Tumor 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) Uptake by PET Correlates with Thymidine Kinase 1 Expression: Static and Kinetic Analysis of 18F-FLT PET Studies in Lung Tumors

Brockenbrough, J. Scott; Souquet, Timothee; Morihara, Janice; Stern, Joshua; Hawes, Stephen E.; Rasey, Janet S.; Leblond, Antoine; Wiens, Linda; Feng, Qinghua; Grierson, John R.; Vesselle, Hubert

doi:10.2967/jnumed.111.089482

Cited by 48 publications

(31 citation statements)

References 27 publications

(25 reference statements)

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“…3). Competition of endogenous thymidine and 18 F-FLT for binding to nucleoside transporters or the catalytic site of TK1 has been described before (22,32). Indeed, we showed a significant negative correlation of tumor thymidine level with 18 F-FLT uptake (Fig.…”

Section: Discussionsupporting

confidence: 75%

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

et al. 2014

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Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3′-deoxy-3′-18 Ffluorothymidine ( 18 F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. Methods: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by 18 F-FDG and 18 F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2′-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry. Results: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. 18 F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in 18 F-FDG uptake were only marginal. No clear relationship between 18 F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence 18 F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. Conclusion: A direct relationship of 18 F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.

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Section: Discussionsupporting

confidence: 75%

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

et al. 2014

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“…Keen et al reported a strong correlation between 18 F-FLT uptake, tk-1 expression, and Ki-67 expression in a human xenograft carcinoma model (29), but the relationship between tk-1 and Ki-67 expression is not evident in every carcinoma model, as Ki-67 represents a somewhat larger amount of the cell cycle than tk-1 (29). Brockenbrough et al recently suggested that the 18 F-FLT uptake may also be influenced by factors besides tk-1 activity, including competition with endogenous thymidine, transport via nucleoside transporters, the degradative metabolism of phosphorylated metabolites, and the rate of DNA repair (37). Additionally, changes in perfusion rate, vascular permeability, and the activity of nucleoside transporters may alter 18 F-FLT uptake independently of cell proliferation (31).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-¹⁸F-Fluorothymidine and Small-Animal PET

Fuchs

Kohlhofer

Quintanilla-Martı́nez

et al. 2012

J Nucl Med

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“…In a cohort of 25 suspected lung cancer patients, 18 F-FLT PET images were performed before surgical resection and compared with expression of Ki-67 and TK1 determined by immunohistochemical staining (67). TK1 enzymatic activity was also determined in extracts from flashfrozen samples of the tumors.…”

Section: Lung Cancermentioning

confidence: 99%

PET Imaging of Proliferation with Pyrimidines

Tehrani

Shields

2013

J Nucl Med

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Tumor 3′-Deoxy-3′-¹⁸F-Fluorothymidine (¹⁸F-FLT) Uptake by PET Correlates with Thymidine Kinase 1 Expression: Static and Kinetic Analysis of ¹⁸F-FLT PET Studies in Lung Tumors

Abstract: The absence of observable correlations of the imaging parameters with TK1 activity suggests that (18)F-FLT uptake and retention within cells may be complicated by a variety of still undetermined factors in addition to TK1 enzymatic activity.

Cited by 48 publications

References 27 publications

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-¹⁸F-Fluorothymidine and Small-Animal PET

PET Imaging of Proliferation with Pyrimidines

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Tumor 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) Uptake by PET Correlates with Thymidine Kinase 1 Expression: Static and Kinetic Analysis of 18F-FLT PET Studies in Lung Tumors

Abstract: The absence of observable correlations of the imaging parameters with TK1 activity suggests that (18)F-FLT uptake and retention within cells may be complicated by a variety of still undetermined factors in addition to TK1 enzymatic activity.

Cited by 48 publications

References 27 publications

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-18F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-18F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-18F-Fluorothymidine and Small-Animal PET

PET Imaging of Proliferation with Pyrimidines

Contact Info

Product

Resources

About

Tumor 3′-Deoxy-3′-¹⁸F-Fluorothymidine (¹⁸F-FLT) Uptake by PET Correlates with Thymidine Kinase 1 Expression: Static and Kinetic Analysis of ¹⁸F-FLT PET Studies in Lung Tumors

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET and Diffusion-Weighted MR Imaging

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-¹⁸F-Fluorothymidine and Small-Animal PET