Monitoring Oxygen Repeatedly for Hypoxic Tumor Therapy

反复监测氧气以进行缺氧肿瘤治疗

• 批准号: 7145971
• 负责人: NADEEM KHAN
• 金额: $ 15.19万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-03 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145971
• 关键词: neoplasm /cancer; oximetry; oxygen

DESCRIPTION (provided by applicant): The level of oxygen in tumors has a profound effect on the efficacy of therapy and tumor progression. Hypoxia influences treatment outcome not only through radio-resistance but also by promoting more aggressive tumor behaviors. Oxygen regulated expression of genes producing proteins, for example VEGF and p53, may increase metastatic growth and resistance to therapy. The level of oxygenation in tumors cannot be predicted based on tumor type, histology, stage of tumor or size, and therefore it has become extremely important to monitor oxygen concentration in tumors in a repeatedly and non-perturbing manner. Radiation therapy is expected to change oxygenation in tumors, and this effect is likely to vary with the tumor size, dose per fraction, and the interval between doses. Many clinical trials have been aimed at overcoming tumor hypoxia but have been only modestly successful, at least in part because of technical limitations in detecting the presence of hypoxia and in following the effects of interventions on oxygen levels. The ability to follow the time-course of tumor pO2 levels repeatedly and non-invasively over the course of therapy could provide the crucial information needed to optimize the effectiveness of hypoxia modifying procedures. It also is feasible that such information could be used to individualize the clinical use of fractionated therapy, including its use in combined treatments developed recently in radiation oncology such as conformal therapy, variations in dose, and/or combined radiation-chemotherapy. This would be accomplished by timing the treatments at the time when the oxygen level in the tumor is optimal. The recent development of in vivo EPR oximetry has the potential to provide non-invasive, accurate, and repetitive direct measurements of tumor oxygen from the same locations in the tissue for periods as long as years. We propose to demonstrate, under realistic conditions, that in vivo EPR oximetry can provide repetitive data on tumor oxygenation during the course of therapy and that this can be used to enhance therapeutic outcome. We plan to test our hypothesis in RIF-1 tumor model in mice, including the monitoring of modifications of tumor hypoxia by an innovative approach to deliver an effective vasoactive agent with maximal effectiveness and minimal toxicity (benzyl nicotinate (BN), delivered transdermally). Preliminary results indicate an increase in pO2 of subcutaneous RIF-1 tumors with topical application of BN in mice. The proposed approach to modulate tumor hypoxia will avoid possible complications and toxicity arising due to oral or injections of drugs. If successful, this approach potentially could be immediately extended for clinical applications.

描述（由申请人提供）：肿瘤中的氧水平对治疗效果和肿瘤进展具有深远影响。缺氧不仅通过放射抗性影响治疗结果，而且还通过促进更具侵袭性的肿瘤行为来影响治疗结果。氧调节的产生蛋白质的基因表达，例如VEGF和p53，可能增加转移性生长和对治疗的抗性。肿瘤中的氧合水平不能基于肿瘤类型、组织学、肿瘤阶段或大小来预测，因此以重复和非干扰的方式监测肿瘤中的氧浓度变得极其重要。放射治疗预计会改变肿瘤中的氧合，并且这种效果可能会随着肿瘤大小、每次剂量和剂量之间的间隔而变化。许多临床试验旨在克服肿瘤缺氧，但仅取得了一定的成功，至少部分原因是在检测缺氧的存在和跟踪干预措施对氧水平的影响方面存在技术限制。在治疗过程中重复和非侵入性地跟踪肿瘤pO 2水平的时间过程的能力可以提供优化缺氧调节程序的有效性所需的关键信息。这也是可行的，这样的信息可以被用来个性化的临床使用分次治疗，包括其在联合治疗中的使用最近开发的放射肿瘤学，如适形治疗，剂量的变化，和/或联合放化疗。这将通过在肿瘤中的氧水平最佳时定时治疗来实现。体内EPR血氧测定法的最新发展有可能在长达数年的时间内从组织中的相同位置提供肿瘤氧的无创、准确和重复的直接测量。我们建议证明，在现实的条件下，在体内EPR血氧饱和度可以提供重复的数据在治疗过程中的肿瘤氧合，这可以用来提高治疗效果。我们计划在小鼠RIF-1肿瘤模型中测试我们的假设，包括通过一种创新方法监测肿瘤缺氧的变化，以最大有效性和最小毒性递送有效的血管活性剂（烟酸苄酯（BN），经皮递送）。初步结果表明，在小鼠中局部应用BN时，皮下RIF-1肿瘤的pO 2增加。所提出的调节肿瘤缺氧的方法将避免由于口服或注射药物而引起的可能的并发症和毒性。如果成功，这种方法可能会立即扩展到临床应用。