356 fractions over 5 days) to Fischer rats. Compared with ani- mals receiving radiation without antibody, there was signif- icantly less fibrosis, TGF- 1 expression, and TGF- 1- induced signaling in the animals treated with the antibody. A higher dose of antibody (1 mg/kg) afforded better protec- tion than did a lower dose (0.1 mg/kg). The same group also tested daily administration of a type I receptor tyrosine ki- nase inhibitor administered daily to a group of Sprague- Dawley rats irradiated to the right lung [102]. The drug was administered beginning 7 days prior to irradiation and con- tinued either for 3 weeks or until sacrifice. Compared with irradiated animals not receiving the drug, there was signif- icantly less fibrosis, TGF- 1 expression and signaling, and chronic oxidative stress in the treated groups, with a better response seen in the high-dose group (0.15 g/kg versus 0.07 g/kg) and in those treated with a long course versus a short course of therapy. Neither compound has been tested in the clinic for this purpose. As stated previously, there is increasing evidence that TGF- 1 signaling through Smad-independent pathways may stimulate overproduction of fibrous tissue in response to radiation or chemotherapy. One such pathway signals through cAbl. The drug imatinib, an inhibitor of the cAbl pathway in use in the clinic for the treatment of gastrointes- tinal stromal tumors, was shown to reduce the development of pulmonary fibrosis in response to bleomycin in an animal model [53]. TGF- 1 was also recently shown to signal through the Rho/Rock pathway, independently of the Smad signal transduction cascade [100, 101]. This pathway has been implicated in the development of radiation-induced small intestinal injury. Inhibition of this signaling pathway has been shown to protect against radiation enteritis. Other potential approaches target TGF- 1 more indi- rectly, for example, by reducing the stimulus for TGF- 1 activation (Fig. 5). Following exposure to radiation, reac- tive oxygen species are produced [103], and these have been shown to be capable of activating latent TGF- 1 [30]. Mice engineered to overexpress one of the isoforms of su- peroxide dismutase, an endogenous free radical scavenger, REFERENCES 1 2 3 4 Emami B, Lyman J, Brown A et al. Tolerance of normal tissue to thera- peutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109 –122. Milano MT, Constine LS, Okunieff P. Normal tissue tolerance dose met- rics for radiation therapy of major organs. Semin Radiat Oncol 2007;17: 131–140. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys 2005;63:5–24. Kong FM, Pan C, Eisbruch A et al. Physical models and simpler dosimet- Targeting TGF- 1 to Prevent Complications have been demonstrated to be resistant to radiation-induced lung injury [104]. Similarly, administration of superoxide dismutase mimetics has been shown to reduce the severity of lung injury in an animal model [105]. Both approaches result in lower expression and activation of TGF- 1 as well as lower activiation of the Smad-dependent TGF- 1 signal- ing pathway. As is the case with radiation therapy, targeting the TGF- 1 pathway may be an effective means to prevent or ameliorate chemotherapy-induced lung injury. Bleomycin- induced lung injury (Fig. 2) is the classic example of this toxicity, although newer agents, such as gefitinib, may be associated with the development of lung injury and fibrosis [106]. Susceptibility to both radiation- and bleomycin- induced lung injury in mice may have a common genetic basis [107]. Bleomycin-induced lung injury in the acute phases is mediated through the epidermal growth factor re- ceptor (EGFR) family, most likely human epidermal growth factor receptor (HER)-2/HER-3 [108]. Blockade of HER-2/HER-3 signaling ameliorates the development of pulmonary fibrosis from bleomycin [109]. Because TGF- may upregulate profibrotic protein expression, in part, through an EGFR-mediated mechanism [110], it should not be surprising that inhibiting the TGF- pathway also ame- liorates the development of this toxicity in animals [50, 111, 112]. In summary, TGF- 1 is a critical cytokine responsible for the development of late normal tissue injury after cancer therapy. Monitoring TGF- 1 in the plasma and/or screen- ing for TGF- 1 polymorphisms may help to identify pa- tients at greater or lesser risk for normal tissue injury, but more work is needed to determine the optimal situations in which to apply this molecular and genetic information in the clinic. Strategies to target TGF- 1 clearly reduce the se- verity of normal tissue injury in animal models. This ap- proach needs to be tested prospectively in the clinic to determine if inhibiting the TGF- 1 pathway is safe and ef- fective in humans. 5 6 7 8 ric descriptors of radiation late toxicity. Semin Radiat Oncol 2007;17: 108 –120. Tsoutsou PG, Koukourakis MI. Radiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future re- search. Int J Radiat Oncol Biol Phys 2006;66:1281–1293. Brush J, Lipnick SL, Phillips T et al. Molecular mechanisms of late normal tissue injury. Semin Radiat Oncol 2007;17:121–130. Rodemann HP, Blaese MA. Responses of normal cells to ionizing radia- tion. Semin Radiat Oncol 2007;17:81– 88. Travis EL. Genetic susceptibility to late normal tissue injury. Semin Ra- diat Oncol 2007;17:149 –155.