Mechanism and modification of gastrointestinal soft tissue response to radiation: Role of growth factors

Purpose: The negative effects of radiation on the bowel critically limit the treatment doses possible for tumors in the abdomen. The purpose of the present study was to measure mRNA levels of inflammatory cytokines in abdominally irradiated mouse bowel. Methods and Materials: Eight- to 12-week-old DBA mice were irradiated to the whole bowel in single fractions of 0 (mock irradiation), 12.5, or 13.5 Gy, and sacrificed 18-25 weeks thereafter. Gross bowel reactions were scored for bowel retraction, bowel wall thickening, mesenteric telangiectasia, and petechia. Tissues were snap frozen and processed for RNase protection assay or reverse transcription polymerase chain reaction assay, or both. Transforming growth factor beta 1 (TGF beta 1), TGF beta 2, TGF beta 3, tumor necrosis factor alpha, interleukin-6, and interferon gamma mRNA were measured. Results: Radiation at 12.5 Gy and at 13.5 Gy produced significant bowel damage. Levels of all cytokines in irradiated mice were significantly increased (p < 0.05). Conclusions: Late radiation-related bowel fibrovascular toxicity includes cytokine signal pathways that parallel those of many other normal tissues. These cytokine responses include elevations of tumor necrosis factor a, TGF beta 1, and interleukin-6. There exist approaches for lowering these cytokine levels that do not also protect tumor, and thus a therapeutic gain is expected. Opportunities to use these cytokine measurements both to predict clinical toxicity and to develop interventions are discussed. (c) 2005 Elsevier Inc.