Abstract C238: Combining vascular-targeting therapies with radiation: The role of hypoxia.

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Abstract Background: The combination of radiation with drugs that target tumor vasculature is an effective therapeutic approach. However, the role of hypoxia, whether already present or induced by the vascular targeting drug, in this interaction is not clear. The aim of this study was to investigate this issue using various clinically relevant vascular disrupting agents (VDAs). Materials and methods: Treatments were performed using restrained non-anethetised female CDF1 mice that had a 200 cubic mm C3H mammary carcinoma growing in the right rear foot. The VDAs were combretastatin A-4 phosphate (CA4P), its structural analogue OXi4503, ZD6126, flavone acetic acid (FAA), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA). All drugs were dissolved in saline and intraperitoneally injected at a volume of 0.02 ml/g mouse body weight; the final doses being 250 mg/kg (CA4P), 50 mg/kg (OXi4503), 200 mg/kg (ZD6126), 150 mg/kg (FAA), and 20 mg/kg (DMXAA). Tumor oxygenation status was determined using the Eppendorf polarographic electrode, the endpoint being the percentage of oxygen measurements less than or equal to 5 mmHg (pO2 ≤ 5 mmHg). Tumors were also locally irradiated (230 kV x-rays) with graded radiation doses given either as single treatments or in a fractionated schedule of 10 fractions in 12 days (5 daily fractions - 2 day gap - 5 daily fractions). The percentage of mice in each treatment group showing local control at 90 days was recorded and the TDC50 values (radiation dose to control 50% of tumors) estimated from full radiation dose response curves. Statistical analysis involved a Student's t-test (Eppendorf) or Chi-squared test (TCD50) with a significance level of p<0.05 for both. Results: Control tumors had a mean (with 1 S.E.) percentage of pO2 values ≤ 5 mmHg of 45% (40–50). This was significantly increased within 3-hours after injecting the VDAs; the values being 91% (87–95), 73% (66–80), 72% (64–80) and 87% (78–96) for CA4P, ZD6126, FAA and DMXAA, respectively. The TCD50 value (with 95% confidence interval) for single radiation treatments was 53 Gy (51–55). Irradiating tumors and then injecting any of the VDAs immediately or within a few hours after irradiating significantly reduced the TCD50 values to between 42 (39–45) and 46 Gy (42–49), depending on the VDA used. Absolutely no enhancement was seen if the VDAs were injected up to 24 hours prior to irradiation, except for OXi4503 where TCD50 values of 44 Gy (41–46) and 38 Gy (34–41) were obtained when the drug was injected 1 or 24 hours before irradiating, respectively. In a fractionated schedule the TCD50 value for radiation alone was 76 Gy (73–79). Irradiating tumors and then injecting CA4DP or OXi4503 only after the last radiation treatment each week significantly reduced the respective TCD50s to 66 Gy (62–69) and 67 Gy (63–71). Conclusions: Hypoxic cells are presumably the first cells to die after treatment with a VDA and this would explain the ability of these drugs to enhance radiation response. However, VDAs also induce hypoxia, so the sequencing of this combination is critical to observe any enhancement. For OXi4503, the induction of hypoxia may not be an issue because while it damages tumor vasculature, it also has a cytotoxic function and thus can kill any hypoxic cells that may be induced. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C238.