Abstract 2494: The protective effect of a novel transforming growth factor-β receptor inhibitor against radiation-induced fibrosis

Abstract

Abstract Although radiation-induced fibrosis (RIF) is one of the common sequelae after irradiation of skin and soft tissue, a protective method was not well investigated. The purpose of present study was to assess the protective effect of a newly developed small molecular inhibitor of transforming growth factor (TGF)-β receptor (ALK5 inhibitor) against RIF in mouse model. BALB/c male mice were irradiated 8 weeks after birth. The left hind limbs of mice received two radiation doses of 22 Gy, once in a week. Specially designed shielding for the rest of the body was used, and 1-cm thickness bolus was applied over the skin to ensure adequate radiation dose at the surface of hind leg. After irradiation, 40 mice were randomly divided into two groups of 20 mice each. Each group was treated with once daily intraperitoneal injections of saline (group 1) or ALK5 inhibitor (group 2, 10 mg/kg/day). RIF was assessed by leg contraction test using specially designed Lucite jig under anesthesia every 2 weeks for 6-16 weeks after irradiation. The length of the extended irradiated leg was compared with the contralateral unirradiated leg. Early and late skin reactions were scored by grading system. Early skin reaction was measured every week for first 4 weeks, and late skin reaction was evaluated at 16 weeks after irradiation. The ALK5 inhibitor was well tolerated, and no toxic effects related to the drug were observed. There were no significant differences in the average of body weight (g) between the two groups during treatment; 22.76 vs. 23.34 in 6-week (p=0.09), 25.73 vs. 26.05 in 10-week (p=0.466), and 28.54 vs. 28.41 in 13-week (p=0.868). The acute skin reaction was almost identical between the two groups. All mice showed moist desquamation for most of hind limb in 4 weeks after irradiation, and no significant skin necrosis was observed in both two groups during acute phase. The leg contraction test showed significant protective effect in group 2. The average length of the irradiated leg (percent of the contralateral leg) was significantly lower in group 1 from 6-16 weeks, and the differences of the contracture between the two groups tended to increase with time; 92.46% vs. 96.07% in 6-week (p<0.001), 92.55% vs. 95.89% in 8-week (p<0.001), 88.23% vs. 93.34% in 10-week (p<0.001), 83.25% vs. 91.59% in 12-week (p<0.001), 76.80% vs. 87.61% in 14-week (p<0.001), and 74.42% vs. 83.08% in 16-week (p=0.001). Also, late skin reactions were more adverse in control group; the average score of late skin reaction was 3.14 in group 1 and 2.73 in group 2 (p=0.034). The current study showed that inhibition of TGF-β signaling by our ALK5 inhibitor has a protective effect on RIF in mouse model. Also, there was no significant toxicity related to the drug administration. This newly developed ALK5 inhibitor could be considered as a novel agent for protection of RIF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2494. doi:10.1158/1538-7445.AM2011-2494