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. ? ? ?
