[18F]FLT-PET Imaging Does Not Always "Light Up" Proliferating Tumor Cells (original) (raw)
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Nuclear Medicine Communications, 2009
Positron emission tomography (PET) using F-18 fluoro-3 0-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. Nucl Med Commun 30:908-917 c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2004
18 F]-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) is becoming accepted as a diagnostic tool for cancer, but the potential uses of PET in oncology extend beyond the imaging of glucose metabolism. The development of a PET proliferation probe would be a useful pharmacodynamic tool. [ 11 C]-thymidine PET has been assessed in man as a specific measure of tumor proliferation. Uptake of [ 11 C]-thymidine is related to DNA synthesis and, in human tumors, correlates with proliferation. When compared with 18 F-FDG, it has been shown to be a more sensitive discriminator of early clinical tumor response. 2-[ 11 C]-thymidine PET scanning of patients enrolled in early phase clinical trials is feasible and should support future drug development. Although recent research is moving away from the validation of thymidine towards thymidine analogues radiolabeled with 18 F, the better specificity of thymidine for DNA should be the rationale for its continued development and application as a PET probe.
PET clinics, 2014
For noninvasive in vivo imaging of proliferation, 18F-FLT PET/CT remains a promising tool, owing to its correlation with proliferation indexes in many tumor entities. Future clinical applications will focus on monitoring response to cancer therapy, whereas tumor detection will be limited to organs with high physiologic 18F-FDG uptake. Use and interpretation of 18F-FLT requires knowledge of the physiologic tracer distribution and how it will be affected by anticancer treatment. Further studies are needed to determine the optimal timing of 18F-FLT PET/CT imaging in the course of cancer therapies or at the conclusion of therapy.
Molecular Imaging and Biology, 2011
Purpose: 3′-deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2′-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [ 18 F]FLT in tumor xenografts. Methods: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[ 125 I]iodo-2′-deoxyuridine biodistribution measurements. In [ 18 F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection.
European Journal of Cancer, 2012
The paradigm of drug development is shifting towards early use of imaging biomarkers as surrogate end-points in clinical trials. Quantitative Imaging in Cancer: Connecting Cellular Processes (QuIC-ConCePT) is an initiative to qualify complementary imaging biomarkers (IB) of proliferation, cell death and tumour heterogeneity as possible tools in early phase clinical trials to help pharmaceutical developers in ‘go, no-go’ decisions early in the process of drug development. One of the IBs is [18F]30-deoxy-30-fluorothymidine with Positron Emission Tomography (FLT–PET). We review results of recent clinical trials using FLT–PET for monitoring tumour response to drug treatment and discuss the potential and the possible pitfalls of using this IB as a surrogate end-point in early phase clinical trials for assessing tumour response to drug treatment. From first human trial results it seems that the degree of FLT accumulation in tumours is governed not only by the tumour proliferation rate but also by other factors. Nevertheless FLT–PET could potentially be used as a negative predictor of tumour response to chemotherapy, and hence evaluation of this IB is granted in multi-centre clinical trials.
2003
3 -Deoxy-3 -[F]fluorothymidine ([F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [F]FLT is regulated by cytosolic S-phasespecific thymidine kinase 1 (TK1). In this article, we have investigated the use of [F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [F]FLT and 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) were measured in three groups of mice (n 8–12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (...
Cancer research, 2003
3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [(18)F]FLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of [(18)F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [(18)F]FLT and 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) were measured in three groups of mice (n = 8-12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [(18)F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [(18)F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological se...
Preclinical Applications of 3'-Deoxy-3'-[(18)F]Fluorothymidine in Oncology - A Systematic Review
Theranostics, 2017
The positron emission tomography (PET) tracer 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]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, [(18)F]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 [(18)F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [(18)F]FLT studies, comprising 174 reports, we identify the factors governing [(18)F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [(18)F]FLT uptake reflects the effects of anticancer therapies. 144 times [(18)F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
Tumor proliferation has prognostic value in resected early stage non-small cell lung cancer (NSCLC) and can, therefore, predict which NSCLCs are at high risk for recurrence after resection and would benefit from additional therapy. It may also predict which tumor will respond to cell cycle-targeted chemotherapy and help assess the tumor response, besides helping to differentiate benign from malignant lung lesions. We evaluated whether the uptake of the new positron emission tomography (PET) tracer 3'deoxy-3'-[18F]fluorothymidine (FLT) in a series of suspected NSCLCs correlated with tumor proliferation assessed by Ki-67 immunohistochemistry and flow cytometry. Ten patients with 11 biopsy-proven or clinically suspected NSCLC underwent 2-h dynamic PET imaging after i.v. injection of 0.07 mCi/kg FLT. Tumor FLT uptake was quantitated with the maximum pixel standardized uptake value (maxSUV), the partial volume corrected maxSUV (PV-corr-maxSUV), the average SUV over a small region...