Monitoring Oxygen Repeatedly for Hypoxic Tumor Therapy

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有深远的影响。缺氧不仅通过放射抵抗影响治疗结果，而且还通过促进更具有攻击性的肿瘤行为影响治疗结果。氧调节产生蛋白质的基因的表达，例如VEGF和p53，可能会增加转移性生长和对治疗的抵抗。肿瘤内氧合水平不能根据肿瘤类型、组织学、肿瘤分期或肿瘤大小来预测，因此对肿瘤内氧浓度进行反复、无干扰的监测变得极为重要。放射治疗有望改变肿瘤中的氧合作用，这种作用可能随肿瘤大小、每部分剂量和剂量间隔而变化。许多临床试验旨在克服肿瘤缺氧，但只取得了适度的成功，至少部分原因是检测缺氧存在的技术限制以及干预对氧水平的影响。在治疗过程中反复和无创地跟踪肿瘤pO2水平的时间过程的能力可以提供优化缺氧修复程序有效性所需的关键信息。同样可行的是，这些信息可以用于个性化的临床使用的分级治疗，包括其在联合治疗中使用的放射肿瘤学最近发展，如适形治疗，剂量的变化，和/或联合放化疗。这将通过在肿瘤中氧含量最佳的时间安排治疗来实现。体内EPR血氧仪的最新发展有可能提供无创、准确和重复的直接测量肿瘤氧从组织中的相同位置长达数年的时间。我们建议在现实条件下证明，体内EPR血氧仪可以在治疗过程中提供肿瘤氧合的重复数据，并可用于提高治疗效果。我们计划在小鼠的RIF-1肿瘤模型中验证我们的假设，包括通过一种创新的方法来监测肿瘤缺氧的变化，这种方法可以提供一种有效的血管活性药物，具有最大的有效性和最小的毒性（尼古丁苯酯（BN），经皮递送）。初步结果表明，局部应用BN可增加小鼠皮下RIF-1肿瘤的pO2。本文提出的调节肿瘤缺氧的方法将避免口服或注射药物可能引起的并发症和毒性。如果成功，这种方法可能会立即扩展到临床应用。

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.