Furukawa Takako, Yuan Qinghua, Jin Zhao-Hui, Aung Winn, Yoshii Yukie, Hasegawa Sumitaka, Endo Hiroko, Inoue Masahiro, Zhang Ming-Rong, Fujibayashi Yasuhisa, Saga Tsuneo
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Oncol Rep. 2015 Sep;34(3):1379-87. doi: 10.3892/or.2015.4079. Epub 2015 Jun 25.
Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [62,64Cu] copper-diacetyl-bis[N(4)-methylthio- semicarbazone] (Cu-ATSM), have been used for imaging hypoxic tumors. High accumulation of these tracers in tumors was shown to predict poor prognosis. Both similar and different intratumoral distributions of these PET tracers have been reported with some studies questioning the dependence of the Cu-ATSM accumulation on hypoxia. In the present study, we compared the intratumoral distribution and cellular uptake of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole (FAZA) and Cu-ATSM. Intratumoral distributions of FAZA and Cu-ATSM compared by double tracer autoradiography in xenografts of 8 cancer cell lines and 3 cancer tissue originated spheroids (CTOSs) showed that only a limited overlap was observed between the regions with high levels of FAZA and Cu-ATSM accumulation in all the xenografts. Immunohistochemistry in the regions enriched with FAZA and Cu-ATSM in xenografts demonstrated that pimonidazole adducts were in regions that accumulated high levels of FAZA, while HIF-1α was in areas enriched with either tracer. In addition, we examined the cellular uptake of FAZA and Cu-ATSM at different levels of oxygen concentration in 4 cell lines and revealed that cellular uptake of FAZA was increased with the decrease of oxygen concentration from 20 to 2 and from 2 to 1%, while the Cu-ATSM uptake increased with the decrease of oxygen concentration from 20 to 2%, but did not increase with the decrease from 2 to 1%. Our findings indicate that intratumoral distributions of FAZA and Cu-ATSM were essentially non-overlapping and although hypoxia affects the buildup of both tracers, the accumulation of Cu-ATSM occurred at milder hypoxia compared to the conditions required for the accumulation of FAZA. Therefore, accumulation levels of FAZA and Cu-ATSM may be considered as independent biomarkers.
肿瘤缺氧的正电子发射断层扫描（PET）成像为癌症治疗方案的制定提供了有价值的信息。两类PET示踪剂，即硝基咪唑化合物和[62,64Cu]二乙酰双[N(4)-甲基硫代半卡巴腙]铜（Cu-ATSM），已被用于缺氧肿瘤的成像。这些示踪剂在肿瘤中的高积聚被证明可预测不良预后。一些研究报道了这些PET示踪剂在肿瘤内的分布既有相似之处也有不同之处，其中一些研究对Cu-ATSM积聚对缺氧的依赖性提出了质疑。在本研究中，我们比较了1-(5-氟-5-脱氧-α-D-阿拉伯呋喃糖基)-2-硝基咪唑（FAZA）和Cu-ATSM在肿瘤内的分布及细胞摄取情况。通过双示踪剂放射自显影法在8种癌细胞系和3种源自癌组织的球体（CTOS）异种移植模型中比较FAZA和Cu-ATSM的肿瘤内分布，结果显示在所有异种移植模型中，FAZA和Cu-ATSM高积聚区域之间仅观察到有限的重叠。对异种移植模型中富含FAZA和Cu-ATSM的区域进行免疫组织化学分析表明，匹莫硝唑加合物存在于FAZA高积聚区域，而缺氧诱导因子-1α（HIF-1α）存在于富含任何一种示踪剂的区域。此外，我们检测了4种细胞系在不同氧浓度水平下对FAZA和Cu-ATSM的细胞摄取情况，结果显示随着氧浓度从20%降至2%以及从2%降至1%，FAZA的细胞摄取增加，而Cu-ATSM的摄取在氧浓度从20%降至2%时增加，但在从2%降至1%时未增加。我们的研究结果表明，FAZA和Cu-ATSM在肿瘤内的分布基本不重叠，尽管缺氧会影响这两种示踪剂的积聚，但与FAZA积聚所需条件相比，Cu-ATSM的积聚发生在较轻的缺氧状态下。因此，FAZA和Cu-ATSM的积聚水平可被视为独立的生物标志物。
