Abstract 5546: Improved gastrointestinal repair post irradiation with AEOL 10150

Abstract

Abstract Background Gastrointestinal toxicity, often manifested as ulceration and diarrhoea (mucositis) occurs following exposure to radiation and many chemotherapeutics. Potential treatments include prophylactic damage limitation or therapeutic/mitigatory wound repair dosing regimes. Treatments that are effective mitigators also have biodefence applications. In both the clinic or following nuclear terrorism effective agents may be given in combination with haematological therapies, in addition to standard supportive care agents. Methods AEOL 10150 [5,10,15,20-tetrakis(1,3-diethylimidazolium-2-yl) porphyrinato] manganese (III) pentachloride was administered to C57BL/6 male mice s.c. daily from 24hrs following a single dose of 13Gy total body X-irradiation. AEOL 10150 was administered at a 2x initial loading dose of 40 or 20mg/kg and then subsequently each day at 20 or 10mg/kg respectively. Animals were euthanized 4 and 6 days post irradiation and the number of regenerating small intestinal crypts measured. In a parallel study the levels diarrhoea and animal viability were measured animals exposed to 15Gy partial body X-irradiation (partially lead shielded to protect the bone marrow). Results Treatment with AEOL 10150 increased the number of surviving regenerating crypt observed in histological cross sections of the small intestine 4 days post irradiation. This was highly significant at both doses (p<0.001 for the 40/20mg/kg schedule and p=0.009 for the 20/10 mg/kg schedule). By day 6, where crypt numbers had increased from day 4, numbers were increased but not statistically significant. Levels of crypt fission, necessary to restore crypt numbers, were also increased. At the highest treatment dose animal mortality was only marginally reduced (p=0.115) but the severity and duration of observed diarrhoea was significantly reduced (p=0.021 and p=0.010 respectively). Conclusion AEOL 10150 demonstrated efficacy in both histological and physiological readouts of radiation induced gastrointestinal toxicity. Studies are currently ongoing to investigate whether other dosing schedules can further improve gastrointestinal repair. 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 5546.