Preclinical Applications of 3'-Deoxy-3'-[¹⁸F] Fluoro-thymidine in Oncology - A Systematic Review

Abstract

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies.

Sex as a Biologic Variable in Preclinical Imaging Research: Initial Observations with 18F-FLT

“…To the best of our knowledge, sex-dependent differences in 18 F-FLT biodistribution and PET imaging of preclinical models have not been previously reported. In a systematic review of 174 primary publications using 18 F-FLT for oncologic imaging, factors influencing 18 F-FLT uptake in tumors were identified (9). The reviewed studies used tumor models grown in only male or female mice and lacked a direct comparison of 18 F-FLT imaging between the sexes.…”

“…Although not yet approved by the U.S. Food and Drug Administration, 18 F-FLT has been studied through clinical trials in over 1,000 individuals and in patients with multiple cancer types (8). Biologic variables that can affect 18 F-FLT uptake include plasma thymidine levels; the expression level and functional activity of thymidine kinase-1, thymidylate synthase, and nucleoside transporters; and the overall balance of de novo versus salvage pathways of thymidine use (9). This study aimed to determine whether sex influences 18 F-FLT uptake and tissue biodistribution in preclinical oncology models.…”

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

“…We employed two lung cancer models to investigate the effect of gemcitabine on There is a range of studies describing the successful use of [ 18 F]FLT PET for predicting response to anti-cancer agents (19,20). When employing agents interfering with TS activity, like 5-FU, an increase in [ 18 F]FLT uptake early after drug administration was frequently reported.…”

Thymidine Metabolism as a Confounding Factor for 3′-Deoxy-3′-18F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model

“…The addition of oxaliplatin to the combination of 5-FU and leucovorin is beneficial for outcome for instance in the adjuvant (5) regards to selectivity. It has already been successfully employed for monitoring tumor response to therapy in a range of preclinical and clinical studies (7,8). [ 18 F]FLT is phosphorylated by thymidine kinase 1 (TK1) and retained within proliferative cells.…”