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.
|Plotnik, David A; Wu, Stephen; Linn, Geoffrey R et al. (2015) In vitro analysis of transport and metabolism of 4'-thiothymidine in human tumor cells. Nucl Med Biol 42:470-4|
|Plotnik, David A; Asher, Camille; Chu, Stephanie K et al. (2012) Levels of human equilibrative nucleoside transporter-1 are higher in proliferating regions of A549 tumor cells grown as tumor xenografts in vivo. Nucl Med Biol 39:1161-6|
|Plotnik, David A; McLaughlin, Lena J; Krohn, Kenneth A et al. (2012) The effects of 5-fluoruracil treatment on 3'-fluoro-3'-deoxythymidine (FLT) transport and metabolism in proliferating and non-proliferating cultures of human tumor cells. Nucl Med Biol 39:970-6|
|Plotnik, David A; McLaughlin, Lena J; Chan, Jenny et al. (2011) The role of nucleoside/nucleotide transport and metabolism in the uptake and retention of 3'-fluoro-3'-deoxythymidine in human B-lymphoblast cells. Nucl Med Biol 38:979-86|
|Plotnik, David A; Emerick, Lindsay E; Krohn, Kenneth A et al. (2010) Different modes of transport for 3H-thymidine, 3H-FLT, and 3H-FMAU in proliferating and nonproliferating human tumor cells. J Nucl Med 51:1464-71|