Abstract

A major limitation of successful radiation therapy in cancer treatment is the increase in normal tissue damage as higher doses are used to achieve greater tumor destruction. Radiation dose optimization in cancer therapy requires achieving maximum tumor destruction with minimal damage to normal tissue Antioxidants have been shown to protect normal tissues against radiation damage, as radiation-induced tissue damage results predominantly from reactive oxygen species that directly damage cellular components. However, for effective use as normal tissue radioprotectants in radiotherapy, these antioxidants must not protect the tumors. Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) is a metalloporphyrin antioxidant that has been shown to have radioprotective properties in normal tissue. The major objective of this project was to evaluate the effects of MnTE-2-PyP on prostate cancer response to radiation and to explore mechanisms responsible for the observed effects. Our results showed that radiation significantly slowed tumor progression and addition of MnTE-2-PyP does not significantly alter tumor growth. However, the evaluation of cytokines in spleen, plasma and tumors suggest that administration of MnTE-2-PyP together with radiotherapy may enhance anti-tumor immune responsiveness and decrease the risk for radiation-induced normal tissue toxicities. Assessment of the effects of Mn-TE-2-PyP on radiation response in human prostate cancer cell lines showed that drug did not protect PCa cells against radiation. In addition, in LNCaP cells, a dose-dependent decrease in DNA synthesis and cell viability was observed with drug treatment. The clinical relevance of this cell line makes it noteworthy, as they are a close representative of prostate cancer that would be treated with radiation therapy in patients. Overall, it was demonstrated that the MnTE-2- PyP does not protect prostate tumors against radiation damage and is not toxic under the conditions used. In addition, the drug-induced enhancement of certain immune parameters suggests that MnTE-2-PyP may be beneficial not only as a normal tissue radioprotectant, but also as a facilitator of antitumor immunity. This study enhances the clinical relevance of antioxidant metalloporphyrins and potentially contributes towards improvement of cancer treatment and radiotherapy.

LLU Discipline

Biochemistry

Department

Biochemistry

School

School of Medicine

First Advisor

Daila S. Gridley

Second Advisor

Carlos A. Casiano

Third Advisor

James D. Crapo

Fourth Advisor

Penelope J. Duerksen-Hughes

Fifth Advisor

Lora M. Green

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2009

Date (Title Page)

6-2009

Language

English

Library of Congress/MESH Subject Headings

Prostatic Neoplasms -- radiotherapy; Prostatectomy; Radiation Dosage; Radiation-Sensitizing Agents; Cell Aging -- drug effects; Cell Line, Tumor; Organ Size -- radiation effects; Antioxidants -- diagnostic use; Disease Models, Animal; Mice; Factor Analysis, Statistical; Treatment Outcome.

Type

Dissertation

Page Count

xvii; 180

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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