Monitoring Oxygen Repeatedly for Hypoxic Tumor Therapy

描述(申请人提供)：肿瘤中的氧气水平对治疗效果和肿瘤进展有着深远的影响。低氧不仅通过辐射抵抗影响治疗结果，还通过促进更具侵袭性的肿瘤行为来影响治疗结果。氧调节产生蛋白质的基因的表达，如血管内皮生长因子和p53，可能会增加转移生长和对治疗的抵抗力。肿瘤的氧合水平不能根据肿瘤的类型、组织学、肿瘤的分期或大小来预测，因此，以重复和非扰动的方式监测肿瘤中的氧气浓度变得极其重要。放射治疗有望改变肿瘤中的氧合作用，这种影响可能会随着肿瘤大小、每部分剂量和剂量间隔的不同而不同。许多临床试验旨在克服肿瘤缺氧，但只取得了一定程度的成功，至少部分原因是在检测缺氧存在和跟踪干预对氧气水平的影响方面存在技术限制。在治疗过程中反复、非侵入性地跟踪肿瘤PO2水平的时间进程的能力，可以提供优化缺氧修改程序有效性所需的关键信息。这些信息也可以用于个体化分割治疗的临床使用，包括它在放射肿瘤学最近发展起来的联合治疗中的使用，例如适形治疗、剂量变化和/或放化疗联合治疗。这将通过在肿瘤内氧气水平最佳的时间进行治疗来实现。体内EPR血氧仪的最新发展有可能提供无创、准确和重复的从组织中相同位置长达数年的肿瘤血氧的直接测量。我们建议证明，在现实条件下，体内EPR血氧测定仪可以提供治疗过程中肿瘤氧合的重复数据，这可以用于提高治疗结果。我们计划在小鼠的RIF-1肿瘤模型中测试我们的假设，包括通过一种创新的方法监测肿瘤缺氧的修改，以提供最有效和最小毒性的有效血管活性物质(烟酸苄酯，经皮给药)。初步结果表明，局部应用BN可增加小鼠皮下RIF-1肿瘤的氧分压。所提出的调节肿瘤缺氧的方法将避免因口服或注射药物而可能出现的并发症和毒性。如果成功，这种方法有可能立即扩展到临床应用。

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.