Monitoring apoptosis in real time
Monitoring apoptosis in real time
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DOI：
10.1097/00130404-200203000-00002
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发表时间：
2002-03-01
期刊：
影响因子：
2.2
通讯作者：
Steinmetz, ND
中科院分区：
文献类型：
--
作者：
Green, AM;Steinmetz, ND
许多治疗活性的抗癌治疗通过诱导细胞凋亡和坏死来发挥其作用。乳腺癌患者的系列活检表明，对治疗的反应与治疗后早期肿瘤凋亡指数的增加相关。放射性标记的锝99m-重组人（rh）膜联蛋白V提供了一种非侵入性成像治疗诱导的细胞死亡的技术。膜联蛋白V是一种天然存在的人类蛋白质，其与膜相关磷脂酰丝氨酸（PS）结合。PS通常仅在细胞膜双层的内小叶上发现，但它作为细胞凋亡的早期事件被主动转运到外层，并可用于膜联蛋白结合。膜联蛋白也由于与坏死相关的膜断裂而进入PS。使用荧光素膜联蛋白的细胞凋亡体外研究显示出与通过核DNA降解和半胱天冬酶活化记录的细胞凋亡评估的良好相关性。静脉内给予的T199m-膜联蛋白V的体内定位已经在许多临床前细胞凋亡模型中得到证实，包括抗Fas介导的肝细胞凋亡、同种异体异位心脏移植物的排斥、环磷酰胺治疗小鼠淋巴瘤、环磷酰胺诱导的骨髓细胞凋亡和与脓肿形成相关的白细胞凋亡。使用Tc 99m-rh膜联蛋白V的人体闪烁成像研究已经证明了在急性心肌梗死、具有高凋亡指数的肿瘤以及对非小细胞肺癌、小细胞肺癌、乳腺癌、淋巴瘤和肉瘤的抗肿瘤化疗的响应中成像细胞死亡的可行性。在化疗的1至3天内，T0 99m-rh膜联蛋白V的定位增加已在一些但不是全部的患有这些肿瘤的受试者中注意到。迄今为止，大多数受试者在第一个疗程化疗后表现出增加的Tc 99m-rh膜联蛋白V摄取，并显示出客观的临床反应。一项在15名受试者中进行的单中心研究（随访1年）表明，治疗后Tc 99m-rh膜联蛋白摄取增加与疾病进展时间和生存时间延长相关。细胞死亡的体内成像可能具有通过允许快速、客观、逐个患者地评估肿瘤细胞杀伤的功效来改善癌症患者的治疗的潜力。
Many therapeutically active anticancer treatments exert their effect by the induction of apoptosis and necrosis. Serial biopsies in breast cancer patients have suggested that response to therapy correlates with early posttreatment increases in tumor apoptotic index. Radiolabeled technetium Tc 99m-recombinant human (rh) annexin V provides a noninvasive technique for imaging treatment-induced cell death. Annexin V is a naturally occurring human protein that binds avidly to membrane-associated phosphatidylserine (PS). PS is normally found only on the inner leaflet of the cell membrane double layer, but it is actively transported to the outer layer as an early event in apoptosis and becomes available for annexin binding. Annexin also gains access to PS as a result of the membrane fragmentation associated with necrosis. In vitro studies of apoptosis using fluorescelin annexin have shown good correlation with assessments of apoptosis documented by nuclear DNA degradation and caspase activation. In vivo localization of intravenously administered To 99m-annexin V has been demonstrated in numerous preclinical models of apoptosis, including anti-Fas-mediated hepatic apoptosis, rejection of allogeneic heterotopic cardiac allografts, cyclophosphamide treatment of murine lymphoma, cyclophosphamide-induced apoptosis in bone marrow, and leukocyte apoptosis associated with abscess formation. Scintigraphic studies in humans using Tc 99m-rh annexin V have demonstrated the feasibility of imaging cell death in acute myocardial infarction, in tumors with a high apoptotic index, and in response to anti-tumorchemo-therapy of non-small cell lung cancer, small-cell lung cancer, breast cancer, lymphoma, and sarcoma. Increased localization of To 99m-rh annexin V within 1 to 3 days of chemotherapy has been noted in some, but not all, subjects with these tumors. To date, most subjects showing increased Tc 99m-rh annexin V uptake after the first course of chemotherapy have shown objective clinical responses. A single site study in 15 subjects with 1-year follow-up has suggested that increased posttreatment Tc 99m-rh annexin uptake is associated with improved time to progression of disease and survival time. In vivo imaging of cell death may have the potential to improve the treatment of cancer patients by allowing rapid, objective, patient-by-patient assessment of the efficacy of tumor cell killing.