Biomarker for Radiation Therapy: The Relationship Between Tissue Oxygenation and Redox Status

Abstract

Tumor hypoxia is prognostic for poor response to cancer therapy. The prognostic value of tumor hypoxia has been demonstrated in radiotherapy studies of human head and neck and uterine cervix tumors, which show that patients with less hypoxic tumors had a better chance of overall or disease-free survival than did patients with more hypoxic tumors. Furthermore, some chemotherapeutic agents such as bleomycin and doxorubicin exhibit a cytotoxicity that is strongly oxygen dependent, suggesting that hypoxia may be a prognostic factor for chemotherapeutic response as well. Therefore, development of methods allowing measurement of hypoxia in human patients may allow physicians to better manage tumors that exhibit considerable hypoxia. The recent development of a bi-modality magnetic resonance imaging/electron paramagnetic resonance imaging (MRI/EPRI) platform has enabled longitudinal monitoring of both tumor oxygenation and redox status in murine cancer models. The current study used this imaging platform to test the hypothesis that a more reducing tumor microenvironment accompanies the development of tumor hypoxia. To test this, the redox status of the tumor was measured using Tempol as a redox-sensitive MRI contrast agent, and tumor hypoxia was measured with Oxo63, which is an oxygen-sensitive EPRI spin probe. Images were acquired every 1-2 days in mice bearing SCCVII tumors. The median pO2 decreased from 14 mmHg at 7 days after tumor implantation to 7 mmHg at 15 days after implantation. Additionally, the hypoxic fraction, defined as the percentage of the tumor that exhibited a pO2<10 mmHg, increased with tumor size (from 10% at 500 mm3 to 60% at 3,500 mm3). The rate of Tempol reduction increased as a function of tumor volume (0.4 min-1 at 500 mm3 to 1.7 min-1 at 3,500 mm3), suggesting that the tumor microenvironment became more reduced as the tumor grew. The results show that rapid Tempol reduction correlates with decreased tumor oxygenation, and that the Tempol decay rate constant may be a surrogate marker for tumor hypoxia. Nitroxides such as Tempol may provide a clinically feasible magnetic resonance imaging based assay of hypoxia for radiotherapy.