Background: OXi4503 is a novel vascular disrupting agent (VDA) with single agent activity against solid tumors. However, its potential application in cancer therapy lies in its combination with more conventional therapies. The aim of this study was to determine its interaction with radiation when given alone or as part of a trimodality treatment schedule that also included cisplatin or mild temperature hyperthermia.
Material and Methods: Restrained non‐anaesthetised CDF1 mice, with a 200 cubic mm C3H mammary carcinoma grown in the right rear foot, were used. Tumors were locally irradiated (240 kV x‐rays) with single graded radiation doses. OXi4503 (50 mg/kg) and cisplatin (6 mg/kg) were prepared fresh before each experiment and injected intraperitoneally in a saline mixture at 0.02 ml/g body weight. Previous tumor growth studies had shown that the combination of OXi4503 with radiation was independent of timing and sequencing, thus it was always given within the first 60 minutes after irradiating. But, for cisplatin the optimal effect with radiation and/or OXi4503 was when the cisplatin was administered 3‐hours later. Mild temperature hyperthermia (41.5°C; 1‐hour) involved immersing the tumor bearing foot in a water bath and was always started 4‐hours after irradiating. The response endpoint was the percentage of mice in each treatment group showing local tumor control 90 days after irradiating. From full radiation dose response curves, the TCD50 values (radiation dose to control 50% of tumors) were estimated. A Chi‐squared test (significance level of p<0.05) was used to statistically compare the TCD50 results.
Results: The TCD50 value (with 95% confidence interval) for radiation alone was 53 Gy (50–56). Irradiating tumors and then injecting OXi4503 significantly reduced this to 43 Gy (40–44). Injecting cisplatin 3‐hours after irradiating had absolutely no effect on radiation response; the TCD50 being 53 Gy (50–56), but combining all 3 modalities gave the lowest TCD50 value of 41 Gy (38–43). Mild temperature hyperthermia produced a small yet significant reduction in the radiation TCD50 value to 47 Gy (45–50), But, the greatest enhancement was obtained when radiation, OXi4503 and heat were combined. With this combination the TCD50 was significantly reduced to 37 Gy (34–41).
Conclusions: OXi4503 on its own significantly enhanced the response of this C3H mammary carcinoma to radiation. Although cisplatin and mild hyperthermia had little or no effect on radiation‐induced local tumor control, combining these therapies with OXi4503 resulted in the greatest enhancement of radiation response. This VDA clearly has a role to play in combination with radiation therapy whether used on its own or as part of a multimodality schedule.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C235.
- Copyright © 2009, American Association for Cancer Research