MR assessment of antiangiogenic therapy

抗血管生成治疗的 MR 评估

• 批准号: 6563961
• 负责人: Edward F Jackson
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563961
• 关键词: angiogenesis; angiogenesis inhibitors; antineoplastics; athymic mouse; bioimaging /biomedical imaging; biomarker; cardiovascular imaging /visualization; contrast media; cooperative study; dosage; drug administration routes; drug screening /evaluation; human subject; magnetic resonance imaging; mathematical model; neoplasm /cancer blood supply; pharmacokinetics; vascular endothelium permeability

Description: (provided by applicant) There is now considerable evidence that dynamic contrast agent-enhanced magnetic resonance imaging (MRI) data, when analyzed with appropriate pharmacokinetic models, are able to provide quantitative information regarding the vascular volume fraction (fvv), permeability-surface area product (PS), and contrast agent reflux rate (kR) in tumors. If shown to be accurate, such non-invasive measures will be highly useful in evaluating the efficacy of antiangiogenic therapies and in predicting how well chemotherapeutic agents will penetrate into tumors through diffusive and convective processes. Limited, and often contradictory, studies have been performed to date to correlate MRI-derived in vivo measures of fvv, PS, and kR with existing "gold standards" such as immunohistochemistry-based measures of microvessel density and vascular permeability. Furthermore, rigorous comparisons of MRI-derived measures obtained using FDA-approved low molecular weight contrast media with those obtained using theoretically advantageous higher molecular weight media currently in clinical trials are limited. Such studies are needed to establish the limitations of using each class of contrast media in assessing fvv, PS, and kR. These issues must be resolved prior to the application of such promising non-invasive measures to clinical monitoring of the efficacy of antiangiogenic therapy. The overall goals of this project are to 1) demonstrate that accurate in vivo quantitative measures of fvv, PS, and kR can be obtained via single and/or dual tracer pharmacokinetic modeling of dynamic contrast agent-enhanced MRI data, and 2) correlate such measures, in both animal models and human studies, with other surrogate markers of angiogenesis, including expression of specific angiogenic factors, proteases, rates of endothelial cell apoptosis, and endothelial cell-specific markers. The specific aims in this project are: 1) correlation of single and dual tracer pharmacokinetic measures of fvv, PS, and kR obtained using high, medium, and low molecular weight contrast agents with immunohistochemical and radionuclide determinations of microvessel density and vascular permeability; 2) acquisition of longitudinal pharmacokinetic measures of fvv, PS, and kR in subcutaneously implanted tumors treated with antiangiogenic therapies, and correlation of these measures with other surrogate markers of angiogenesis and vascular permeability; and 3) acquisition of longitudinal pharmacokinetic measures in patients enrolled in clinical trials of antiangiogenic drugs, and correlation of these measures with other invasive surrogate markers of angiogenesis.

说明：（申请人提供） 现在有大量证据表明动态造影剂增强 磁共振成像（MRI）数据，当使用适当的分析时 药代动力学模型能够提供有关的定量信息 血管体积分数 (fvv)、渗透性表面积乘积 (PS)、 和肿瘤中造影剂回流率（kR）。如果被证明是准确的，这样的 非侵入性措施对于评估疗效非常有用 抗血管生成疗法和预测化疗药物的效果 将通过扩散和对流过程渗透到肿瘤中。 迄今为止，已经进行了有限且常常相互矛盾的研究 将 MRI 衍生的 fvv、PS 和 kR 体内测量值与现有的“金 标准”，例如基于免疫组织化学的微血管密度测量 和血管通透性。此外，严格比较 MRI 得出的 使用 FDA 批准的低分子量造影剂获得的测量结果 使用理论上有利的较高分子量介质获得的那些 目前正在进行的临床试验有限。需要进行此类研究来确定 使用各类造影剂评估 fvv、PS、 和kR。在应用此类技术之前必须解决这些问题 有前景的非侵入性措施来临床监测疗效 抗血管生成治疗。该项目的总体目标是 1) 证明 fvv、PS 和 kR 的准确体内定量测量可以 通过单和/或双示踪剂动态药代动力学模型获得 对比剂增强的 MRI 数据，以及 2) 将这些测量值关联起来， 动物模型和人体研究，以及血管生成的其他替代标记， 包括特定血管生成因子、蛋白酶的表达、 内皮细胞凋亡和内皮细胞特异性标记物。这 该项目的具体目标是：1）单示踪剂和双示踪剂的关联 使用高、中、和获得的 fvv、PS 和 kR 的药代动力学测量值 免疫组织化学和放射性核素低分子量造影剂 微血管密度和血管通透性的测定； 2） 获得 fvv、PS 和 kR 的纵向药代动力学测量值 用抗血管生成疗法治疗的皮下植入肿瘤，以及 这些措施与血管生成的其他替代标志物的相关性 血管通透性； 3) 纵向药代动力学的获取 参加抗血管生成药物临床试验的患者的措施，以及 这些措施与其他侵入性替代标志物的相关性 血管生成。