TUMOR RADIATION SENSITIVITY AFTER PHYSIOLOGICAL CHANGES

生理变化后的肿瘤辐射敏感性

• 批准号: 3199798
• 负责人: DIETMAR W SIEMANN
• 金额: $ 20万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-17 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3199798
• 关键词: animal tissue; blood pressure; breast neoplasms; hemoglobin; human tissue; hypoxia; laboratory mouse; neoplasm /cancer; neoplasm /cancer radiation therapy; nicotinamide; oxygen tension; oxygen transport; perfusion; radiation sensitivity; sarcoma; stainings; xenotransplantation

The central focus of this grant application is to utilize pathophysiological manipulations to attempt to overcome the radiation resistance associated with transient (acute) and diffusion-limited (chronic) tumor hypoxia. Investigations will evaluate the effects of changes in hemoglobin (Hb) affinity for oxygen (O2) and/or tumor blood flow on tumor response to radiation. Hb affinity will be altered by the direct administration of agents which shift the Hb-02 dissociation curve or the transfusion of biochemically modified erythrocytes into tumor-bearing recipients. Tumor blood flow will be manipulated through the administration of the agents flunarizine and nicotinamide. Changes in tumor blood flow will be monitored using a variety of techniques including laser Doppler flowmetry, and the relationship between blood flow changes and radiation sensitivity will be established. To study whether specific manipulations of tumor oxygenation are producing the desired effects at the microregional level, intravascular HbO2 saturations distributions will be determined cryospectrophotometrically. Additionally, dual-staining procedures with Hoechst 33342 and DiOC 7(3) will be used to determine the relative fraction of vessels involved in transient perfusion. These studies initially will utilize the rodent KHT and SCCVII tumor models since chronically hypoxic cells dominate the former while acutely hypoxic cells can be demonstrated in the latter. For comparison, more limited experiments in human ovarian tumor xenografts also are proposed. Xenograft studies are of particular interest given the recent. controversy concerning the activity of vasoactive -agents in human versus rodent tumor models. It also is our objective to evaluate in these tumor models the therapeutic potential of combining therapies directed at the different types of hypoxia. Those conditions leading to the greatest antitumor activity will be evaluated using fractionated dose radiotherapy protocols. These investigations should improve our understanding of tumor hypoxia and may have implications for strategies aimed at overcoming hypoxia-mediated treatment resistance by specifically targeting acute and chronically hypoxic cells.

本次拨款申请的重点是利用 试图克服辐射的病理生理学操作 与瞬态（急性）和扩散限​​制相关的阻力 （慢性）肿瘤缺氧。 调查将评估影响 血红蛋白 (Hb) 对氧 (O2) 和/或肿瘤血流的亲和力发生变化 关于肿瘤对辐射的反应。 Hb 亲和力将通过直接改变 施用可改变 Hb-02 解离曲线或 将生化修饰的红细胞输注至荷瘤体内 收件人。 肿瘤血流将通过 给予氟桂利嗪和烟酰胺药剂。 变化 将使用多种技术监测肿瘤血流，包括 激光多普勒血流测定，与血流变化的关系 并将建立辐射敏感性。 研究是否具体 肿瘤氧合的操作正在产生预期的效果 微区域水平，血管内 HbO2 饱和度分布为 冷冻分光光度法测定。 另外，双染色 Hoechst 33342 和 DiOC 7(3) 程序将用于确定 参与瞬时灌注的血管的相对分数。 这些研究最初将利用啮齿动物 KHT 和 SCCVII 肿瘤模型 因为慢性缺氧细胞在前者中占主导地位，而急性缺氧细胞则占主导地位 细胞可以在后者中得到证明。 为了比较，更有限 还提出了在人类卵巢肿瘤异种移植物中进行的实验。 异种移植 鉴于最近的研究特别令人感兴趣。有关的争议 血管活性剂在人类与啮齿动物肿瘤模型中的活性。 我们的目标也是在这些肿瘤模型中评估治疗效果 针对不同类型的联合疗法的潜力 缺氧。 那些导致最大抗肿瘤活性的条件将 使用分次剂量放射治疗方案进行评估。 这些 研究应该提高我们对肿瘤缺氧的理解，并可能 对旨在克服缺氧介导的策略具有影响 通过专门针对急性和慢性治疗抵抗 缺氧细胞。