Tumor pO₂ as a Surrogate Marker to Identify Therapeutic Window during Metronomic Chemotherapy of 9L Gliomas

Abstract

Glioblastomas are aggressive and highly vascularized primary brain tumors with a 5-year survival rate of less than 10%. Approaches targeting tumor vasculature are currently being investigated to achieve therapeutic benefits for this fatal malignancy. However, lack of suitable markers that can be used to monitor therapeutic effects during such treatments has restricted their optimization. We have focused on the development of tumor pO₂ as a surrogate marker to identify the therapeutic window during metronomic chemotherapy.We report the effect of four weekly administrations of cyclophosphamide (140 mg/Kg, i.p), a chemo drug, on tumor pO₂ and growth of subcutaneous 9L tumors in SCID mice. The repeated measurement of tumor pO₂ was carried out using in vivo EPR oximetry. The subcutaneous 9L tumors were hypoxic with a pre-treatment tumor pO₂ of 5.1 ± 1 mmHg and a tumor volume of 236 ± 45 mm3 on day 0. The tumor pO₂ increased significantly to 26.2 ± 2 mmHg on day 10, and remained at an elevated level till day 31 during weekly treatments with cyclophosphamide. The tumor pO₂ then declined to 20 ± 9 mmHg on day 43. The tumor volume of the control group increased significantly with no change in tumor pO₂over days.Results indicate a transient increase in tumor pO₂ duringmetronomic chemotherapy of 9L gliomas and could be potentially used as amarker to identify vessel normalization during metronomic chemotherapy. The ability to identify therapeutic window non-invasively using EPR oximetry can have a significant impact on the optimization of clinical protocols. In vivo EPR oximetry is currently being tested for repeated pO₂ measurements in patients with superficial tumors.