Dearling Jason L J, Flynn Aiden A, Sutcliffe-Goulden Julie, Petrie Ingrid A, Boden Robert, Green Alan J, Boxer Geoffrey M, Begent Richard H J, Pedley R Barbara
Cancer Research UK Targeting and Imaging Group, Academic Department of Oncology, Royal Free and University College Medical School, Royal Free Campus, University College London, Hampstead, London, United Kingdom.
J Nucl Med. 2004 Jan;45(1):101-7.
It has been shown in vitro that the cell uptake of (18)F-FDG, a tracer of glucose metabolism, increases under hypoxia. This is consistent with increased glycolytic metabolism. We have previously shown that in ischemic heart ex vivo the rates of uptake of (18)F-FDG and 2-(14)C-deoxy-D-glucose ((14)C-2DG) are both reduced. In this study, we investigated this effect in tumors by comparing the microdistribution of (18)F-FDG and (14)C-2DG in hypoxic and normoxic regions.
Mice (MF1) bearing LS174T human tumor xenografts were injected with premixed (18)F-FDG (100 MBq), (14)C-2DG (0.37 MBq), and pimonidazole hydrochloride (60 mg/kg). After 30, 60, and 120 min, tissues (n = 4) were taken and counted for whole-body biodistribution. Tumors were frozen, sectioned, and exposed to phosphor image plates to obtain a quantitative digital image of radionuclide distribution. Sections were then stained to reveal tumor pathophysiology: Hematoxylin and eosin staining demonstrated viable and necrotic regions, and immunohistochemical staining detected pimonidazole metabolism in hypoxic cells. The images of radionuclide microdistribution and histology were then coregistered and analyzed to assess radionuclide trapping throughout the tumor on a pixel-by-pixel basis. The Pearson correlation coefficients between the 2 radionuclides were calculated. The relative amounts of nuclide were then analyzed in viable and necrotic regions and in normoxic and hypoxic regions.
Whole-body biodistributions for the 2 radiotracers were similar. A high Pearson correlation coefficient was obtained for the 2 radionuclides throughout the tumors (r = 0.85 +/- 0.10, P < 0.0001), indicating a highly similar microdistribution. When the tumors were divided into viable and necrotic regions, the ratio of mean counts per pixel was 1.96 (P < 0.0001), whereas for hypoxic versus normoxic regions it was 1.26 (P < 0.0001). There was no significant difference in selectivity for hypoxia between the 2 radiotracers (P = 0.86).
The tumor microdistribution of deoxyglucose in viable, hypoxic, and necrotic regions show that there was little change in the microdistribution of deoxyglucose throughout this time course. This study extends previous in vitro work and confirms the selectivity of deoxyglucose for viable cells over necrotic regions and for hypoxic cells over normoxic regions in vivo.
体外研究表明，作为葡萄糖代谢示踪剂的（18）F-FDG的细胞摄取在缺氧状态下会增加。这与糖酵解代谢增加是一致的。我们之前已经表明，在离体缺血心脏中，（18）F-FDG和2-（14）C-脱氧-D-葡萄糖（（14）C-2DG）的摄取率均降低。在本研究中，我们通过比较（18）F-FDG和（14）C-2DG在缺氧和正常氧合区域的微观分布，研究了肿瘤中的这种效应。
给携带LS174T人肿瘤异种移植物的小鼠（MF1）注射预混的（18）F-FDG（100 MBq）、（14）C-2DG（0.37 MBq）和盐酸匹莫硝唑（60 mg/kg）。30、60和120分钟后，取组织（n = 4）并进行全身生物分布计数。将肿瘤冷冻、切片，然后暴露于磷光成像板以获得放射性核素分布的定量数字图像。然后对切片进行染色以揭示肿瘤病理生理学：苏木精和伊红染色显示存活和坏死区域，免疫组织化学染色检测缺氧细胞中的匹莫硝唑代谢。然后将放射性核素微观分布图像和组织学图像进行配准并分析，以逐像素评估整个肿瘤中的放射性核素捕获情况。计算两种放射性核素之间的Pearson相关系数。然后分析存活和坏死区域以及正常氧合和缺氧区域中核素的相对含量。
两种放射性示踪剂的全身生物分布相似。在整个肿瘤中，两种放射性核素获得了较高的Pearson相关系数（r = 0.85 +/- 0.10，P < 0.0001），表明微观分布高度相似。当将肿瘤分为存活和坏死区域时，每像素平均计数的比值为1.96（P < 0.0001），而对于缺氧与正常氧合区域，该比值为1.26（P < 0.0001）。两种放射性示踪剂对缺氧的选择性没有显著差异（P = 0.86）。
脱氧葡萄糖在存活、缺氧和坏死区域的肿瘤微观分布表明，在整个时间过程中脱氧葡萄糖的微观分布变化很小。本研究扩展了先前的体外研究工作，并证实了脱氧葡萄糖在体内对存活细胞相对于坏死区域以及对缺氧细胞相对于正常氧合区域的选择性。
