Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Int J Radiat Biol. 2013 Mar;89(3):162-70. doi: 10.3109/09553002.2013.741281. Epub 2012 Nov 19.
Dermal fibrosis is a disabling late toxicity of radiotherapy. Several lines of evidence suggest that overactive signaling via the Platelet-derived growth factor receptor-beta (PDGFR-β) and V-abl Abelson murine leukemia viral oncogene homolog 1 (cAbl) may be etiologic factors in the development of radiation-induced fibrosis. We tested the hypothesis that imatinib, a clinically available inhibitor of PDGFR-β, Mast/stem cell growth factor receptor (c-kit) and cAbl, would reduce the severity of dermal fibrosis in a murine model.
The right hind legs of female C3H/HeN mice were exposed to 35 Gy of X-rays. Cohorts of mice were maintained on chow formulated with imatinib 0.5 mg/g or control chow for the duration of the experiment. Bilateral hind limb extension was measured serially to assess fibrotic contracture. Immunohistochemistry and biochemical assays were used to evaluate the levels of collagen and cytokines implicated in radiation-induced fibrosis.
Imatinib treatment significantly reduced hind limb contracture and dermal thickness after irradiation. Immunohistochemical studies demonstrated a substantial reduction in PDGFR-β phosphorylation. We also observed reduced Transforming Growth factor-β (TGF-β) and collagen expression in irradiated skin of imatinib-treated mice, suggesting that imatinib may suppress the fibrotic process by interrupting cross-talk between these pathways.
Taken together, these results support that imatinib may be a useful agent in the prevention and treatment of radiation-induced dermal fibrosis.
皮肤纤维化是放疗的一种晚期致残性毒性。有几条证据表明，血小板衍生生长因子受体-β（PDGFR-β）和 V-abl 致癌基因 Abelson 鼠白血病病毒同源物 1（cAbl）的过度信号转导可能是放射性纤维化发展的病因因素。我们测试了这样一个假设，即伊马替尼是一种临床上可用于抑制 PDGFR-β、肥大细胞/干细胞生长因子受体（c-kit）和 cAbl 的抑制剂，可减少小鼠模型中皮肤纤维化的严重程度。
将雌性 C3H/HeN 小鼠的右后腿暴露于 35Gy 的 X 射线下。将小鼠分为两组，一组用含有 0.5mg/g 伊马替尼的饲料饲养，另一组用对照饲料饲养，实验全程保持这种状态。通过双侧后腿伸展测量来评估纤维性挛缩的严重程度。免疫组织化学和生化分析用于评估与放射性纤维化相关的胶原蛋白和细胞因子的水平。
伊马替尼治疗可显著减少照射后后肢挛缩和皮肤厚度。免疫组织化学研究表明 PDGFR-β 磷酸化显著减少。我们还观察到伊马替尼治疗组照射皮肤中的转化生长因子-β（TGF-β）和胶原蛋白表达减少，这表明伊马替尼可能通过阻断这些途径之间的串扰来抑制纤维化过程。
综上所述，这些结果支持伊马替尼可能是预防和治疗放射性皮肤纤维化的一种有效药物。
