Biophysics/Biomathematics Institute, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
Nucl Med Biol. 2010 Feb;37(2):125-32. doi: 10.1016/j.nucmedbio.2009.11.001. Epub 2009 Dec 16.
Colorectal cancer is one of the most common malignancies in the Western world and is an example of a solid tumour in which hypoxia is a common feature and develops because of the inability of the vascular system to supply adequate amounts of oxygen to growing tumours. Hypoxia effects on tumour cell biology can be detected and characterized using different methods. The use of imaging with gamma-emitting radionuclides to detect hypoxic tissue was first suggested by Chapman in 1979 [N Engl J Med 301 (1979) 1429-1432]. (99m)Tc-4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime, also known as (99m)Tc-HL-91, has been among the most studied hypoxia markers. The objective of this study was to correlate the uptake of (99m)Tc-HL-91 and (99m)Tc-MIBI in colon cancer cells under normoxic and hypoxic conditions and to compare this information with some parameters such as oxidative stress and mitochondrial dysfunction of the cells analyzed by flow cytometry. Our results show that the in vitro (99m)Tc-HL-91 uptake is higher in hypoxic conditions, which is confirmed by the decreased uptake of (99m)Tc-MIBI. Flow cytometry results demonstrate that hypoxic conditions used are not enough to induce cellular death, but are responsible for the alterations in the intracellular redox environment, namely, increase of ROS production, proteic pimonidazol-derived adduct formation and alteration in the mitochondrial membrane permeability. Therefore, these results confirm that (99m)Tc-HL-91 is a radiopharmaceutical with favourable characteristics for detecting hypoxia.
结直肠癌是西方世界最常见的恶性肿瘤之一，是一种实体瘤，其特点是缺氧普遍存在，并且由于血管系统无法为生长中的肿瘤提供足够的氧气而导致缺氧。可以使用不同的方法检测和描述缺氧对肿瘤细胞生物学的影响。1979 年 Chapman 首次提出使用发射伽马射线的放射性核素来检测缺氧组织[N Engl J Med 301 (1979) 1429-1432]。（99m）Tc-4,9-二氮杂-3,3,10,10-四甲基十二烷-2,11-二酮肟，也称为（99m）Tc-HL-91，是研究最多的缺氧标志物之一。本研究的目的是在常氧和缺氧条件下比较（99m）Tc-HL-91 和（99m）Tc-MIBI 在结肠癌细胞中的摄取，并将这些信息与通过流式细胞术分析的一些参数（如氧化应激和线粒体功能障碍）进行比较。我们的结果表明，（99m）Tc-HL-91 的体外摄取在缺氧条件下更高，这可以通过（99m）Tc-MIBI 摄取减少得到证实。流式细胞术结果表明，所使用的缺氧条件不足以诱导细胞死亡，但会导致细胞内氧化还原环境发生变化，即 ROS 产生增加、蛋白质 pimonidazol 衍生加合物形成和线粒体膜通透性改变。因此，这些结果证实（99m）Tc-HL-91 是一种具有检测缺氧特性的放射性药物。
