Evaluation of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas
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The thymidine analog 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of 18F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood–brain barrier (BBB) breakdown in human brain gliomas.
A total of 21 patients with newly diagnosed gliomas were examined by 18F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of 18F-FLT in the tumor and 18F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.
18F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K 1; P = 0.001 and P < 0.001, respectively), but not with the phosphorylation rate constant (k 3). IHC and real-time PCR studies demonstrated a significant correlation between K 1 and TK-1 mRNA expression (P = 0.001), but not between k 3 and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K 1 and the Ki-67 index (P = 0.003), but not between k 3 and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P = 0.009). 18F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P = 0.003 and P = 0.011, respectively).
These results indicate that 18F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k 3 determined by 18F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.
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- Evaluation of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas
European Journal of Nuclear Medicine and Molecular Imaging
Volume 40, Issue 2 , pp 175-185
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- Positron emission tomography
- Thymidine kinase-1
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- Author Affiliations
- 1. Department of Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1 Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- 2. Department of Neurobiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
- 3. Department of Diagnostic Pathology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
- 4. Department of Medical Physics, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
- 5. Department of Radiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
- 6. Department of Cell Physiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan