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

Viertl, David; Delaloye, Angelika Bischof; Lanz, Bernard; Poitry‐Yamate, Carole; Gruetter, Rolf; Mlynarik, Vladimir; Ametamey, Simon M.; Roß, Tobias L.; Lehr, Hans‐Anton; André, Pierre-Alain; Perillo-Adamer, Florence; Kosinski, Marek; Dupertuis, Y.M.; Buchegger, Franz

doi:10.1007/s11307-010-0368-z

Cited by 12 publications

(42 citation statements)

References 23 publications

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“…This is in accordance with studies showing that sub-therapeutic doses of TS inhibiting agents induce an [ 18 F]FLT increase in vitro (33) and in vivo (34).…”

Section: Discussionsupporting

confidence: 92%

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

et al. 2016

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3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.

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“…This is in accordance with studies showing that sub-therapeutic doses of TS inhibiting agents induce an [ 18 F]FLT increase in vitro (33) and in vivo (34).…”

Section: Discussionsupporting

confidence: 92%

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

et al. 2016

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“…Although 18 F-FLT is not a substrate for phosphorolysis by thymidine phosphorylase, the endogenous thymidine competing with 18 F-FLT is, so thymidine phosphorylase activity, which has been shown to be elevated in a variety of tumor types including NSCLC (35), may also indirectly affect 18 F-FLT uptake, as reported in rats undergoing 18 F-FLT PET (36). Similarly, depletion of endogenous blood thymidine levels by coadministration of 5-fluoro-29-deoxyuridine has been demonstrated to greatly enhance 18 F-FLT uptake of human tumors xenografted into mice (37). These findings illustrate that a kinetic rate constant (e.g., k 3 ) does not necessarily represent a discrete step in subcellular tracer movement and processing, which can be correlated with a single catalytic activity; each rate constant is potentially dependent on multiple catalytic activities and their respective substrate affinities for 18 F-FLT relative to endogenous thymidine.…”

Section: Discussionmentioning

confidence: 99%

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

Brockenbrough¹,

Souquet²,

Morihara³

et al. 2011

J Nucl Med

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“…Because FLT correlates with thymidine kinase I expression, it is used as a means to measure cellular proliferation found within malignancies (Viertl et al , 2010; Brockenbrough et al , 2011). Clinically, it has been used extensively for diagnosis and grading (Dittmann et al , 2003; Choi et al , 2005).…”

Section: Methodsmentioning

confidence: 99%

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

et al. 2012

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Introduction We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Methods Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n=10), or a ‘fast-clearing agent, 18F-FLT (3′-deoxy-3′-fluorothymidine) (n=13), and imaged via microPET/CT pseudo-dynamically or dynamically, respectively. Regions-of-interest (ROI) were drawn within the heart and tumor to create time-concentration-curves (TCC) for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao Lower Bounds (CRLB) theory. Accuracy was assessed using correlation coefficient, bias, and standard error of the estimate normalized to the mean (SEE/mean). Results The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 hr−1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, kel (0.050 ± 0.025 min−1), normal body retention, k12/k21 (2.21 ± 0.62) and tumor retention, k34/k43 (0.65 ± 0.17), and predicted dosimetry, Dtumor (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k12, and central compartment influx rate constant, k21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C0, was most sensitive at early time points; central elimination, kel, and tumor efflux, k43, are most sensitive at later time points. Conclusions A PK model for TRT was applied to both a slow-clearing, NM404, and fast-clearing, FLT, agent in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k12, k21, kel, k34, and k43 will translate ...

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

Cited by 12 publications

References 23 publications

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

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

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

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

Cited by 12 publications

References 23 publications

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

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

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

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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