Pretreatment with transforming growth factor beta-3 protects small intestinal stem cells against radiation damage in vivo

Abstract

Summary The gastrointestinal tract, with its rapid cell replacement, is sensitive to cytotoxic damage and can be a site of dose-limiting toxicity in cancer therapy. Here, we have investigated the use of one growth modulator to manipulate the cell cycle status of gastrointestinal stem cells before cytotoxic exposure to minimize damage to this normal tissue. Transforming growth factor beta-3 (TGF-,3), a known inhibitor of cell cycle progression through G,, was used to alter intestinal crypt stem cell sensitivity before 12-16 Gy of gamma irradiation, which was 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-P3 over a 24-h period before irradiation increased the number of surviving crypts by four-to six-fold.To test whether changes in crypt survival are reflected in the well-being of the animal, survival time analyses were performed. After 14.5 Gy of radiation, only 35% of the animals survived within a period of about 12 days, while prior treatment with TGF-,B3 provided significant protection against this early gastrointestinal animal death, with 95% of the treated animals surviving for greater than 30 days.

Prosurvival and antiapoptotic effects of PGE2in radiation injury are mediated by EP2receptor in intestine

“…The number of surviving crypts per cross section was determined for each mouse by scoring the number of surviving crypts in at least eight complete, welloriented cross sections and dividing the total by the number of cross sections scored. Because size differences in regenerative crypts may affect the probability that a regenerative crypt will appear in a cross section (38,41) we determined the width of 20 representative crypts for EP2 Ϫ/Ϫ mice and their wild-type littermates in longitudinal sections of proximal jejunum at their widest point in each crypt. We did not find any difference in the size of regenerative crypts in EP2 Ϫ/Ϫ mice compared with wild type after 14 Gy ␥-irradiation (data not shown).…”

Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis – are there new strategies?

“…139 TGF-␤ 3 inhibits cell cycle progression through G1. 140 In an animal model for radiation-induced small intestine damage, Potten et al 140 could demonstrate a fourto six-fold increase in survival of small intestinal crypts and a significantly increased survival of animals, if TGF-␤ was administered over a 24 h period prior to irradiation.…”

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

“…Positive results have been obtained in humans using mouthwashes containing recombinant TGF-b3 (Wymenga et al, 1999), indicating a promising treatment against the oral complications of anti-cancer therapy. Administration of recombinant TGF-b3 directly into the small intestine of mice had a protective effect during radiation (Potten et al, 1997) by reducing stem cell cycling (Booth et al, 2000). To our knowledge however, no study has been done investigating the potential protective effects of orally administrated TGF-b2 originating from a natural source.…”