Thymidine Metabolism as a Confounding Factor for 3′-Deoxy-3′-<sup>18</sup>F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model

Schelhaas, Sonja; Wachsmuth, Lydia; Hermann, Sven; Rieder, Natascha; Heller, Astrid; Heinzmann, Kathrin; Honess, Davina J.; Smith, Donna-Michelle; Fricke, Inga B.; Just, Nathalie; Doblas, Sabrina; Sinkus, Ralph; Döring, Christian; Schäfers, Klaus P.; Griffiths, John R.; Faber, Cornelius; Schneider, Richard; Aboagye, Eric O.

doi:10.2967/jnumed.117.206250

Cited by 6 publications

(23 citation statements)

References 31 publications

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“…Despite the imaging of glial activation has been fully characterized with TSPO radiotracers during the last decade, the investigation of glial cell proliferation using PET imaging still remains unexplored. PET imaging of cellular proliferation has been mainly limited to the use of 3′-Deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT) in both preclinical and clinical routine ( McHugh et al, 2018 ; Schelhaas et al, 2018 ; Bashir et al, 2020 ). [ 18 F]FLT is an analog of thymidine which is phosphorylated by thymidine kinase-1 (TK-1), an enzyme expressed during the DNA synthesis and up-regulated during the S phase of the cell cycle ( Shields et al, 1998 ).…”

Section: Introductionmentioning

confidence: 99%

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

Ardaya¹,

Joya²,

Padró³

et al. 2020

Front. Neurosci.

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In vivo positron emission tomography of neuroinflammation has mainly focused on the evaluation of glial cell activation using radiolabeled ligands. However, the non-invasive imaging of neuroinflammatory cell proliferation has been scarcely evaluated so far. In vivo and ex vivo assessment of gliogenesis after transient middle cerebral artery occlusion (MCAO) in rats was carried out using PET imaging with the marker of cell proliferation 3′-Deoxy-3′-[18F] fluorothymidine ([ 18 F]FLT), magnetic resonance imaging (MRI) and fluorescence immunohistochemistry. MRI-T 2 W studies showed the presence of the brain infarction at 24 h after MCAO affecting cerebral cortex and striatum. In vivo PET imaging showed a significant increase in [ 18 F]FLT uptake in the ischemic territory at day 7 followed by a progressive decline from day 14 to day 28 after ischemia onset. In addition, immunohistochemistry studies using Ki67, CD11b, and GFAP to evaluate proliferation of microglia and astrocytes confirmed the PET findings showing the increase of glial proliferation at day 7 after ischemia followed by decrease later on. Hence, these results show that [ 18 F]FLT provides accurate quantitative information on the time course of glial proliferation in experimental stroke. Finally, this novel brain imaging method might guide on the imaging evaluation of the role of gliogenesis after stroke.

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Section: Introductionmentioning

confidence: 99%

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

Ardaya¹,

Joya²,

Padró³

et al. 2020

Front. Neurosci.

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“…Vehicle treatment (for comparison to gemcitabine treatment) was conducted by intraperitoneal injection of 2.5 µl/g bodyweight 0.9% NaCl and PET, and MR imaging was performed on the following day (d1), as well as before treatment initiation (d-6). For the colorectal cancers [9], 5 × 10 6 Colo205 were implanted in CD1 nude mice, and vehicle treatment (for comparison to a FOLFOX-like therapy; 0 h: 0.9% NaCl 1.6 µl/g bodyweight i.p. ; 1.5 h: 5% glucose 9 µl/g bodyweight retrobulbar; 2 h and 6 h: 0.9% NaCl 0.6 µl/g bodyweight) was done on d0 and d7.…”

Section: Schelhaas S Et Al: [ 18 F]flt and Adc Voxel Analysis In Tumor Modelsmentioning

confidence: 99%

“…[ 18 F]FLT was calculated as %ID/ml using the in-house developed software MEDgical. ADC was calculated using a monoexponential fit as described in detail previously [8,9]. In order to assess the correlation between [ 18 F]FLT-PET and ADC-MRI data, a voxel-wise analysis in MATLAB (The MathWorks, Natick, MA, USA) has been developed.…”

Section: Image Analysismentioning

confidence: 99%

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Voxel-Based Analysis of the Relation of 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET and Diffusion-Weighted (DW) MR Signals in Subcutaneous Tumor Xenografts Does Not Reveal a Direct Spatial Relation of These Two Parameters

et al. 2021

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Purpose Multimodal molecular imaging allows a direct coregistration of different images, facilitating analysis of the spatial relation of various imaging parameters. Here, we further explored the relation of proliferation, as measured by [18F]FLT PET, and water diffusion, as an indicator of cellular density and cell death, as measured by diffusion-weighted (DW) MRI, in preclinical tumor models. We expected these parameters to be negatively related, as highly proliferative tissue should have a higher density of cells, hampering free water diffusion. Procedures Nude mice subcutaneously inoculated with either lung cancer cells (n = 11 A549 tumors, n = 20 H1975 tumors) or colorectal cancer cells (n = 13 Colo205 tumors) were imaged with [18F]FLT PET and DW-MRI using a multimodal bed, which was transferred from one instrument to the other within the same imaging session. Fiducial markers allowed coregistration of the images. An automatic post-processing was developed in MATLAB handling the spatial registration of DW-MRI (measured as apparent diffusion coefficient, ADC) and [18F]FLT image data and subsequent voxel-wise analysis of regions of interest (ROIs) in the tumor. Results Analyses were conducted on a total of 76 datasets, comprising a median of 2890 data points (ranging from 81 to 13,597). Scatterplots showing [18F]FLT vs. ADC values displayed various grades of relations (Pearson correlation coefficient (PCC) varied from − 0.58 to 0.49, median: -0.07). When relating PCC to tumor volume (median: 46 mm3, range: 3 mm3 to 584 mm3), lung tumors tended to have a more pronounced negative spatial relation of [18F]FLT and ADC with increasing tumor size. However, due to the low number of large tumors (> ~ 200 mm3), this conclusion has to be treated with caution. Conclusions A spatial relation of water diffusion, as measured by DW-MRI, and cellular proliferation, as measured by [18F]FLT PET, cannot be detected in the experimental datasets investigated in this study.

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“…The high rate of aerobic glycolysis is one of the prominent features of cancer cells. Therefore, 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/ computed tomography (PET/CT) has been widely used in cancer diagnosis, including in clinical staging and efficacy monitoring [14,15]. High levels of glycolysis allow cancer cells to sustain rapid proliferation and evade programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging

Zhang,

Kong

et al. 2024

Cancer Cell Int

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Background Breast cancer is a serious threat to women’s health with high morbidity and mortality. The development of more effective therapies for the treatment of breast cancer is strongly warranted. Growing evidence suggests that targeting glucose metabolism may be a promising cancer treatment strategy. We previously identified a new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated the anticancer potential of DC-5163 in breast cancer cells. Methods The effects of DC-5163 on breast cancer cells were investigated in vitro and in vivo. Seahorse, glucose uptake, lactate production, and cellular ATP content assays were performed to examine the impact of DC-5163 on cellular glycolysis. Cell viability, colony-forming ability, cell cycle, and apoptosis were assessed by CCK8 assay, colony formation assay, flow cytometry, and immunoblotting respectively. The anticancer activity of DC-5163 in vivo was evaluated in a mouse breast cancer xenograft model. Results DC-5163 suppressed aerobic glycolysis and reduced energy supply of breast cancer cells, thereby inhibiting breast cancer cell growth, inducing cell cycle arrest in the G0/G1 phase, and increasing apoptosis. The therapeutic efficacy was assessed using a breast cancer xenograft mouse model. DC-5163 treatment markedly suppressed tumor growth in vivo without inducing evident systemic toxicity. Micro-PET/CT scans revealed a notable reduction in tumor 18F-FDG and 18F-FLT uptake in the DC-5163 treatment group compared to the DMSO control group. Conclusions Our results suggest that DC-5163 is a promising GAPDH inhibitor for suppressing breast cancer growth without obvious side effects. 18F-FDG and 18F-FLT PET/CT can noninvasively assess the levels of glycolysis and proliferation in tumors following treatment with DC-5163.

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Thymidine Metabolism as a Confounding Factor for 3′-Deoxy-3′-¹⁸F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model

Cited by 6 publications

References 31 publications

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

Voxel-Based Analysis of the Relation of 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET and Diffusion-Weighted (DW) MR Signals in Subcutaneous Tumor Xenografts Does Not Reveal a Direct Spatial Relation of These Two Parameters

The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging

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Thymidine Metabolism as a Confounding Factor for 3′-Deoxy-3′-18F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model

Cited by 6 publications

References 31 publications

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

Voxel-Based Analysis of the Relation of 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET and Diffusion-Weighted (DW) MR Signals in Subcutaneous Tumor Xenografts Does Not Reveal a Direct Spatial Relation of These Two Parameters

The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging

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Thymidine Metabolism as a Confounding Factor for 3′-Deoxy-3′-¹⁸F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model