Abstract 1796: Targeting the microenvironment and vasculature of tumors to improve response to radiation administered using a dose and schedule equivalent to those of a stereotactic radiation treatment
Authors: Horsman Michael R. , Wittenborn Thomas R. 
Published: August 2015

Abstract
Purpose: The vasculature and microenvironment of tumors play significant roles in influencing tumor response to radiation. Applying approaches that target these tumor parameters can effectively enhance radiation response when using large single doses or a conventional fractionated schedule. This pre-clinical study was designed to use such vascular and microenvironmental modifiers to improve tumor response to radiation administered in a schedule equivalent to a stereotactic radiation treatment.
Materials and methods: C3H mammary carcinomas, grown in the right rear foot of female CFD1 mice, were treated when at 200 cubic mm in size. Tumors were locally irradiated in restrained, non-anesthetized mice with 3×15 Gy during a 1-week period, followed 3-days later by a clamped top-up dose to produce a dose-response curve; the endpoint being tumor control at 90 days. Following logit analysis of the radiation dose-response curve, the TCD50 values (radiation dose that controlled 50% of tumors) were calculated. Statistical analysis was achieved using a Chi-squared test (p&lt;0.05). The radiation modifiers were nimorazole (200 mg/kg), injected intraperitoneally (i.p.) 30 minutes before irradiating; nicotinamide (120 mg/kg; injected i.p. 20 minutes before irradiation) and carbogen (95% oxygen + 5% carbon dioxide) breathing (started 5 minutes before and continued during the irradiation period); OXi4503 (10 mg/kg; injected i.p. 1-hour after irradiating); and hyperthermia (41.5 degrees C for 1-hour started 4-hours after irradiating).
Results: The clamped TCD50 dose following 3×15 Gy was 30 Gy. Giving nimorazole or nicotinamide+carbogen prior to the final 15 Gy irradiation non-significantly reduced this TCD50 to 20-23 Gy; when administered with each 3×15 Gy irradiation these values were significantly reduced to 2.5 Gy or below. Injecting OXi4503 or heating significantly reduced the TCD50 to 9-12 Gy regardless of whether administered with one or all three 15 Gy treatments. Combining OXi4503 and heat with the final 15 Gy irradiation had a significantly larger effect (TCD50 = 2 Gy).
Conclusions: Clinically relevant modifiers of the vasculature or microenvironment of a tumor effectively enhanced radiation given in a stereotactic equivalent schedule. But, different effects were obtained with the various agents, which may be related to the different mechanisms of action. This latter issue is under investigation.
Supported by grants from the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences.
Citation Format: Michael R. Horsman, Thomas R. Wittenborn. Targeting the microenvironment and vasculature of tumors to improve response to radiation administered using a dose and schedule equivalent to those of a stereotactic radiation treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1796. doi:10.1158/1538-7445.AM2015-1796