Previous studies have shown that tumor necrosis factor-α (TNF-α) can augment the antitumor effects of radiation, inhibiting tumor progression to a greater extent than either modality alone. However, nonspecific toxicities associated with TNF-α have limited its use as an adjuvant. This limitation is potentially resolved with the encapsulation of TNF-α in sterically stabilized, PEGylated liposomes (STEALTH®). Thus, the overall hypothesis of the research was that the combination of radiation with STEALTH® liposome encapsulated TNF-α (SL-TNF-α) will have greater efficacy and fewer dose-limiting side effects in the LS174T human colorectal tumor xenograft model compared to the combination of free TNF-α and radiation, as well as to each modality alone. Furthermore, the increased antitumor efficacy of SL-TNF-α plus radiation will be associated with greater and more prolonged augmentation of innate immune mechanisms.
Nude mice were subcutaneously injected with LS174T adenocarcinoma cells into the right hind leg and treated with different regimens of intravenously injected free TNF-α or SL-TNF-α and/or radiation. Tumor volume and mouse weight were measured throughout the treatment. Furthermore, various immunological assays were performed on the blood and the spleen, and immunohistological analyses were completed on the tumor excised from the mice.
Collectively, the data of this research demonstrated for the first time that the addition of SL-TNF-α to radiation results in more than additive tumor growth inhibition using the LS174T xenograft model. Furthermore, the increased antitumor effect was achieved without any observable toxicity. The measurements of innate immunity performed in this research showed that SL-TNF-α produced a spatially and temporally different modulation of these immune parameters compared to free TNF-α when measured in the spleen, blood, and tumor, which correlated with the greater decrease in tumor growth after SL-TNF-α plus radiation treatment and thus, could account, at least partly, for its greater efficacy. Overall, the research demonstrated that combination of SL-TNF-α plus radiation is effective in inhibiting tumor growth without causing unwanted toxicities and that the potential usefulness of this combination warrants further study and consideration.
Microbiology and Molecular Genetics
Daila S. Gridley
Lora M. Green
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Colonic Neoplasms -- drug therapy; Colonic Neoplasms -- radiotherapy; Colonic Neoplasms -- immunology; Lymphocyte Subsets -- radiation effects; Tumor Necrosis Factor; Xenograft Model Antitumor Assays; Radiation-Sensitizing Agents -- therapeutic Use; Cell Division -- radiation effects.
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Kim, Dong Won, "Effects of Liposome-Encapsulated TNF-Alpha and Radiation against Colon Cancer" (2001). Loma Linda University Electronic Theses, Dissertations & Projects. 1541.
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