[18F]FLT–PET Imaging Does Not Always “Light Up” Proliferating Tumor Cells

Zhang, Cathy C.; Yan, Zhengming; Li, Wenlin; Kuszpit, Kyle; Painter, Cory L.; Zhang, Qin; Lappin, Patrick B.; Nichols, Timothy C.; Lira, Maruja E.; Affolter, Timothy; Fahey, Neeta; Cullinane, Carleen; Spilker, Mary E.; Zasadny, Kenneth R.; O’Brien, Peter J.; Buckman, Dana; Wong, Anthony; Christensen, James G.

doi:10.1158/1078-0432.ccr-11-1433

Cited by 70 publications

(67 citation statements)

References 29 publications

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“…The proliferation marker BrdU is a thymidine analog that is incorporated into DNA and can be detected by specific antibodies. Consequently, it is more specific for the S phase and supposedly correlates better with 18 F-FLT (22). In accordance with its cell cycle specificity the Ki67 index was higher than the BrdU index in the tumors tested (Fig.…”

Section: Discussionsupporting

confidence: 58%

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: 58%

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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“…Moreover, in preclinical models high intrinsic thymidine levels can also inversely affect 18 F-FLT uptake, leading to less uptake despite a high tumor proliferation rate. The clinical impact of this phenomenon remains to be determined (28).…”

Section: Discussionmentioning

confidence: 99%

¹⁸F-FDG or 3′-Deoxy-3′-¹⁸F-Fluorothymidine to Detect Transformation of Follicular Lymphoma

et al. 2015

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Considering the different treatment strategy for transformed follicular lymphoma (TF) as opposed to follicular lymphoma (FL), diagnosing transformation early in the disease course is important. There is evidence that 18 F-FDG has utility as a biomarker of transformation. However, quantitative thresholds may require inclusion of homogeneous non-Hodgkin lymphoma subtypes to account for differences in tracer uptake per subtype. Moreover, because proliferation is a hallmark of transformation, 3′-deoxy-3′-18 F-fluorothymidine ( 18 F-FLT) might be superior to 18 F-FDG in this setting. To define the best tracer for detection of TF, we performed a prospective a headto-head comparison of 18 F-FDG and 18 F-FLT in patients with FL and TF. Methods: 18 F-FDG and 18 F-FLT PET scans were obtained in 17 patients with FL and 9 patients with TF. We measured the highest maximum standardized uptake value (SUV max ), defined as the lymph node with the highest uptake per patient, and SUV range , defined as the difference between the SUV max of the lymph node with the highest and lowest uptake per patient. To reduce partial-volume effects, only lymph nodes larger than 3 cm 3 (A50 isocontour) were analyzed. Scans were acquired 1 h after injection of 185 MBq of 18 F-FDG or 18 F-FLT. To determine the discriminative ability of SUV max and SUV range of both tracers for TF, receiver-operatingcharacteristic curve analysis was performed. Results: The highest SUV max was significantly higher for TF than FL for both 18 F-FDG and 18 F-FLT (P , 0.001). SUV range was significantly higher for TF than FL for 18 F-FDG (P 5 0.029) but not for 18 F-FLT (P 5 0.075). The ability of 18 F-FDG to discriminate between FL and TF was superior to that of 18 F-FLT for both the highest SUV max (P 5 0.039) and the SUV range (P 5 0.012). The cutoff value for the highest SUV max of 18 F-FDG aiming at 100% sensitivity with a maximum specificity was found to be 14.5 (corresponding specificity, 82%). For 18 F-FLT, these values were 5.1 and 18%, respectively. When the same method was applied to SUV range , the cutoff values were 5.8 for 18 F-FDG (specificity, 71%) and 1.5 for 18 F-FLT (specificity, 36%). Conclusion: Our data suggest that 18 F-FDG PET is a better biomarker for TF than 18 F-FLT PET. The proposed thresholds of highest SUV max and SUV range should be prospectively validated.

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“…18 F-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization, whereas Ki-67 is a more general proliferation marker. 49,50 Since Ki-67 staining is positive for any cell not in the G0-phase, and activity of the thymidine pathway is typically confined to the S-phase, 18 F-FLT uptake seems to reflect tumor proliferation in a more specific way. The lack of correlation between Ki-67 and 18 F-FLT uptake could also be due to the fact that some tumors could have a high level of de novo thymidine synthesis (via thymidine synthetase), and therefore are less dependent on the salvage pathway.…”

Section: Discussionmentioning

confidence: 99%

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

et al. 2014

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Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. Osteosarcoma is the most commonly diagnosed primary malignant tumor of the bone mainly affecting children and adolescents. 1 Current standard treatment regimens consist of surgery and polychemotherapy. Unfortunately, despite multimodal treatment the final outcome has not improved significantly during the last decade and severe side effects of intensive chemotherapy treatment schedules are observed frequently. On top of that, research on targeted treatments in osteosarcomas lags behind. This underscores the absolute need for novel, targeted therapies to treat these often young patients.Blocking of mammalian target of rapamycin (mTOR) signaling emerged as a promising approach to target osteosarcomas. mTOR, also known as sirolimus effector protein, is an intracellular serine/threonine kinase involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade and signals downstream of several receptor tyrosine kinases (RTKs), including but not limited to the insulin-like growth factor 1

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[18F]FLT–PET Imaging Does Not Always “Light Up” Proliferating Tumor Cells

Cited by 70 publications

References 29 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

¹⁸F-FDG or 3′-Deoxy-3′-¹⁸F-Fluorothymidine to Detect Transformation of Follicular Lymphoma

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

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[18F]FLT–PET Imaging Does Not Always “Light Up” Proliferating Tumor Cells

Cited by 70 publications

References 29 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

18F-FDG or 3′-Deoxy-3′-18F-Fluorothymidine to Detect Transformation of Follicular Lymphoma

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

Contact Info

Product

Resources

About

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

¹⁸F-FDG or 3′-Deoxy-3′-¹⁸F-Fluorothymidine to Detect Transformation of Follicular Lymphoma