Chemotherapy- and Radiotherapy-Induced Intestinal Damage Is Regulated by Intestinal Trefoil Factor

Background & Aims: Injury to the intestinal mucosa is frequently a dose-limiting complication of radiotherapy and chemotherapy. Approaches to limit the damage to the intestine during radiation and chemotherapy have been largely ineffective. Trefoil factors are produced throughout the gastrointestinal tract and regulate cell migration, restitution, and repair. Studies were undertaken to define the role of intestinal trefoil factor in modulating the intestinal response to chemotherapy and radiation. Methods: The effect of intestinal trefoil factor on migration and cell survival in intestinal epithelial monolayer exposed to methotrexate was studied in vitro. Chemotherapy and radiation damage was assessed in wild-type and intestinal trefoil factor-null mice in the presence or absence of supplemental intestinal trefoil factor administered in drinking water. Results: Radiation and chemotherapy induced a marked reduction in goblet cell number and intestinal trefoil factor messenger RNA, as well as intestinal trefoil factor promoter activity. Intestinal trefoil factor improved intestinal epithelial cell viability and wound repair after chemotherapy exposure in vitro. Intestinal trefoil factor-deficient mice (intestinal trefoil factor^-/-) were more susceptible to chemotherapy- and radiation-induced mucositis. Oral recombinant intestinal trefoil factor reduced the severity of both chemotherapy-induced and chemotherapy/radiotherapy-induced intestinal mucositis. Conclusions: These studies suggest that intestinal trefoil factor is involved in protection against and recovery from intestinal mucositis induced by radiation and chemotherapy.