Therapeutic potential of using the vascular disrupting agent OXi4503 to enhance mild temperature thermoradiation

Abstract

Purpose: The response of tissues to radiation with mild temperature hyperthermia is dependent on the interval between the two modalities. This study investigated the effect that the vascular disrupting agent OXi4503 had on this time-interval interaction.

Methods: The normal right rear foot of female CDF1 mice or foot-implanted C3H mammary carcinomas were locally irradiated (230 kV X-rays) and heated (41.5 °C for 60 min) by foot immersion in a water bath. OXi4503 (50 mg/kg) was injected intraperitoneally 1.5 h before irradiating. Irradiation was performed either in the middle of the heating period (simultaneous treatment) or at 1 or 4 h prior to starting the heating (sequential treatments). Response was the percentage of mice showing local tumour control at 90 days or skin moist desquamation between days 11–23. From the radiation dose response curves the dose producing tumour control (TCD₅₀) or moist desquamation (MDD₅₀) in 50% of mice was calculated.

Results: The TCD₅₀ and MDD₅₀ values for radiation alone were 54 Gy and 29 Gy, respectively. Simultaneously heating the tissues enhanced radiation response, the respective TCD₅₀ and MDD₅₀ values being significantly (chi-square test, p < 0.05) reduced to 33 Gy and 14 Gy. A smaller enhancement was obtained with a sequential treatment in both tissues. OXi4503 enhanced the radiation response of tumour and skin. Combined with radiation and heat, the only effect was in tumours where OXi4503 prevented the decrease in sensitisation seen with the sequential treatment.

Conclusion: Combining OXi4503 with a sequential radiation and heat treatment resulted in a 1.4-fold therapeutic gain.

• C3H mammary carcinoma
• mild temperature hyperthermia
• radiation
• OXi4503
• vascular disrupting agents

Acknowledgements

The author would like to thank Dorthe Grand, Pia Schjerbeck, and Inger Marie Horsman for excellent technical assistance, and Marianne Verner Bjerre and Marianne Kristiansen for animal care. This study was made possible by financial support from the Danish Cancer Society, the Danish Council for Independent Research, Medical Sciences, and the Danish Hyperthermia Fund.

Declaration of interest

The author reports no conflict of interest and is entirely responsible for the content and writing of this paper.