Dong Won Kim

Abstract

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.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology

School

Graduate School

First Advisor

Daila S. Gridley

Second Advisor

Carlos Casiano

Third Advisor

Lora M. Green

Fourth Advisor

Gregory Nelson

Fifth Advisor

Andre Obenaus

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2001

Date (Title Page)

8-2001

Language

English

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.

Type

Dissertation

Page Count

xvii; 259

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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