Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation

Abstract

Positron emission tomography (PET) using F-18 fluoro-3'-deoxy-3-L-fluorothymidine (FLT) offers noninvasive assessment of cell proliferation in vivo. The most important application refers to the evaluation of tumour proliferative activity, representing a key feature of malignancy. Most data to date suggest that FLT is not a suitable biomarker for staging of cancers. This is because of the rather low fraction of tumour cells that undergo replication at a given time with subsequently relatively low tumour FLT uptake. In addition, generally, the high FLT uptake in liver and bone marrow limits the diagnostic use. We describe the current status on preclinical and clinical applications of FLT-PET including our own experience in brain tumours. The future of FLT-PET probably lies in the evaluation of tumour response to therapy and more importantly, in the prediction of early response in the course of treatment. The level of FLT accumulation in tumours depends on thymidine kinase 1 activity and on the therapy-induced activation of the salvage pathway and expression of nucleoside transporters. Therefore, cytostatic agents that cause arrest of the cell cycle in the S-phase may initially increase FLT uptake rather than reducing the tumour cell accumulation. In addition, agents that block the endogenous thymidine pathway may lead to overactivity of the salvage pathway and increase tumour FLT uptake. In contrast, many therapeutic agents inhibit both pathways and subsequently reduce tumour FLT uptake. Further studies comparing FLT with F-18 fluorodeoxyglucose-PET will be important to determine the complementary advantage of FLT-PET in early cancer therapy response assessment. Further research should be facilitated by simplified synthesis of FLT with improved yields and an increasing commercial availability.

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

“…The tumor uptake of [ 18 [24,25] and others [26,27] in vitro and in patients. These observations, considered as a "flare" phenomenon, were to be taken into account when interpreting […”

PET for Therapy Response Assessment in Glioblastoma

“…18 F-fluorothymidine ( 18 F-FLT) has been proposed to directly assess DNA synthesis to estimate tumor cell proliferation and has been proposed for therapy monitoring, based on the concept that change in DNA synthesis should be the most direct index of therapeutic effects on tumor proliferation (59). A direct correlation between 18 F-FLT uptake and Ki67 expression in tumor cells has been documented (56), leading to the use of this tracer in many tumor types as a surrogate for aggressiveness and an early marker of response (39,56,(107)(108)(109)(110)(111). Obviously, tumor size is an important prognostic indicator, and tumor volume determined by 18 F-FLT was assumed to be a better predictor of overall survival than the intensity of uptake (112).…”

PET/CT imaging in cancer: Current applications and future directions

“…Initial efforts focused on synthesizing analogs of thymidine, because thymidine is used by proliferating cells for DNA synthesis during the S-phase of the cell cycle but, unlike other nucleosides, is not incorporated into RNA. 60 The gold standard for assessing proliferation in vitro has long been 3 H-thymidine incorporation. 17 More recently, studies using 11 C-thymidine and PET demonstrated promise in assessing response to therapy; however, the short half-life of 11 C and its rapid metabolism to thymine and other metabolites made 11 Cthymidine impractical for routine clinical use outside of academic centers.…”

“…In addition, FLT demonstrates significant interfering physiologic activity in bone marrow and liver, and proliferating lymphocytes in reactive lymph nodes still have the potential to yield false-positive findings. 60,66 Thus, it is unlikely that FLT will have a dominant role in the initial diagnosis and staging of most cancers. Conversely, there is a general consensus that FLT-PET can be a valuable method for monitoring tumor response to treatment, especially as an early measure of response.…”

“…An alternative hypothesis relates to the finding that FLT traces only the salvage pathway for incorporation of thymidine into DNA, whereas many gastrointestinal cancers rely heavily on the de novo pathway, which is not tracked by FLT. 60,61 These findings indicate some potential limitations of FLT for monitoring the response to treatment, and it is likely that the choice of approach for early assessment of therapeutic response will need to be matched to the cancer and treatment types under study. Also, there is one report of a temporary rise in FLT uptake in patients with lung cancer who were receiving chemoradiation.…”