M1738 The Genetically Modified Lactococcus Lactis Ova Modulates T-Cells Through an Antigen-Specific Effect on Dendritic Cells

Abstract

Background: Colorectal cancer is one of the most serious complications of ulcerative colitis (UC) and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. As we have shown previously, the selective cyclooxygenase (COX)-2 inhibitor is effective in diminishing carcinogenesis in an murine model of UC (DDW 2006).1 However, this might exacerbate dextran sulfate sodium (DSS) colitis in mice. The selective COX-2 inhibitor Etodolac is marketed as a racemic mixture of the Rand Senantiomers that are not metabolically interconvertible. The biochemical and pharmacological effects of Etodolac are due to the S-enantiomer, while R-enantiomer lacks COX-inhibitory activity. Therefore, R-Etodolac has potential advantage of avoiding COX-2 inhibitory adverse effects. In this study, we evaluated the effect of R-Etodolac on colitis-related mouse colon carcinogenesis. Methods: The mice received 1,2-dimethlhydrazine (DMH) at a dose of 20mg/kg body wt subcutaneously three times within 1 week of reaching 6 weeks of age. Starting 1 week after the DMH injection, chronic colitis was induced in mice by administration of 2 cycles of DSS (each cycle: 3% DSS for 7 days and then distilled water for 14 days). The mice were killed 28 days after the completion of the 2 cycles. The mice were divided into the following groups: group A served as a disease control; group B received low (2mg/kg) dose of REtodolac every 3 days by oral gavage during the whole period; group C received high (10mg/ kg) dose of R-Etodolac every 3 days by oral gavage during the whole period; group D received no agents including DSS and served as a normal control. Results: The administration of R-Etodolac decreased the disease activity index during the administration cycle of DSS. The mean number of tumors was 17.8 in group A, 15.2 in group B and 6.0 in group C. In group C, R-Etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Strong COX-2 expression was detected by immunohistochemistry in the neoplastic lesions while E-cadherin expression was not observed. Although treatment of R-Etodolac unaffected to the COX-2 expression, it was found that R-Etodolac significantly enhanced the expression of E-cadherin in the neoplastic lesions and background mucosa (i.e. lesion-free colon). Conclusion: The administration of R-Etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS induced colitis without exacerbation of the colitis. These results suggest that R-Etodolac could be useful in the prevention of UC-associated neoplasia. 1. Inoue T et al. J Gastroenterol Hepatol 2009; 22: 1474-81.