Influence of Short-Term Octreotide Administration on Chronic Tissue Injury, Transforming Growth Factor beta (TGF-beta) Overexpression, and Collagen Accumulation in Irradiated Rat Intestine.

The somatostatin analog octreotide was recently found to ameliorate radiation-induced tissue injury in rat intestine. The present study addressed whether octreotide reduces chronic intestinal radiation fibrosis, whether enteroprotection is conferred by direct or indirect mechanisms, and whether the effects are dose-dependent. Using a rat model designed for fractionated irradiation, a segment of small intestine was sham-irradiated or exposed to 67.2 Gy X-radiation in 16 daily fractions. Octreotide (0, 2, or 10 microg/kg/h) was administered subcutaneously by osmotic minipumps for 4 weeks, from 2 days before to 10 days after irradiation. Tissue injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) by quantitative histopathology and morphometry. Epithelial and smooth muscle cell proliferation was assessed by proliferating cell nuclear antigen staining; connective tissue mast cell hyperplasia by metachromatic staining; and TGF-beta1 and collagen protein and mRNA by quantitative immunohistochemistry, in situ hybridization, and/or real-time fluorogenic probe reverse transcription-polymerase chain reaction. Octreotide conferred dose-dependent protection against early (p = 0.0003) and chronic (p < 0.0001) tissue injury. Octreotide abrogated radiation-induced chronic increases in extracellular matrix-associated TGF-beta (p < 0.0001), collagen I (p = 0.0001), and collagen III (p = 0.0002) immunoreactivity. Octreotide did not affect radiation-induced changes in steady-state TGF-beta1 mRNA levels, mast cell hyperplasia, or smooth muscle cell proliferation. Octreotide reduced crypt epithelial cell proliferation (p = 0.01), but did not otherwise affect unirradiated intestine. Octreotide confers dose-dependent protection against delayed small bowel radiation toxicity and ameliorates radiation fibrosis predominantly by reducing acute mucosal injury. These data strengthen the rationale for using somatostatin analogs as enteroprotective agents in clinical radiation therapy.