Impact of Long-Term Exposure to the Tyrosine Kinase Inhibitor Imatinib on the Skeleton of Growing Rats
Impact of Long-Term Exposure to the Tyrosine Kinase Inhibitor Imatinib on the Skeleton of Growing Rats
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DOI：
10.1371/journal.pone.0131192
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发表时间：
2015-06-24
期刊：
影响因子：
3.7
通讯作者：
Suttorp, Meinolf
中科院分区：
文献类型：
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作者：
Tauer, Josephine T.;Hofbauer, Lorenz C.;Suttorp, Meinolf
酪氨酸激酶 (TK) 抑制剂伊马替尼通过抑制致癌 TK BCR-ABL1 为慢性粒细胞白血病 (CML) 提供高效疗法。然而，参与骨重塑的脱靶 TK，如血小板衍生生长因子受体 (PDGF-R) 和集落刺激因子 1 受体 (c-fms)，也会受到抑制。因此，服用伊马替尼的慢性粒细胞白血病儿科患者表现出骨代谢改变，导致线性生长障碍。由于 TKI 治疗可能终生都需要，因此对儿童骨骼的长期影响是人们主要关注的问题。因此，我们在幼年大鼠模型中研究了连续和间歇性伊马替尼暴露对骨骼的长期影响。4周大的雄性Wistar大鼠通过饮用水长期暴露于伊马替尼10周。将动物连续暴露于标准和高伊马替尼剂量并间歇暴露于高伊马替尼剂量。使用 pQCT、微型计算机断层扫描 (mu CT) 和青春期前、青春期和青春期后年龄的生物力学测试来评估骨量和强度。分析了骨长度和椎骨高度以及骨转换的生化标志物。股骨和胫骨长度呈剂量依赖性减少高达 24% (p
The tyrosine kinase (TK) inhibitor imatinib provides a highly effective therapy for chronic myeloid leukemia (CML) via inhibition of the oncogenic TK BCR-ABL1. However, off-target TKs like platelet-derived growth factor receptors (PDGF-R) and colony-stimulating factor-1 receptor (c-fms), involved in bone remodeling, are also inhibited. Thus, pediatric patients with CML on imatinib exhibit altered bone metabolism, leading to linear growth failure. As TKI treatment might be necessary for a lifetime, long-term effects exerted on bone in children are of major concern. Therefore, we studied the skeletal long-term effects of continuous and intermittent imatinib exposure in a juvenile rat model.Four-weeks-old male Wistar rats were chronically exposed to imatinib via drinking water over a period of 10 weeks. Animals were exposed to a standard and high imatinib dosage continuously and to the high imatinib dose intermittently. Bone mass and strength were assessed using pQCT, micro-computed tomography (mu CT), and biomechanical testing at the prepubertal, pubertal, and postpubertal age. Bone length and vertebral height as well as biochemical markers of bone turnover were analyzed.Femoral and tibial bone length were dose-dependently reduced by up to 24% (p