Kinetics of 3′-Deoxy-3′-[F-18]Fluorothymidine Uptake and Retention in Dogs

Shields, Anthony F.; Grierson, John R.; Muzik, Otto; Stayanoff, Joseph C.; Lawhorn-Crews, Jawana M.; Obradovich, Joyce E.; Mangner, Thomas J.

doi:10.1016/s1095-0397(01)00070-x

Cited by 38 publications

(26 citation statements)

References 9 publications

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“…On average, about 25% of the plasma activity is present as 18 F-FLT-glucuronide at 60 min after injection. This factor must be considered in measurement of the blood level of the tracer for use in kinetic modeling (60,61,64). Although clearance can vary from patient to patient, 18 F-FLT-glucuronide can be rea- sonably estimated by simple separation of a blood sample obtained at 60 min.…”

Section: Methods For In Vivo Imaging Of Cell Proliferation Radiotracementioning

confidence: 99%

Imaging of Cell Proliferation: Status and Prospects

Bading¹,

Shields²

2008

J Nucl Med

288

184

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Increased cellular proliferation is an integral part of the cancer phenotype. Several in vitro assays have been developed to measure the rate of tumor growth, but these require biopsies, which are particularly difficult to obtain over time and in different areas of the body in patients with multiple metastatic lesions. Most of the effort to develop imaging methods to noninvasively measure the rate of tumor cell proliferation has focused on the use of PET in conjunction with tracers for the thymidine salvage pathway of DNA synthesis, because thymidine contains the only pyrimidine or purine base that is unique to DNA. Imaging with 11 C-thymidine has been tested for detecting tumors and tracking their response to therapy in animals and patients. Its major limitations are the short half-life of 11 C and the rapid catabolism of thymidine after injection. These limitations led to the development of analogs that are resistant to degradation and can be labeled with radionuclides more conducive to routine clinical use, such as 18 F. At this point, the thymidine analogs that have been studied the most are 39-deoxy-39-fluorothymidine (FLT) and 1-(29-deoxy-29-fluoro-1-b-D-arabinofuranosyl)-thymine (FMAU). Both are resistant to degradation and track the DNA synthesis pathway. FLT is phosphorylated by thymidine kinase 1, thus being retained in proliferating cells. It is incorporated by the normal proliferating marrow and is glucuronidated in the liver. FMAU can be incorporated into DNA after phosphorylation but shows less marrow uptake. It shows high uptake in the normal heart, kidneys, and liver, in part because of the role of mitochondrial thymidine kinase 2. Early clinical data for 18 F-FLT demonstrated that its uptake correlates well with in vitro measures of proliferation. Although 18 F-FLT can be used to detect tumors, its tumor-to-normal tissue contrast is generally lower than that of 18 F-FDG in most cancers outside the brain. The most promising use for thymidine and its analogs is in monitoring tumor treatment response, as demonstrated in animal studies and pilot human trials. Further work is needed to determine the optimal tracer(s) and timing of imaging after treatment.

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Section: Methods For In Vivo Imaging Of Cell Proliferation Radiotracementioning

confidence: 99%

Imaging of Cell Proliferation: Status and Prospects

Bading¹,

Shields²

2008

J Nucl Med

288

184

View full text Add to dashboard Cite

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“…The 24 animals were divided into 4 equal groups according to the time of arterial blood sampling (5,10,30, and 60 min after the initiation of scanning). Dynamic PET scans were started immediately after the injection of 37 MBq of 18 F-FLT into tail veins and were completed at each group time for blood sampling by direct cardiac puncture.…”

Section: Validation Of LV Input Functionmentioning

confidence: 99%

“…A significant loss of phosphorylated 18 F-FLT nucleotides was also evident in kinetic studies of non-small cell lung cancer (11) and gliomas (12). However, previous 18 F-FLT kinetic studies in dogs bearing non-Hodgkin's lymphoma and soft-tissue sarcoma (30) and in patients with colorectal cancer (9) demonstrated that the incorporation of k 4 6 ¼ 0 is not necessary to improve model accuracy. In these studies, dynamic PET scans were acquired for only up to 60 min, a length of time that might not have been sufficient to accurately estimate the effects of the k 4 parameter.…”

Section: Compartmental Modelingmentioning

confidence: 99%

Kinetic Modeling of 3′-Deoxy-3′-¹⁸F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice

Kim

Lee²,

Im³

et al. 2008

J Nucl Med

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39-Deoxy-39-18 F-fluorothymidine ( 18 F-FLT) is a thymidine analog that was developed for measuring tumor proliferation with PET. The aim of this study was to establish a kinetic modeling analysis method for quantitative 18 F-FLT PET studies in subcutaneous tumor models in mice. Methods: To explore the validity of an image-derived left ventricular input function, we measured equilibrium constants for plasma and whole blood and metabolite fractions in blood after 18 F-FLT injection. In parallel, dynamic 18 F-FLT PET scans were acquired in 24 mice with a small-animal dedicated PET scanner to compare arterial blood activities obtained by PET and blood sampling. We then investigated kinetic models for 18 F-FLT in human epithelial carcinoma (A431) and Lewis lung carcinoma tumor models in mice. Three-compartment models with reversible phosphorylation (k 4 6 ¼ 0, 3C5P) and irreversible phosphorylation (k 4 5 0, 3C4P) and a 2-compartment model (2C3P) were examined. The Akaike information criterion and F statistics were used to select the best model for the dataset. Gjedde-Patlak graphic analysis was performed, and standardized uptake values in the last frame were calculated for comparison purposes. In addition, quantitative PET parameters were compared with Ki-67 immunostaining results. Results: 18 F-FLT equilibrated rapidly (within 30 s) between plasma and whole blood, and metabolite fractions were negligible during PET scans. A high correlation between arterial blood sampling and PET data was observed. For 120-min dynamic PET data, the 3C5P model best described tissue time-activity curves for tumor regions. The net influx of 18 F-FLT (K FLT ) and k 3 obtained with this model showed reasonable intersubject variability and discrimination ability for tumor models with different proliferation properties. The K FLT obtained from the 60-or 90-min data correlated well with that obtained from the 120-min data as well as with the Ki-67 results. Conclusion: The image-derived arterial input function was found to be feasible for kinetic modeling studies of 18 F-FLT PET in mice, and kinetic modeling analysis with an adequate compartment model provided reliable kinetic parameters for measuring tumor proliferation.

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“…1A). The high signal intensity in the liver and vertebrae has been attributed to glucuronidation and bone marrow cell proliferation, respectively (36). [ 18 F]FLT tumor localization was lower in an inflammatory tumor ( Fig.…”

Section: Visual Distribution Of 3v -Deoxy-3v -[mentioning

confidence: 99%

“…]FLT-PET images showed high tumor-to-background contrast. Uptake was also seen in the liver and bone marrow due to catabolism of the radiotracer, as well as its uptake by the proliferating bone marrow cells (28,36).…”

Section: Visual Distribution Of 3v -Deoxy-3v -[mentioning

confidence: 99%

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

Kenny¹,

et al. 2005

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There is an unmet need to develop imaging methods for the early and objective assessment of breast tumors to therapy. 18 F]FLT (K i ) ranged from 0.6 to 10.4 Â 10 À4 and from 0 to 0.6 Â 10 À4 mL plasma cleared/s/mL tissue in tumor (29 regions, 15 patients) and normal tissues, respectively. Tumor K i and fractional retention of radiotracer determined by spectral analysis correlated with Ki-67 labeling index (r = 0.92, P < 0.0001 and r = 0.92, P < 0.0001, respectively). These correlations were superior to those determined by semiquantitative methods. We conclude that [ 18 F]FLT-positron emission tomography is a promising clinical tool for imaging cellular proliferation in breast cancer, and is most predictive when analyzed by graphical and spectral methods. (Cancer Res 2005; 65(21): 10104-12)

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Kinetics of 3′-Deoxy-3′-[F-18]Fluorothymidine Uptake and Retention in Dogs

Cited by 38 publications

References 9 publications

Imaging of Cell Proliferation: Status and Prospects

Imaging of Cell Proliferation: Status and Prospects

Kinetic Modeling of 3′-Deoxy-3′-¹⁸F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice

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

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Kinetics of 3′-Deoxy-3′-[F-18]Fluorothymidine Uptake and Retention in Dogs

Cited by 38 publications

References 9 publications

Imaging of Cell Proliferation: Status and Prospects

Imaging of Cell Proliferation: Status and Prospects

Kinetic Modeling of 3′-Deoxy-3′-18F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice

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

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Kinetic Modeling of 3′-Deoxy-3′-¹⁸F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice