Abstract 1404: Mitochondrial-targeted nitroxide JP4-039 ameliorates irradiation-induced delay in bone wound healing and inhibits orthotopic tumor growth

In the case of a nuclear explosion, combined injuries will result from radiation dispersal resulting in burns and cellular damage as well as a concussion wave resulting in traumatic bone fractures. Currently no available drugs are available to protect against both irradiation damage and traumatic bone damage. A new mitochondrial targeted small molecule hemigramicidin S nitroxide JP4-039 has been developed and shown to protect against total body irradiation. JP4-039 was tested to determine its effects on irradiation-induced delay of osseous wound healing. A model for osseous would healing was used where the right hind legs of C57BL/6NHsd female mice were irradiated to doses 0 to 30 Gy 24 hours prior to drilling tibial wounds. JP4-039 (10 mg/kg) was injected either 10 min before or after irradiation. Mice were sacrificed weekly after wounding; tibiae were removed and radiographed for measurement of hole diameter. The left non-irradiated leg served as a control for the irradiated right leg. To determine whether JP4-039 might enhance tumor growth while stimulating bone growth, we injected Lewis lung carcinoma cells subcutaneously above the knee in both legs. The tumor on the right leg was within the 10Gy irradiation field. Tumor growth was monitored daily with calipers. Tukey9s test was used to assess statistical significance between control and treated groups. Mice treated with JP4-039 before bone drilling showed significant improvement in osseous wound healing at 14 days and 21 days after drilling (0.55 ± 0.3 and 0.47 ± 0.04 mm, respectively), compared with 0.84 ± 0.05 and 0.64 ± 0.05 mm, respectively for control, untreated mice (p Thus, treatment with JP4-039 enhanced osseous bone healing when administered before wounding. Furthermore, JP4-039 enhanced healing when administered before or after irradiation. Finally, JP4-039 inhibited tumor growth and may have useful applications in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1404.