Ibadronate may prevent colorectal carcinogenesis in mice with ulcerative colitis.
An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis, which displays a cycle of recurrence-remission in the colorectal mucosa. Repeated oral doses of 3% dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane induces chronic ulcerative colitis, resulting in an increased incidence of high-grade dysplasia and submucosal-invasive adenocarcinomas in the mouse colorectum. The features of the colitis induced in this animal model are very similar to the ulcerative colitis in patients in terms of both clinical and histopathological characteristics. Bisphosphonates are known to increase bone mass by suppressing bone turnover in postmenopausal women. A novel single-nitrogen bisphosphonate, ibandronate, is effective in preventing skeletal events in patients with bone metastases from colorectal cancer. Decreasing the bone mineral affinity of bisphosphonates is an effective therapeutic strategy to inhibit skeletal tumor growth in vivo. In the present study, the preventative effects of the bisphosphonate ibadronate on colorectal carcinogenesis in mice treated with azoxymethane and dextran sulfate sodium was investigated. Additive treatment with bisphosphonate prevented the shrinkage of colorectum which was affected by a cycle of recurrence-remission in colorectal mucosa, resulting in a reduced incidence of colorectal dysplasia and a reduced expression of thymidine kinase mRNA in the colorectum. Taken together, the present results indicate that ibadronate may inhibit colorectal carcinogenesis and its development by inhibiting colorectal epithelial cell proliferation and the neoplastic process.
Sassa
Shuji
S
Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Okabe
Hitomi
H
Nemoto
Nahoko
N
Kikuchi
Hiroyuki
H
Kudo
Hideki
H
Sakamoto
Shinobu
S
D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics
D002273:Carcinogens; D004164:Diphosphonates; D012333:RNA, Messenger; C071542:cimadronate; D016264:Dextran Sulfate; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D001397:Azoxymethane