PRETREATMENT WITH TRANSFORMING-GROWTH-FACTOR BETA-3 PROTECTS SMALL-INTESTINAL STEM-CELLS AGAINST RADIATION-DAMAGE IN-VIVO

The gastrointestinal tract, with its rapid cell replacement, is sensit ive to cytotoxic damage and can be a site of dose-limiting toxicity in cancer therapy. Here, we have investigated the use of one growth modu lator to manipulate the cell cycle status of gastrointestinal stem cel ls before cytotoxic exposure to minimize damage to this normal tissue. Transforming growth factor beta 3 (TGF-beta 3), a known inhibitor of cell cycle progression through G(1), was used to alter intestinal cryp t stem cell sensitivity before 12-16 Gy of gamma irradiation, which wa s used as a model cytotoxic agent. Using a crypt microcolony assay as a measure of functional competence of gastrointestinal stem cells, it was shown that the administration of TGF-beta 3 over a 24-h period bef ore irradiation increased the number of surviving crypts by four- to s ix-fold. To test whether changes in crypt survival are reflected in th e well-being of the animal, survival time analyses were performed, Aft er 14.5 Gy of radiation, only 35% of the animals survived within a per iod of about 12 days, while prior treatment with TGF-beta 3 provided s ignificant protection against this early gastrointestinal animal death , with 95% of the treated animals surviving for greater than 30 days.