In addition, at 6 months, compared with the irradiated control rats, the irradiated rats fed high-dose SM16 for the long term had levels of lung injury and TGF-b activation that were significantly lower, by roughly 35% to 50%.
Specifically, the high-dose SM16 group had less lung damage as assessed by architecture and collagen(Drug information on collagen) deposition in histologic sections; less macrophage activity, as assessed by ED1 staining; less TGF-b-1 activity; less staining for integrin (an activator of TGF-b in the lung); less free radical production, as assessed by 8-hydroxyguanosine staining; and less activation of TGF-b signaling, whether assessed by smad 3 staining or by staining for the active (phosphorylated) form, p-smad 2/3.
Rats fed SM16 for the long term but with the low dose had smaller reductions in these measures of lung injury and TGF-b activation, and most of the differences compared with controls were not significant.Similarly, rats fed SM16 for the short term only, regardless of whether they received the high dose or the low dose, had smaller and generally nonsignificant reductions in these measures.
Does not promote tumor growth
Research thus far suggests that SM16 does not promote tumor cell growth, Dr. Anscher said. "Most tumor epithelial cells are no longer responsive to the growth inhibitory effects of TGF-b, so that the presence of TGF-b in most cell types actually is a growth stimulatory phenomenon," he explained. "We have observed that SM16 actually has a growth inhibitory effect on the tumor cell lines we've tested."
Summing up, Dr. Anscher said, "Oral administration of the anti-TGF-b type 1 receptor kinase SM16 reduces all measures of lung injury in this animal modelthere is less lung damage, there is less fibrosis, there is less of an inflammatory response, less activation of TGF-b, and less transduction of the signaling pathway." He added that the data also suggest that response varies with both dose and duration of treatment."I hope you'll all agree with me that targeting the TGF-b pathway may be an effective strategy to try to either prevent or ameliorate radiation-induced lung injury," he commented.
Clinical development of SM16 is planned, Dr. Anscher said. However, he noted that studies of radiation-induced lung injury in the lung cancer population can be difficult, while the incidence of this outcome in the non-lung-cancer population is so low that many patients would be needed.