Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

David A. Gewirtz

Abstract

Radiation therapy is a widely used tool in cancer therapy and is frequently offered as the first line of treatment for cancers of the breast. While radiotherapy is often initially effective in killing tumor cells or suppressing their growth, there are factors that confer tumor cell resistance to irradiation. Development of resistance may lead to disease recurrence despite the use of surgery, chemotherapy and radiation therapy. A primary goal of the studies in Dr. Gewirtz’s laboratory is to develop strategies to overcome resistance to radiation (and chemotherapy) in breast cancer, with the ultimate goal of preventing or attenuating disease recurrence. One of these approaches involves combining the active form of vitamin D, 1,25-di hydroxy vitamin D3 or its analogs with radiotherapy. Our proposed studies were designed to build upon and extend previous work from this laboratory focused on determining the nature of cell death when vitamin D3 is combined with ionizing radiation in breast tumor cells. Studies were extended to the wild type p53, estrogen receptor positive, ZR-75-1 breast cancer cell line. We were able to validate that vitamin D3 does in fact, sensitize ZR-75-1 breast cancer cells to radiation therapy and substantiate that autophagy is the mode of sensitization by vitamin D3. Interestingly, our experimental system demonstrated that autophagy can actually have dual roles. Specifically, inhibition of autophagy both enhanced sensitivity to radiation and attenuated radiation sensitization by 1,25D3. Moreover, this experimental model proved to be a useful tool in trying to distinguish the factors involved in cytoprotective and cytotoxic autophagy, as we were able to demonstrate a potential role of 5' adenosine monophosphate-activated protein kinase in the sensitization of breast tumor cells to radiation by vitamin D3 as well as cytotoxic autophagy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2012

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