Repeated tumor oximetry to identify therapeutic window during metronomic cyclophosphamide treatment of 9L gliomas

Abstract

Malignant gliomas are aggressive and angiogenic tumors with high VEGF content. Consequently, approaches such as metronomic chemotherapy, which have an antiangiogenic effect, are being investigated. However, a lack of an appropriate technique that can facilitate the identification of vascular changes during antiangiogenic treatments has restricted therapeutic optimization. We have investigated the potential of tumor pO2 as a marker to detect vascular changes during metronomic chemotherapy. Electron paramagnetic resonance (EPR) oximetry was used to repeatedly assess tumor pO2 during metronomic cyclophosphamide treatment of subcutaneous 9L tumors. The 9L tumors were hypoxic with a pO2 of 5.6-8 mmHg and a tumor volume of 247-300 mm3 prior to any treatment Tumor pO2 increased significantly to 19.7 mmHg on day 10 and remained at an elevated level until day 33 during 4 weekly treatments with 140 mg/kg cyclophosphamide. A significant decrease in the tumor volume on days 21-31 occurred in the cyclophosphamide group, while the tumor volume of the control group significantly increased during measurements for two weeks. A significant tumor growth delay was achieved with two weekly treatments of cyclophosphamide plus radiotherapy (4 Gy x 5) as compared to control, cyclophosphamide and radiotherapy alone groups. The results indicate the potential of EPR oximetry to assess tumor pO2 during metronomic chemotherapy. The ability to identify the duration of an increase in tumor pO2, therapeutic window, non-invasively by EPR oximetry could have a significant impact on the optimization of antiangiogenic approaches for the treatment of gliomas. This vital information could also be used to schedule radiotherapy to enhance therapeutic outcome.