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Intestinal injury following abdominal radiation therapy or accidental exposure remains a significant clinical problem that can result in varying degrees of mucosal destruction such as ulceration, vascular sclerosis, intestinal wall fibrosis, loss of barrier function, and even lethal gut-derived sepsis. We determined the ability of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15–20, to protect the intestine against the early and late effects of radiation in mice and rats and to determine its mechanism of action by examining cultured rat intestinal epithelia. Rats were exposed to fractionated radiation in an established model of intestinal injury, whereby an intestinal segment is surgically placed into the scrotum and radiated daily. Radiation injury score was decreased in a dose-dependent manner in rats gavaged with 0.5 or 2.0 g/kg per day of PEG 15–20 ( n = 9–13/group, P < 0.005). Complementary studies were performed in a novel mouse model of abdominal radiation followed by intestinal inoculation with Pseudomonas aeruginosa ( P. aeruginosa ), a common pathogen that causes lethal gut-derived sepsis following radiation. Mice mortality was decreased by 40% in mice drinking 1% PEG 15–20 ( n = 10/group, P < 0.001). Parallel studies were performed in cultured rat intestinal epithelial cells treated with PEG 15–20 before radiation. Results demonstrated that PEG 15–20 prevented radiation-induced intestinal injury in rats, prevented apoptosis and lethal sepsis attributable to P. aeruginosa in mice, and protected cultured intestinal epithelial cells from apoptosis and microbial adherence and possible invasion. PEG 15–20 appeared to exert its protective effect via its binding to lipid rafts by preventing their coalescence, a hallmark feature in intestinal epithelial cells exposed to radiation.

TNFα was initially described as inducing necrotic death in tumors in vivo, and more recently as a cytokine that mediates cytoprotection and inflammation. The anti-tumor effects of TNFα are poorly characterized because TNFα- induced death of human tumor cells has largely been studied in the presence of agents that block transcription or protein synthesis. Also, most reports in model cell systems describe apoptosis within relatively early time points as the principal mode of cell death induced by TNFα. We investigated the cytotoxic effects of 10 ng/ml TNFα on human tumor cells of different histological types without concomitant exposure to these inhibitors. Eleven of 21 human tumor cell lines underwent TNFα-induced cell death which ranged from 41% to complete loss of viability. Only one cell line demonstrated caspase-dependent apoptosis within 24 h. Nine cell lines underwent death between 48 h and 21 days. Seven of these lines underwent caspase-3 independent death consistent with necrosis. One tumor line exhibited characteristics of senescence following TNFα exposure. Nine of 9 cell lines activated NF-κB following TNFα exposure by 24 h. In all cell lines studied, with the exception of the epidermoid carcinoma cell line that underwent early apoptosis, expression of one or more NF-κB target genes was demonstrated at 24-96 h. BMS-345541, a specific IKK inhibitor, increased TNFα killing in TNFα resistant tumor cell lines by increasing apoptosis, suggesting that inhibition of NF-κB may be an effective strategy to enhance the tumoricidal effects of TNFα.