NONINVASIVE PROBES FOR TUMOR OXYGENATION STATUS

用于肿瘤氧合状态的无创探针

• 批准号: 3200464
• 负责人: J D CHAPMAN
• 金额: $ 29.44万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3200464
• 关键词: chemical structure function; chemical synthesis; drug screening /evaluation; gamma radiation; high performance liquid chromatography; hypoxia; imidazole; laboratory mouse; laboratory rat; neoplasm /cancer radionuclide diagnosis; noninvasive diagnosis; nuclear magnetic resonance spectroscopy; nuclear medicine; pharmacokinetics; radiation sensitivity; radionuclide imaging /scanning; radiopharmacology; tissue /cell culture

Recent studies with both rodent and human tumors utilizing oxygen electrodes, 31P-NMR spectroscopy, sensitizer adducts and tumor perfusion measures by 99m/Tc-HMPAO show solid tumor oxygenation status to be extremely heterogeneous. To date, this tumor property cannot be estimated from histology, size nor growth rate and must be measured for each individual tumor. The proposed research will build upon our discovery and experience with nitroaromatic drugs which were shown to be reduced intra- cellularly at rates inversely proportional to cellular oxygen concen- tration producing adducts to cellular biomolecules indicative of intra- cellular oxygen tension and radiosensitivity. Autoradiography and liquid scintillation counting of beta-labelled sensitizer adducts are now accepted techniques for measuring relative oxygenation status in both rodent and human tumors. gamma-emitting radionuclides attached to appropriate bioreductive drugs could provide useful non-invasive measures of this tumor property. Previous research at the Cross Cancer Institute (Edmonton, Canada) had identified iodinated azomycin nucleosides as possible candidates for such nuclear medicine probes. Iodinated azomycin arabinoside (IAZA) has been administered to 40 patients before and/or during tumor therapy. While tumor retention of IAZA probably indicates low oxygen levels in some human tumors, this imaging compound Is far from optimum. The clearance and excretion of unbound marker is prerequisite for developing an optimal image of bound sensitizer in hypoxic tissue. The plasma half-life of IAZA in humans is about 10 hr. In addition, Its dehalogenation and hepatobiliary excretion results in isotope image unrelated to tissue bioreductive status. This research will synthesize novel hypoxic markers of the bioreductively-activated ligating (BRAL) class and determine structure/activity relationships in animal models for selecting improved compounds with shorter plasma half-lives and with iodine more resistant to pharmacologic dehalogenation. The hypoxic marking ability of superior compounds will be tested and compared with a radiosensitivity measure of individual EMT-6 tumors and with a radiosensitivity measure and the 31P-NMR spectra of individual Dunning 3327-AT rat prostate tumors. Both animal tumor models display a wide heterogeneity of oxygenation status. These correlative studies will assist in defining an Improved probe for the non-invasive measurement of solid tumor oxygenation. The emphasis of this research is the identification of an improved marker with which clinical scientists can make reliable non-invasive measures of human tumor oxygenation and reoxygenation.

啮齿动物和人类肿瘤利用氧气的最新研究 电极、31P-核磁共振波谱、增敏剂加合物和肿瘤灌注 99m/Tc-HMPAO检测显示实体瘤氧合状态为 异质性极强。到目前为止，这种肿瘤的性质还无法估计 从组织学上看，大小和生长率都必须测量 个别肿瘤。拟议的研究将建立在我们的发现和 使用硝基芳香族药物的经验表明，这些药物在 细胞内的速率与细胞内氧浓度成反比- 产生加合物的细胞生物分子指示内- 细胞氧分压与辐射敏感性。放射自显影与液体 β标记增敏剂加合物的闪烁计数现在正在进行 被接受的测量两者相对氧合状态的技术 啮齿动物和人类肿瘤。附着到的发射伽马的放射性核素 适当的生物还原药物可以提供有用的非侵入性措施 这块肿瘤的财产。交叉癌症研究所之前的研究 (加拿大埃德蒙顿)已将碘化阿奇霉素核苷鉴定为 这类核医学探测的可能候选者。碘化阿奇霉素 阿糖胞苷(IAZA)在治疗前和/或治疗过40例患者 在肿瘤治疗期间。而IAZA的肿瘤滞留可能表明 在一些人类肿瘤中的低氧水平，这种成像化合物远远不是 最好的。非结合标志物的清除和排泄是前提 用于在缺氧组织中显影结合敏化剂的最佳图像。 IAZA在人体内的血浆半衰期约为10小时。此外，ITS 脱卤化和肝胆排泄导致同位素图像 与组织生物还原状态无关。这项研究将综合 生物还原激活结扎术(BLAR)的新缺氧标志物 分类并确定动物模型中的结构/活性关系 选择具有更短的血浆半衰期和 碘更能抵抗药理脱卤化作用。缺氧者 高级化合物的标记能力将被测试并与 单个EMT-6肿瘤的放射敏感性测量 丹宁个体的放射敏感性测量和31P-核磁共振谱 3327-AT大鼠前列腺癌。两种动物肿瘤模型都显示出广泛的 氧合状态的非均质性。这些相关研究将 协助定义改进的探头，用于非侵入性测量 实体瘤氧合。本研究的重点是 一种改进的标志物的鉴定，临床科学家可以用它来 制定可靠的人体肿瘤氧合和非侵入性测量 复氧作用。