Abstract
[(18)F]FLT (3'-Fluoro-3' deoxythymidine)-PET imaging was proposed as a tool for measuring in vivo tumor cell proliferation. The aim of this article was to validate the use of [(18)F]FLT-PET imaging for measuring xenograft proliferation and subsequent monitoring of targeted therapy. In exponentially growing xenografts, factors that could impact the outcome of [(18)F]FLT-PET imaging, such as nucleoside transporters, thymidine kinase 1, the relative contribution of DNA salvage pathway, and the ratio of FLT to thymidine, were evaluated. The [(18)F]FLT tracer avidity was compared with other proliferation markers. In a panel of proliferating xenografts, [(18)F]FLT or [(3)H]thymidine tracer avidity failed to reflect the tumor growth rate across different tumor types, despite the high expressions of Ki67 and TK1. When FLT was injected at the same dose level as used in the preclinical [(18)F]FLT-PET imaging, the plasma exposure ratio of FLT to thymidine was approximately 1:200. Thymidine levels in different tumor types seemed to be variable and exhibited an inverse relationship with the FLT tracer avidity. In contrast, high-dose administration of bromdeoxyuridine (BrdUrd; 50 mg/kg) yielded a plasma exposure of more than 4-fold higher than thymidine and leads to a strong correlation between the BrdUrd uptake and the tumor proliferation rate. In FLT tracer-avid models, [(18)F]FLT-PET imaging as a surrogate biomarker predicted the therapeutic response of CDK4/6 inhibitor PD-0332991. Tumor thymidine level is one of the factors that impact the correlation between [(18)F]FLT uptake and tumor cell proliferation. With careful validation, [(18)F]FLT-PET imaging can be used to monitor antiproliferative therapies in tracer-avid malignancies.
Highlights
In 1998, Shields and colleagues introduced [18F]FLT (30-Fluoro-30 deoxythymidine)–PET imaging as a noninvasive tool for visualizing tumor cell proliferation [1]
To understand the correlation between tumor growth rate and FLT tracer avidity in the preclinical setting, [18F]FLT– PET imaging was done in a panel of xenograft models
After being transported into cells by the nucleoside transporters, FLT or thymidine is phosphorylated by thymidine kinase 1 (TK1) and retained in the proliferating cells, [18F]FLT–PET
Summary
In 1998, Shields and colleagues introduced [18F]FLT (30-Fluoro-30 deoxythymidine)–PET imaging as a noninvasive tool for visualizing tumor cell proliferation [1]. The principal mechanism in [18F]FLT–PET imaging [2] is the uptake of the tracer by proliferating cells in the pyrimidine salvage pathway, most-. Tumor cells predominately synthesize the nucleosides that are needed for cell growth de novo [6], which results in low [18F]FLT tracer avidity in the proliferating tumor, leading to false negative results [7, 8]. In order for [18F]FLT– PET imaging to "light up" proliferating cells, a number of factors must come into play. This may explain why clinical [18F]FLT–PET imaging exhibited lower overall uptake and less specificity compared with [18F] FDG–PET imaging, despite being a more favorable tool for visualizing malignant tissues. [18F]FLT–PET imaging is less appropriate for clinical tumor staging [9]
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