Biomedical Sciences ETDs

Publication Date

7-1-2015

Abstract

Lung cancer is the leading cause of cancer related mortality in the United States and in the world. One of the carcinogenic compounds found in cigarette smoke, Benzo[a]pyrene (B[a]P), at high levels elicits a number of inflammatory events consistent with those found in lung cancer patients. In our studies, the effects of low-dose gamma radiation (LDR) on carcinogenesis and tumor progression in a murine model of B[a]P-induced lung cancer were investigated. Two studies (46 weeks in duration) were conducted to assess the effects of fractionated doses of low-dose gamma rays on whole body irradiated A/J mice either before or following intraperitoneal injection with the carcinogen. Additionally, a series of short-term studies were performed to investigate the effects of LDR and B[a]P on Kras mutation in tumors, leukocyte cytotoxicity and function, and oxidative stress in mice. Treatment with fractionated doses of LDR (100 mGy) delivered post B[a]P injection suppressed carcinogen-induced lung adenoma formation and prevented the multiplicity of these tumors, however exposure to LDR delivered prophylactically failed to prevent B[a]P-induced carcinogenesis or tumor progression. Radiation alone did not induce lung tumors in either study. B[a]P was cytotoxic to leukocytes and promoted inflammation through pro-inflammatory cytokine secretion (IL-β, IL-6, IL-17, TNF-α), infiltration of inflammatory cells, and increased lipid peroxidation in lungs and spleens of mice. LDR increased anti-inflammatory cytokine secretion (IL-2, IL-4, IL-10) in the spleen but this did not mitigate the inflammatory response induced by B[a]P. In addition we found no evidence that LDR reduces B[a]P-mediated lipid peroxidation in either spleen or lung. We also observed no change in Kras mutation incidence between treatment groups. Therefore we believe that it is unlikely that LDR suppresses B[a]P-mediated tumor progression through modulating Kras mutation, the immune response, or by reducing oxidative stress. Herein we have demonstrated that exposure to radiation at low doses does not increase cancer risk and suppresses the progression of lung cancer when delivered as a treatment. Our studies support the continued research of LDR in animal models to identify the mechanisms behind its ability to inhibit cancer progression for the potential use of LDR in human treatment of cancer in the future.

Keywords

Low-dose radiation, Benzo[a]pyrene, lung cancer, gamma radiation, radiation, cytokine

Sponsors

United States Department of Energy

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Wilder, Julie

First Committee Member (Chair)

Hathaway, Helen

Second Committee Member

Cannon, Judy

Third Committee Member

Thompson, Todd

Fourth Committee Member

Scott, Bobby

Fifth Committee Member

Wilder, Julie

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