Date of Degree

2-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Shengping Zheng

Committee Members

NagaVaraKishore Pillarsetty

Wayne W. Harding

Mark R. Biscoe

Jason S. Lewis

Subject Categories

Organic Chemistry | Radiochemistry

Keywords

Cancer imaging, Positron Emission Tomography, Iodine-124, biomarker, gemcitabine

Abstract

Gemcitabine (gem) is a nucleoside analog that is used to treat pancreatic cancers (PaCa), which have dismal prognosis and low survival rate. Though gem is used as first line of treatment for PaCa, the response rate is quite low (~30%). Currently, there is no a priori way to determine a responder from a non-responder to gem therapy either invasively or non-invasively. Any biomarker that can act as a prognostic indicator of gem response will greatly aid in selecting responsive patients to gem therapy and provide alternative options such as Folfirinox or other treatments to resistant patient population. Amongst various known biomarkers, deoxycytidine kinase (dCK) is considered to be an important rate limiting enzyme that is necessary to convert gem into its cytotoxic derivativeand therefore, levels of dCK in tumors could aid in predicting the drug’s efficacy to treat cancers and patient response to therapy.

Investigation into synthesis of novel radioactive-iodine (radioiodine) labeled gem analogs, 2′-fluoro-2′-deoxy-1-β-D-ribofuranosyl-5-iodocytosine (FIRC), 2′,2′-difluoro-2′,2′-dideoxy-1-β–D-furanosyl-5-iodocytosine (5-Iodogemcitabine, IGem) and 2′-Fluoro-2′-deoxy-1-β-D-arabinofuranosyl-5-iodocytosine (FIAC) and their evaluation as potential to predict dCK levels in pancreatic tumor cell lines will be described. The most promising iodine labeled gem analog, FIAC will be described in detail and potential of [124I]FIAC as an imaging agent to image various pancreatic tumors over extended periods of time by PET (positron emission tomography) to provide a better tumor to background ratio will be evaluated. Further, it will be compared to 1-(2′-deoxy-2′-[18F]fluoro-b-D-(arabinofuranosyl)cytosine) ([18F]FAC), which has been previously investigated as a surrogate marker for dCK.

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