Abstract
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-beta3), a known inhibitor of cell cycle progression through G1, 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-beta3 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-beta3 provided significant protection against this early gastrointestinal animal death, with 95% of the treated animals surviving for greater than 30 days.
Highlights
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
We report here the results of experiments using TGF-P3 administered before a range of doses of gamma rays on the survival of intestinal stem cells
Summary
Animal studiesBDF1 mice (Paterson Institute), aged 10-12 weeks and weighing about 25 g, housed under conventional conditions with food and water ad libitum and a 12-h light cycle (lights on at 0700 h) were used throughout the experiment. For the crypt microcolony assay, groups of six mice were treated at each dose. For the animal survival time studies, groups of 20 mice were used for each treatment protocol. For the crypt microcolony assay, animals were irradiated in a caesium-137 gamma irradiator at a dose rate of 3.5 Gray (Gy) min-1 delivered whole-body to animals breathing pumped air. We have shown that the crypt microcolony survival curves generated using the caesium whole-body irradiation, anaesthetized partial-body X-rays and whole-body X-rays anaesthetized or unanaesthetized were all essentially indistinguishable (Potten, unpublished data). Radiation doses were all delivered at the same time of day (03.00 h; making use of a room where the light cycle was reversed so that the radiation could be delivered at 15.00 h real time). The animals were acclimatized to the reverse-cycle room for 2 weeks before an experiment
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