Chemoprevention in Ulcerative Colitis: Narrowing the Gap between Clinical Practice and Research

• Colitis, ulcerative
• Ursodiol
• Colorectal neoplasms
• Cholangitis, sclerosing
• Colonic dysplasia

Although the incidence of colorectal cancer has been decreasing in the United States over the past decade, it remains the fourth most frequently diagnosed type of cancer and is second only to lung cancer in causing cancer-related death. This dismal situation has been offset by a recent convergence of insights into the molecular pathogenesis of colorectal cancer, validated screening technologies, and proof that early detection coupled with polypectomy reduces the risk for incident cancer and, indirectly, death. Indeed, the prospects for prevention of colorectal cancer have never been better.

Persons with ulcerative colitis are at increased risk for colorectal dysplasia and cancer; cancer occurs in up to 13% of patients within 20 years (1). Patients who have ulcerative colitis with primary sclerosing cholangitis may be at even greater risk. Such patients have accelerated rates and numbers of neoplastic events and are likely to benefit considerably from chemopreventive interventions that complement established preventive measures (screening, surveillance, polypectomy, and prophylactic surgery).

Fecal bile acids have long been associated with increased risk for colorectal cancer. Evidence supporting this association includes in vitro mutagenesis with deoxycholic acid (2), bile acid–induced tumor promotion in animal models (3), and epidemiologic investigations (4). Ursodiol, a noncytotoxic hydrophilic epimer of chenodeoxycholic acid, has shown promising chemopreventive efficacy in two carcinogen-induced rat models of colorectal carcinogenesis. Although the precise mechanisms underlying these effects are incompletely understood, ursodiol has been reported to enhance the expression of major histocompatibility antigens on premalignant tissues, modulate carcinogen-induced changes in protein kinase C, stabilize cellular membranes, reduce mucosal concentrations of phospholipase A2 at the …