There is great need for a quantitative imaging test that can be done serially and will report on the growth rate of a tumor and how that rate has been changed by treatment. Clinical and preclinical studies have established the potential of thymidine analogs as positron emission tomography (PET)-based measure of tumor cell proliferation that may provide information on tumor response to cancer therapy in vivo. However, questions remain as to which analog to use, and what would be the most appropriate approach to image analysis. The proposed work will address these questions as well as the usually overlooked role of tumor-associated factors that can influence the specificity of tracer measurements. The primary goal of this study is to quantify how variations in tumor-associated genotypes influence the relationship between tracer uptake and proliferation both in vitro and in vivo. The study will examine whether the relationship between tumor cell proliferation and the uptake of two nucleoside tracers, (FLT (3'- deoxy-3'-L-fluorothymidine), FMAU (2'-fluoro-5-methyl-1-(_-D-2-arabino-furanosyl) uracil), and thymidine), can be modified by alterations in (1) nucleoside transporter levels, (2) cell cycle checkpoint control integrity, (3) de novo nucleotide biosynthesis activity, and (4) the presence of nucleotide efflux transporters. Isogenic cell lines will be studied under both growth and nongrowth conditions, before and after exposure to ionizing radiation, 5-fluorouracil, or paclitaxel and with both in vitro and in vivo (tumor explant) assays. Dynamic kinetic-based PET analysis will be used in the in vivo studies in order to better understand differential effects on transport versus retention. Our goal is to develop a simplified and clinically feasible approach to quantify FLT uptake that is based upon detailed knowledge of FLT kinetics and factors, such as tumor genotype and treatment modality, that affect kinetics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118130-05
Application #
8242860
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Menkens, Anne E
Project Start
2008-04-01
Project End
2014-03-30
Budget Start
2012-04-01
Budget End
2014-03-30
Support Year
5
Fiscal Year
2012
Total Cost
$304,178
Indirect Cost
$109,192
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195