Basic Studies on Biochemical and Molecular Biological Diagnosis of Tumor Hypoxia by PET

肿瘤缺氧的无创成像对预测治疗结果和制定治疗计划有很大帮助。Cu-二乙酰-双（n4 -甲基硫代氨基脲）（Cu- atsm）是一种正电子发射Cu标记的PET显像剂，在缺氧条件下被还原并困在细胞内。我们研究了几种不同组织来源的小鼠肿瘤细胞移植形成的小鼠肿瘤块中Cu-ATSM高^<64>摄取区的特征。Cu-ATSM高富集区为低血管区，由处于细胞周期停滞的肿瘤细胞组成，并伴有少量凋亡细胞。相反，FDG高积累的区域血管化良好，由活跃增殖细胞、高缺氧细胞和坏死死亡细胞组成。与血管丰富且细胞增殖的高FDG区域相比，高Cu-ATSM积累区域由于缺氧和缺乏血管，似乎对放疗和化疗具有抗性。Cu-ATSM可用于治疗计划。令人感兴趣的是，肿瘤肿块中含有大量具有如此独特特征的区域。Cu-ATSM可以描述缺氧和细胞周期阻滞区域，可能为癌症治疗提供有价值的信息。在临床小型回旋加速器生产Cu-64和制备Cu-ATSM方面，我们成功实现了从轰炸后靶盘纯化Cu-64到制备Cu-64甘氨酸溶液的自动化过程，建立了Cu-64 Cu-ATSM的安全、可重复性供应。通过对肿瘤细胞代谢特性的研究，我们发现Acss2介导的醋酸盐代谢在肿瘤细胞中高于正常细胞，并且在缺氧条件下代谢增加。这些发现提示了一种可能性，即^<11 bb0 C-acetate PET显示了肿瘤细胞中乙酸代谢的缺氧上调。

Noninvasive imaging of tumor hypoxia would be a great help to predict therapy outcome and make treatment planning. Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) labeled with positron-emitting Cu is a PET imaging agent which is reduced and trapped in cells under hypoxia. We examined the characteristics of high ^<64>Cu-ATSM uptake regions in mouse tumor mass formed by transplantation of several mouse tumor cells of different tissue origin. The high Cu-ATSM accumulation regions were hypovascular and consisted of tumor cells arrested in the cell cycle, with a few apoptotic cells. In contrast, the regions with high FDG accumulation were well vascularized and consisted of actively proliferating cells as well as highly hypoxic cells and dying cells from necrosis. The region of high Cu-ATSM accumulation seemed to be resistant to radiation and chemotherapy because of hypoxia and lack of vessels compared to high FDG regions where vessels are abundant and cells are proliferating. Cu-ATSM could be useful for therapy planning. It was intriguing that tumor mass contains regions with such unique characteristics in substantial volume. ^<64>Cu-ATSM, which can delineate hypoxic and cell cycle-arrested regions, may provide valuable information for cancer treatment.As for the production of Cu-64 by clinical small cyclotron and preparation of Cu-ATSM, we have successfully automated the process from the purification of Cu-64 from the target disc after bomberment to preparation of Cu-64 glycine solution, which established safe and reproducible supply of Cu-64 Cu-ATSM.Studying the characteristics of tumor cell metabolism, we found that acetate metabolism mediated by Acss2 in tumor cells was higher than in normal cells, and the metabolism was increased under hypoxia. These findings suggest a possibility that ^<11>C-acetate PET is visualizing hypoxic up-regulation of acetate metabolism in tumor cells.