Yuan Hong, Schroeder Thies, Bowsher James E, Hedlund Laurence W, Wong Terence, Dewhirst Mark W
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.
J Nucl Med. 2006 Jun;47(6):989-98.
Cu-Diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate (64)Cu-ATSM as a hypoxia PET marker by comparing autoradiographic distributions of (64)Cu-ATSM with a well-established hypoxia marker drug, EF5.
R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochemical analysis. (64)Cu-ATSM microPET and autoradiography were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiography, EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-and-eosin histology-were superimposed, evaluated, and compared.
A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation analysis between (64)Cu-ATSM autoradiography and EF5 immunostained images varied between the 3 tumor types. There was close correlation of (64)Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated (64)Cu-ATSM uptake was observed in well-perfused areas in FSA, indicating a correlation between (64)Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was observed with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of (64)Cu-ATSM. These results indicate that some other (64)Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor.
To our knowledge, this study is the first comparison between (64)Cu-ATSM uptake and immunohistochemistry in these 3 tumors. Although we have shown that (64)Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of (64)Cu-ATSM challenges the use of (64)Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.
铜-双乙酰双（N(4)-甲基硫代半卡巴腙）（Cu-ATSM）是一种最近开发的用于肿瘤缺氧的正电子发射断层显像（PET）显像剂。然而，其在体内测量缺氧的准确性和可靠性尚未得到充分表征。本研究的目的是通过比较（64）Cu-ATSM的放射自显影分布与一种成熟的缺氧标记药物EF5，来评估（64）Cu-ATSM作为缺氧PET标记物的情况。
本研究使用了R3230乳腺腺癌（R3230Ac）、纤维肉瘤（FSA）和9L胶质瘤（9L）。将EF5和血管灌注标记物Hoechst 33342给予动物进行免疫组织化学分析。对同一动物进行（64）Cu-ATSM微型PET和放射自显影。对这3种不同类型的肿瘤进行肿瘤与肌肉比值（T/M比值）和标准化摄取值（SUV）的表征。将微型PET、放射自显影、EF5免疫染色、Hoechst荧光血管成像以及苏木精-伊红组织学这5种图像进行叠加、评估和比较。
与R3230Ac和9L相比，FSA的T/M比值和SUV显著更高。（64）Cu-ATSM放射自显影与EF5免疫染色图像之间的空间相关性分析在这3种肿瘤类型之间有所不同。在R3230Ac和9L肿瘤中，（64）Cu-ATSM摄取与缺氧密切相关，但在FSA肿瘤中并非如此。有趣的是，在FSA中灌注良好的区域观察到（64）Cu-ATSM摄取升高，这表明（64）Cu-ATSM摄取与血管灌注而非缺氧之间存在相关性。在FSA肿瘤中，用另外两种缺氧标记物匹莫硝唑和碳酸酐酶IX也观察到了相同的关系。吸入卡波金气体显著降低了荷FSA大鼠中通过EF5染色测量的缺氧水平，但并未降低（64）Cu-ATSM的摄取。这些结果表明，在这种类型的肿瘤中，存在一些与缺氧不同的其他（64）Cu-ATSM保留机制。
据我们所知，本研究是首次在这3种肿瘤中比较（64）Cu-ATSM摄取与免疫组织化学。虽然我们已经表明（64）Cu-ATSM在某些肿瘤类型中是一种有效的PET缺氧标记物，但并非对所有肿瘤类型都有效，（64）Cu-ATSM这种肿瘤类型依赖性的缺氧选择性对将其用作通用的PET缺氧标记物提出了挑战。需要进一步研究来确定这种PET标记物的保留机制。
