Imaging of Pharmacotherapy Induced Apoptosis

药物治疗诱导细胞凋亡的影像学

• 批准号: 7123407
• 负责人: LEE JOSEPHSON
• 金额: $ 38.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123407
• 关键词: annexins; apoptosis; bioimaging /biomedical imaging; biomarker; confocal scanning microscopy; cytotoxicity; disease /disorder model; flow cytometry; fluorescence microscopy; fluorescent dye /probe; laboratory mouse; magnetic resonance imaging; method development; molecular /cellular imaging; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer radiodiagnosis; neoplastic cell; phosphatidylserines; protein binding; radiotracer

DESCRIPTION (provided by applicant): The development of an imaging method capable of measuring the increase in apoptosis early in the course of pro-apoptotic/anti-proliferative pharmacotherapies will accelerate the evaluation of experimental pre- clinical therapies and permit the personalization of established therapies in the clinic. The molecular basis for such an imaging method lies in the fact that as cells proceed along pathways to apoptosis or death, phosphatidylserine (PS), a lipid normally facing the cytoplasm, flips and faces the extracellular milieu. PS is an attractive target for imaging pharmacotherapy because (i) diverse pharmacotherapies have a common propensity to induce apoptosis, (ii) PS is an early and general marker of apoptosis and, (iii) PS can be imaged using annexin V, a protein that binds PS selectively and which has been used as a radiolabeled clinical diagnostic agent. Using fluorescent annexin V's, we have obtained important proof of principle data that the accumulation of fluorescent annexin V (38kDa) reflects the early response to anti-proliferative drug treatment in animal models of diverse diseases (cancer, arthritis). We have also shown that a magneto/optical annexin V (50 nm) can be used to image ischemia induced apoptosis by MRI in vivo. Though Tc-annexin V has been used for imaging chemotherapeutic response, clinical results to date are can be described as limited and mixed. The premise of this proposal is that annexin V based probes can be successfully used to image chemotherapy induced apoptosis, provided a vastly improved understanding of how annexin V binds to tumor and endothelial cells stressed by various chemotherapic agents in vitro is obtained. In addition, key variables regarding annexin V probe behavior in vivo must be understood, including elucidation of the cellular targets of these probes and determination of whether chemotherapy induced changes in tumor blood volume complicate the quantitation of the molecular marker, PS. This proposal will provide essential information regarding the interaction of annexin V probes with cells subjected to chemotherapeutic stress, and allow imaging apoptosis to realize its as yet unrecognized and vast potential. It will provide a basis for the selection pharmotherapeutic regimes based on the expression of a molecular marker upregulated on tumors undergoing treatment, indicating which regimes will be efficacious for specific individuals, and sparing many side-effect prone regimes which provide no benefit.

描述（由申请人提供）：在促凋亡/抗凋亡/抗增殖性药物治疗过程中，能够测量凋亡增加的成像方法的发展将加速对实验性临床治疗的评估并允许该诊所的既定疗法的个性化。这种成像方法的分子基础在于一个事实，即当细胞沿着凋亡或死亡的途径进行时，磷脂酰丝氨酸（PS）是一种通常面对细胞质的脂质的脂质，会翻转并面对细胞外环境。 PS是成像药物疗法的有吸引力的靶标，因为（i）多样化的药物治疗具有诱导凋亡的共同倾向，（ii）PS是凋亡的早期和一般标志物，并且可以使用Annexin V进行成像，可以选择性地结合PS，并且已被用作放射性临床临床诊断药物。使用荧光膜融合蛋白V，我们获得了主要数据的重要证明，即荧光膜联蛋白V（38KDA）的积累反映了在各种疾病（癌症，关节炎）动物模型中对抗增殖药物治疗的早期反应。我们还表明，磁磁/光学膜剂V（50 nm）可用于对缺血诱导的MRI在体内诱导的凋亡。尽管TC-抗肽V已用于成像化学治疗反应，但迄今为止，临床结果可以描述为有限和混合。该提议的前提是，基于膜联蛋白V的探针可以成功地用于化学疗法诱导的凋亡，但对膜联蛋白V与肿瘤和内皮细胞的结合有了极大的提高，可以在体外得到各种化学治疗剂的压力。此外，必须了解有关体内膜联蛋白V探针行为的关键变量，包括阐明这些探针的细胞靶标，并确定化学疗法诱导的肿瘤血液体积变化是否使分子标记的定量变化复杂，PS。该提案将提供有关膜联蛋白V探针与受到化学治疗应激的细胞相互作用的基本信息，并允许成像凋亡实现其尚未被识别和巨大潜力。它将基于在接受治疗的肿瘤上调的分子标记的表达，为选择药物治疗方案提供基础，表明哪些方案对特定的个体有效，并保留许多副作用的下发方案，而这些方案无益。