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    Enhancing the Therapeutic Effects of PARP Inhibitors in Combination with DNA Methyltransferase Inhibitors Using Fractionated Low Doses of Ionizing Radiation in Non-Small Cell Lung Cancers.

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    Author
    Fontaine, Daniel Thomas
    Advisor
    Rassool, Feyruz V.
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the US. Treatment relies on radiation therapy and chemotherapeutics when surgery is not an option. These treatments have significant negative effects on long-term survival. Previous work in the Rassool laboratory found that combining low, non-cytotoxic doses of poly(ADP-ribose) polymerase (PARP) and DNA-methyltransferase (DNMT) inhibitors increased cytotoxicity in AML and breast cancers. This work highlighted the trapping of both proteins at DNA damage sites, creating cytotoxic double strand breaks (DSBs). We examined this combination in NSCLC and whether low doses of ionizing radiation (IR) would increase treatment efficacy. Introduction of IR with this combination, resulted in decreased cell clonogenicity and increased DSB formation. In vivo testing of this combination with IR showed significantly reduced tumor growth and extended survival rates. This suggests that PARP and DNMT inhibitors in combination with IR could be a novel therapeutic for NSCLC.
    Description
    University of Maryland, Baltimore. Molecular Medicine. M.S. 2017
    Keyword
    DNA methyltransferase inhibitors
    Carcinoma, Non-Small-Cell Lung--therapy
    Combined Modality Therapy
    Poly(ADP-ribose) Polymerase Inhibitors
    Radiation, Ionizing
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/6763
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    Theses and Dissertations School of Medicine
    Theses and Dissertations All Schools

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