Induction of hypoxia by vascular disrupting agents and the significance for their combination with radiation therapy

Abstract

Purpose. This pre-clinical study was designed to investigate the effect of various vascular disrupting agents (VDAs) that have undergone or are in clinical evaluation, had on the oxygenation status of tumours and what effects that could have on the combination with radiation. Material and methods. The tumour model was a C3H mammary carcinoma grown in the right rear foot of female CDF1 mice and treated when at 200 mm³ in size. The VDAs were the flavenoid compounds flavone acetic acid (FAA) and its more recent derivative 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and the leading tubulin binding agent combretastatin A-4 phosphate (CA4P) and the A-1 analogue OXi4503. Oxygenation status was estimated using the Eppendorf oxygen electrode three hours after drug injection. Radiation response was determined following single or fractionated (10 fractions in 12 days) irradiations with a 240 kV x-ray machine using either a tumour re-growth or local tumour control assay. Results. All VDAs significantly reduced the oxygenation status of the tumours. They also influenced radiation response, but the affect was time and sequence dependent using single radiation schedules; an enhanced effect when the VDAs were injected at the same time or after irradiating, but no or even a reduced effect when given prior to irradiation. Only OXi4503 showed an increased response when given before the radiation. CA4P and OXi4503 also enhanced a fractionated radiation treatment if the drugs were administered after fractions 5 and 10. Conclusions. VDAs clearly induced tumour hypoxia. This had the potential to decrease the efficacy of radiation. However, if the appropriate timing and scheduling were used an enhanced effect was observed using both single and fractionated radiation treatments.

Acknowledgements

The authors would like to thank Ms. Dorthe Grand, Ms. Inger Marie Horsman, Ms. Pia Schjerbeck, Ms. Marianne Verner Bjerre, and Ms. Marianne Kristiansen for excellent technical assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by grants from the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences.