FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3'-deoxy-3'-[18F]fluorothymidine.

Positron emission tomography (PET) using the radiotracer 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) can image cellular proliferation in human cancers in vivo. FLT uptake has been shown to correlate with pathology-based proliferation measurements, including the Ki-67 score, in a variety of human cancers. Unlike pathology-based measurements, imaging-based methods, including FLT-PET, are noninvasive, easily repeatable, and less prone to sampling errors. FLT-PET may therefore be a useful tool for assessing tumor aggressiveness, predicting outcome, planning therapy, or monitoring response to treatment. Three recent clinical studies have reported that FLT-PET can accurately predict response very early after the initiation of chemotherapy. Especially with the advent of cytostatic chemotherapy agents, methods of biologically assessing a tumor's response will take on increasing importance, since changes in tumor size will not always be expected. To date, most studies of FLT-PET have focused on validating it as a means of quantifying cellular proliferation and testing its ability to accurately stage cancer. In some settings, FLT-PET has shown greater specificity for cancer than (18)F-fluorodeoxyglucose (FDG)-PET, which can show false-positive uptake in areas of infection or inflammation. However, because of FLT's lower overall uptake and higher background activity in liver and bone marrow, FLT-PET should not be considered a potential replacement for staging by FLT-PET. Instead, FLT-PET should be considered a powerful addition to FDG-PET, providing additional diagnostic specificity and important biological information that could be useful in predicting prognosis, planning treatment, and monitoring response.

[1]  Kyung-Ja Cho,et al.  Use of 3′-deoxy-3′-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors , 2006, European Journal of Nuclear Medicine and Molecular Imaging.

[2]  T K Lewellen,et al.  Carbon-11-thymidine and FDG to measure therapy response. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  M. Muzi,et al.  Metabolism of 3'-deoxy-3'-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. , 2004, Nuclear medicine and biology.

[4]  H. Hoekstra,et al.  3'-18F-fluoro-3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[5]  Y. Yonekura,et al.  Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. , 2002, Nuclear medicine and biology.

[6]  W. Mikulits,et al.  Overexpression of Thymidine Kinase mRNA Eliminates Cell Cycle Regulation of Thymidine Kinase Enzyme Activity (*) , 1996, The Journal of Biological Chemistry.

[7]  H. Sakahara,et al.  Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[8]  Mark Muzi,et al.  True tracers: comparing FDG with glucose and FLT with thymidine. , 2005, Nuclear medicine and biology.

[9]  H. Dittmann,et al.  Early changes in [18F]FLT uptake after chemotherapy: an experimental study , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[10]  H. Vesselle,et al.  Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses , 2007, BMC nuclear medicine.

[11]  J. Baak,et al.  Prognostic value of proliferation in invasive breast cancer: a review , 2004, Journal of Clinical Pathology.

[12]  Karl Herholz,et al.  18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[13]  I. McNeish,et al.  Quantifying the activity of adenoviral E1A CR2 deletion mutants using renilla luciferase bioluminescence and 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography imaging. , 2006, Cancer research.

[14]  Y. Nishiyama,et al.  Correlation of 18F-FLT and 18F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[15]  L. Ståhle,et al.  Transport of alovudine (3'-fluorothymidine) into the brain and the cerebrospinal fluid of the rat, studied by microdialysis. , 2000, Life sciences.

[16]  J. Lafitte,et al.  Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis , 2004, British Journal of Cancer.

[17]  S. Conrad,et al.  Independent regulation of thymidine kinase mRNA and enzyme levels in serum-stimulated cells. , 1990, The Journal of biological chemistry.

[18]  M. Berger,et al.  2-[C-11]thymidine imaging of malignant brain tumors. , 1999, Cancer research.

[19]  D. Wood,et al.  Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  Otto Muzik,et al.  A simplified analysis of [18F]3′-deoxy-3′-fluorothymidine metabolism and retention , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[21]  W. Vaalburg,et al.  18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  C. Dence,et al.  Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  Falko Fend,et al.  Early Response Assessment Using 3′-Deoxy-3′-[18F]Fluorothymidine-Positron Emission Tomography in High-Grade Non-Hodgkin's Lymphoma , 2007, Clinical Cancer Research.

[24]  Ur Metser,et al.  Increased (18)F-fluorodeoxyglucose uptake in benign, nonphysiologic lesions found on whole-body positron emission tomography/computed tomography (PET/CT): accumulated data from four years of experience with PET/CT. , 2007, Seminars in nuclear medicine.

[25]  W. Vaalburg,et al.  Detection and Grading of Soft Tissue Sarcomas of the Extremities with 18F-3′-Fluoro-3′-Deoxy-l-Thymidine , 2004, Clinical Cancer Research.

[26]  J. Sherley,et al.  Regulation of human thymidine kinase during the cell cycle. , 1988, The Journal of biological chemistry.

[27]  K. Krohn,et al.  Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3'-deoxy-3'fluorothymidine uptake. , 2004, Nuclear medicine and biology.

[28]  Jae Seung Kim,et al.  [18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[29]  K. Ishiwata,et al.  Early response of sigma-receptor ligands and metabolic PET tracers to 3 forms of chemotherapy: an in vitro study in glioma cells. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[30]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  U. Haberkorn,et al.  Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐thymidine with 2,3′‐anhydro‐5′‐O‐(4,4′‐dimethoxytrityl)‐thymidine , 2000 .

[32]  J. R. Grierson,et al.  Simplified Labeling Approach for Synthesizing 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) , 2000 .

[33]  S. Eriksson,et al.  Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. , 1991, The Journal of biological chemistry.

[34]  J B Bassingthwaighte,et al.  Contribution of labeled carbon dioxide to PET imaging of carbon-11-labeled compounds. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[35]  T. Chou,et al.  Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine , 1992, Antimicrobial Agents and Chemotherapy.

[36]  T. Mattfeldt,et al.  Molecular imaging of proliferation in malignant lymphoma. , 2006, Cancer research.

[37]  M. Hirsch,et al.  Enhanced in vitro inhibition of HIV-1 replication by 3'-fluoro-3'-deoxythymidine compared to several other nucleoside analogs. , 1988, AIDS Research and Human Retroviruses.

[38]  H. Dittmann,et al.  [18F]FLT PET for diagnosis and staging of thoracic tumours , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[39]  Otto Muzik,et al.  Imaging proliferation in vivo with [F-18]FLT and positron emission tomography , 1998, Nature Medicine.

[40]  A. Harris,et al.  Measuring tumor pharmacodynamic response using PET proliferation probes: the case for 2-[(11)C]-thymidine. , 2004, Biochimica et biophysica acta.

[41]  D. Mankoff,et al.  A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labeled metabolites. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[42]  E. Wintersberger,et al.  Different regulation of thymidine kinase during the cell cycle of normal versus DNA tumor virus-transformed cells. , 1994, The Journal of biological chemistry.

[43]  D. Visvikis,et al.  Potential impact of [18F]3'-deoxy-3'-fluorothymidine versus [18F]fluoro-2-deoxy-d-glucose in positron emission tomography for colorectal cancer , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[44]  D. Mankoff,et al.  Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[45]  Michael E Phelps,et al.  Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-positron emission tomography. , 2006, Chest.

[46]  Qimin He,et al.  3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. , 2003, Cancer research.

[47]  T. Powles,et al.  Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma , 2000, Cancer.

[48]  K. Gatter,et al.  Ki67 protein: the immaculate deception? , 2002, Histopathology.

[49]  F. O’Sullivan,et al.  Kinetic Analysis of 2-[11C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Compartmental Model Investigation and Mathematical Analysis , 2002 .

[50]  Gerald Reischl,et al.  PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study , 2004, European Journal of Nuclear Medicine and Molecular Imaging.

[51]  L. Wiens,et al.  Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[52]  S. Reske,et al.  [18F]3'-deoxy-3'-fluorothymidine-PET in NHL patients: whole-body biodistribution and imaging of lymphoma manifestations--a pilot study. , 2004, Cancer biotherapy & radiopharmaceuticals.

[53]  E. Wintersberger,et al.  Regulation of thymidine kinase during growth, cell cycle and differentiation. , 1992, Advances in enzyme regulation.

[54]  Eric O. Aboagye,et al.  Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[55]  B. Drayer,et al.  Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? , 1998, AJNR. American journal of neuroradiology.

[56]  Torsten Mattfeldt,et al.  Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[57]  K. Krohn,et al.  Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[58]  C. Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[59]  Stephen R Thomas,et al.  MIRD dose estimate report no. 19: radiation absorbed dose estimates from (18)F-FDG. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[60]  M. Kitajima,et al.  Cell-Cycle Regulators and the Ki-67 Labeling Index Can Predict the Response to Chemoradiotherapy and the Survival of Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus , 2003, Annals of Surgical Oncology.

[61]  H. Hoekstra,et al.  18F-fluorodeoxythymidine PET for evaluating the response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcomas. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[62]  Janet F. Eary,et al.  Kinetic Analysis of 2-[11C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Preliminary Patient Results , 2002 .

[63]  J. Wesseling,et al.  Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[64]  C Flexner,et al.  Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. , 1994, The Journal of infectious diseases.

[65]  J Grierson,et al.  Utilization of labeled thymidine in DNA synthesis: studies for PET. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[66]  Mark Muzi,et al.  Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[67]  B. Oberg,et al.  Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action , 1992, Antimicrobial Agents and Chemotherapy.

[68]  Mark Muzi,et al.  In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[69]  D. Mankoff,et al.  Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[70]  H. Vesselle,et al.  FDG PET of the retroperitoneum: normal anatomy, variants, pathologic conditions, and strategies to avoid diagnostic pitfalls. , 1998, Radiographics : a review publication of the Radiological Society of North America, Inc.

[71]  S. Osman,et al.  Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intra-abdominal malignancies. , 2002, Cancer research.

[72]  A. Shields,et al.  Radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine: [(18)F]FLT for imaging of cellular proliferation in vivo. , 2000, Nuclear medicine and biology.

[73]  P. Martiat,et al.  In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin's lymphoma using positron emission tomography. , 1988, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[74]  F. O’Sullivan,et al.  Kinetic analysis of 2-[11C]thymidine PET imaging studies of malignant brain tumors: preliminary patient results. , 2002, Molecular imaging.

[75]  Paul Workman,et al.  In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. , 2006, Cancer research.

[76]  Michael E. Phelps,et al.  Usefulness of 3′-[F-18]Fluoro-3′-deoxythymidine with Positron Emission Tomography in Predicting Breast Cancer Response to Therapy , 2005, Molecular Imaging and Biology.

[77]  T. Mattfeldt,et al.  Early assessment of therapy response in malignant lymphoma with the thymidine analogue [18F]FLT , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[78]  T. Mattfeldt,et al.  Clinical relevance of imaging proliferative activity in lung nodules , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[79]  Bengt Långström,et al.  Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[80]  Ludwig G. Strauss,et al.  Fluorine-18 deoxyglucose and false-positive results: a major problem in the diagnostics of oncological patients , 1996, European Journal of Nuclear Medicine.

[81]  Adeeba Kamarulzaman,et al.  AIDS Res Hum Retroviruses , 2006 .

[82]  J. Ajani,et al.  Early Detection of Chemoradioresponse in Esophageal Carcinoma by 3′-Deoxy-3′-3H-Fluorothymidine Using Preclinical Tumor Models , 2006, Clinical Cancer Research.

[83]  Mark Muzi,et al.  Kinetic modeling of 3'-deoxy-3'-fluorothymidine in somatic tumors: mathematical studies. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[84]  H. Groen,et al.  Is 18F-3'-fluoro-3'-deoxy-L-thymidine useful for the staging and restaging of non-small cell lung cancer? , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[85]  Y. Yonekura,et al.  Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring. , 2006, Nuclear medicine and biology.

[86]  H. Hoekstra,et al.  Positron emission tomography in patients with breast cancer using (18)F-3'-deoxy-3'-fluoro-l-thymidine ((18)F-FLT)-a pilot study. , 2006, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[87]  Sven N Reske,et al.  3'-[18F]fluoro-3'-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease. , 2003, Cancer research.

[88]  D. Kinzel,et al.  Fluorine-18-FDG PET and iodine-123-IMT SPECT in the evaluation of brain tumors. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[89]  S. Shousha,et al.  Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods. , 2005, Cancer research.

[90]  P. Price,et al.  The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[91]  W. Oyen,et al.  18F-FLT PET Does Not Discriminate Between Reactive and Metastatic Lymph Nodes in Primary Head and Neck Cancer Patients , 2007, Journal of Nuclear Medicine.

[92]  D. Mankoff,et al.  Kinetic analysis of 2-[carbon-11]thymidine PET imaging studies: compartmental model and mathematical analysis. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[93]  T. Manabe,et al.  Evaluation of Primary Brain Tumors With FLT-PET: Usefulness and Limitations , 2006, Clinical nuclear medicine.

[94]  Mark Muzi,et al.  Kinetic analysis of 3'-deoxy-3'-fluorothymidine PET studies: validation studies in patients with lung cancer. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[95]  Mark Muzi,et al.  Positron emission tomography imaging of brain tumors. , 2003, Neuroimaging clinics of North America.

[96]  H. Vesselle,et al.  The Ki‐67 Index and Survival in Non‐‐‐Small Cell Lung Cancer: A Review and Relevance to Positron Emission Tomography , 2002, Cancer journal.

[97]  M. J. van de Vijver,et al.  Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome , 2003, British Journal of Cancer.

[98]  H. Vesselle,et al.  A SepPak unit for batch processing serial blood plasma samples for PET , 2007 .

[99]  E. Aboagye,et al.  Early detection of tumor response to chemotherapy by 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography: the effect of cisplatin on a fibrosarcoma tumor model in vivo. , 2005, Cancer research.

[100]  D. Mankoff,et al.  18F-Fluorothymidine radiation dosimetry in human PET imaging studies. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[101]  Marvin Bergsneider,et al.  Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.