352 a wound. Among the wound-healing properties of this cy- tokine are recruitment of monocytes and macrophages to an injury site [32], inhibition of the proliferation of epithelial cells [33], enhancement of the maturation of fibroblasts into postmitotic fibrocytes that increase production of fibrous tissue [34], promotion of angiogenesis [35, 36], and inhibi- tion of the breakdown of extracellular matrix [23, 37]. De- spite its role in normal wound healing, increased expression of TGF- 1 has been demonstrated in a number of condi- tions characterized by excessive fibrosis, including chronic hepatitis and glomerulosclerosis [24, 38 – 41]. In addition, effective treatments for these conditions have been shown to reduce the development of fibrosis in the affected organ, with a corresponding decrease in the expression of TGF- 1 [42–53]. Following exposure to ionizing radiation, the expres- sion of TGF- 1 increased in a dose-dependent manner in the rat liver [54]. Similarly, in a rat model of radiation- induced lung injury, fibrosis developed, which was accom- panied by an increase in TGF- 1 expression and activation of the TGF- 1 signal transduction pathway [55, 56]. Fur- thermore, TGF- 1 activation by radiation has been shown to occur at doses 10 cGy and is roughly proportional to dose in the range of 10 cGy to 5 Gy [57, 58]. Although ge- netically engineered loss of TGF- 1 expression is a lethal mutation, knockout mice missing a component of the TGF- 1 signaling pathway (Smad3) are viable, and have been shown to be resistant to radiation-induced soft tissue fibrosis [59]. In contrast, humans expressing certain sin- gle nucleotide polymorphisms in the TGF- 1 gene have been found to be at a higher risk for normal tissue injury [60]. In animal models of pulmonary fibrosis induced by bleomycin [52] and in humans exposed to high doses of chemotherapy in preparation for bone marrow transplanta- tion who develop pulmonary drug toxicity or hepatic veno- occlusive disease (Fig. 2), the associated fibrosis is accompanied by increased expression of TGF- 1 in af- fected tissues. Thus, there is substantial evidence on the im- portance of TGF- 1 in the development of excessive fibrosis following exposure to radiation and/or chemother- apy in both animals and humans. TGF- 1 AS A PREDICTOR OF NORMAL TISSUE INJURY RISK Dosing of chemotherapy or radiation is generally based ei- ther on a prospectively determined maximum-tolerated dose or, more commonly, in the case of radiation, an em- pirically determined estimate of the risk for a particular in- jury developing in a certain percentage of patients within a defined period of time [1, 2]. In either case, the accepted tolerance dose of radiation or chemotherapy produces dose- Targeting TGF- 1 to Prevent Complications Figure 2. TGF- expression in chemotherapy-induced liver injury. Section of normal liver (A) and liver from patient that died of hepatic veno-occlusive disease after high-dose chemo- therapy (B). In (B), evidence of extensive fibrosis around the central veins (C) is noted (arrow) and there is greater staining for transforming growth factor 1 (reddish brown areas) im- mediately adjacent to regions of fibrosis than in the normal liver in (A). P, portal vein. Reprinted from Anscher MS, Kong FM, Jirtle RL. The relevance of transforming growth factor beta 1 in pulmonary injury after radiation therapy. Lung Can- cer 1998;19:109 –120, with permission from Elsevier. limiting toxicity in a minority of patients, yet it is precisely these patients that dictate the dose of chemotherapy or ra- diation for an entire population, when in reality any given population of patients is likely to contain people who may be more or less likely to experience toxicity than the “aver- age” population used to determine dosing guidelines (Fig. 3). Thus, the ability to determine the likelihood of toxicity for an individual patient, rather than rely on dosing based on the average sensitivity of a population, is a desirable goal that should improve the therapeutic ratio (i.e., reduce the likelihood of toxicity, increase the likelihood of cure, or both). In addition to being widely produced throughout the body, TGF- 1 can also be measured in the blood [61]. In- creased circulating levels of TGF- 1 have been found in patients with many diseases, including various types of can- cer [62, 63]. Because of the fact that TGF- 1 expression in