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

肿瘤乏氧的无创性成像有助于预测治疗结果和制定治疗计划。铜-二乙酰-双(N4-甲基氨基硫脲)(Cu-ATSM)是一种正电子发射铜标记的PET显像剂，在低氧条件下被还原并捕获在细胞内。我们研究了几种不同组织来源的小鼠肿瘤细胞移植后形成的小鼠肿瘤高摄取区的特点。高铜-ATSM聚集区血管稀少，由停滞于细胞周期的肿瘤细胞组成，有少量凋亡细胞。相比之下，FDG高积聚的区域血管丰富，由活跃的增殖细胞和高度缺氧的细胞和因坏死而死亡的细胞组成。与血管丰富、细胞增殖的高FDG区相比，铜-ATSM高聚集区似乎对放疗和化疗具有抵抗力，因为低氧和缺乏血管。CU-ATSM可能对治疗计划有帮助。耐人寻味的是，肿瘤肿块中包含了体积巨大、具有如此独特特征的区域。对于临床小回旋加速器生产铜-和制备铜-ATP，我们成功地实现了从轰击后靶盘提纯铜-到制备铜-甘氨酸溶液的自动化过程，建立了安全、可重复的铜-铜-ATP的供应。研究了肿瘤细胞代谢的特点，发现Acss 2介导的肿瘤细胞醋酸酯代谢高于正常细胞，在低氧条件下代谢增强。这些发现提示了一种可能性，即C-乙酸酯PET显示了肿瘤细胞中醋酸酯代谢的低氧上调。

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.