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  • Title: Liposome-mediated adenomatous polyposis coli gene therapy: a novel anti-adenoma strategy in multiple intestinal neoplasia mouse model.
    Author: Lee J, Hargest R, Wasan H, Phillips RK.
    Journal: Dis Colon Rectum; 2004 Dec; 47(12):2105-13. PubMed ID: 15657662.
    Abstract:
    PURPOSE: Familial adenomatous polyposis is a highly penetrant, autosomal dominant disease resulting from a germline mutation of the adenomatous polyposis coli gene. Besides colorectal polyps and cancer, more than 90 percent of familial adenomatous polyposis patients also develop duodenal polyposis with an approximately 5 percent lifetime risk of malignant transformation. Because adenomatous polyposis coli protein has a "gatekeeper role" in the adenoma-carcinoma sequence, replacing its function may reduce polyp formation. We studied the functional outcome of per-oral, liposome-mediated adenomatous polyposis coli gene replacement therapy in a multiple intestinal neoplasia mouse model. METHODS: Twenty multiple intestinal neoplasia mice, heterozygous for the human homologue adenomatous polyposis coli gene, were randomly assigned to three groups: no treatment (n = 8); control plasmid containing green fluorescence protein reporter gene (n = 6); and plasmid containing the full-length adenomatous polyposis coli gene (n = 6). For the adenomatous polyposis coli-treated and green fluorescence protein reporter gene-treated groups, each mouse received the appropriate plasmid complexed with liposome, administered twice per week by oral gavage regime. Treatment lasted four weeks and all animals were killed at the end of treatment period with harvesting of intestinal tissue for polyp number estimation. RESULTS: There was a statistically significant 25 percent reduction in the total number of polyps in the adenomatous polyposis coli-treated (73.1 +/- 1.4) group compared with untreated control (97.8 +/- 5.3, P < 0.01, Tukey test) and multiple intestinal neoplasia mice treated with control green fluorescence protein gene (103.3 +/- 1.7, P < 0.01, Tukey test). CONCLUSION: Adenomatous polyposis coli gene dysfunction underlies tumorigenesis in familial adenomatous polyposis patients and multiple intestinal neoplasia mice. This in vivo study provides evidence to support a novel anti-adenoma strategy using enteral adenomatous polyposis coli gene replacement therapy.
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