Department of Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Eur J Nucl Med Mol Imaging. 2013 Jan;40(2):175-85. doi: 10.1007/s00259-012-2275-9. Epub 2012 Nov 15.
The thymidine analog 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-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 (18)F-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 (18)F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of (18)F-FLT in the tumor and (18)F-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.
(18)F-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). (18)F-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 (18)F-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 (18)F-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.
胸苷类似物 3'-脱氧-3'-[(18)F]氟胸苷 ((18)F-FLT) 已被开发为正电子发射断层扫描 (PET) 示踪剂，以评估体内肿瘤的增殖活性。本研究探讨了 (18)F-FLT 体内动力学参数与胸苷激酶-1 (TK-1) 表达和体外细胞增殖率以及人脑胶质瘤血脑屏障 (BBB) 破坏之间的关系。
对 21 例新诊断的脑胶质瘤患者进行 (18)F-FLT PET 动力学分析。测定肿瘤的最大标准化摄取值 (SUVmax) 和肿瘤与正常组织 (T/N) 比值，以及相应对侧区域的 (18)F-FLT 动力学参数。采用免疫组织化学 (IHC) 和实时聚合酶链反应 (PCR) 分别测定手术标本中 TK-1 蛋白和 mRNA 的表达水平。肿瘤细胞增殖率以 Ki-67 标记指数表示。通过对比增强 MRI 评估 BBB 破坏。
(18)F-FLT SUVmax 和 T/N 比值与摄取率常数 (K (1)) 呈显著相关 (P = 0.001 和 P < 0.001)，但与磷酸化率常数 (k (3)) 无关。IHC 和实时 PCR 研究表明，K (1) 与 TK-1 mRNA 表达之间存在显著相关性 (P = 0.001)，但 k (3) 与 TK-1 蛋白和 mRNA 表达之间无相关性。线性回归分析显示，K (1) 与 Ki-67 指数呈显著相关 (P = 0.003)，但 k (3) 与 Ki-67 指数无关。TK-1 mRNA 表达与 Ki-67 指数显著相关 (P = 0.009)。(18)F-FLT SUVmax 和 T/N 比值与 MRI 对比增强评估的 BBB 破坏显著相关 (P = 0.003 和 P = 0.011)。
这些结果表明，肿瘤中 (18)F-FLT 的摄取与通过破坏的 BBB 的转运密切相关，但与磷酸化活性无关。尽管组织 TK-1 表达反映了肿瘤增殖活性，但 (18)F-FLT PET 动力学分析确定的磷酸化率常数 k (3) 并不能准确反映组织中的 TK-1 表达，不应作为人脑胶质瘤细胞增殖活性的替代生物标志物。
