TK Inhibitor Treatment Disrupts Growth Hormone Axis: Clinical Observations in Children with CML and Experimental Data from a Juvenile Animal Model
TK Inhibitor Treatment Disrupts Growth Hormone Axis: Clinical Observations in Children with CML and Experimental Data from a Juvenile Animal Model
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TK 抑制剂治疗扰乱生长激素轴：慢性粒细胞白血病儿童的临床观察和幼年动物模型的实验数据
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
M. Suttorp
中科院分区：
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作者：
A. Ulmer;J. Tauer;I. Glauche;Roland Jung;M. Suttorp
摘要背景：长期使用酪氨酸激酶抑制剂（TKI）治疗慢性粒细胞白血病（CML）会通过生长激素（GH）作用受损或骨建模受损对骨生长产生脱靶效应。研究方法：在21例接受标准化伊马替尼治疗的儿童CML患者中，在2年内每3个月重复测定身高和GH相关参数胰岛素样生长因子1（IGF-1）和胰岛素样生长因子结合蛋白3（IGFBP-3）。在动物模型中，4周龄雄性Wistar大鼠通过饮用水暴露于不同浓度的伊马替尼、达沙替尼或博舒替尼超过10周。分别在青春期前年龄、青春期年龄和成年年龄收集血液，并测量动物的血清IGFBP-3水平。结果如下：与年龄匹配的参考相比，与治疗持续时间无关，患者的IGF-1和IGFBP-3水平几乎完全在非常低的范围内。未观察到IGF-1和IGFBP-3水平升高或降低的明显模式。在大鼠中，与对照组相比，所有检测TKI、所有应用浓度和所有研究年龄的血清IGFBP-3均显著降低。结论：除了对骨骼生长的直接脱靶效应外，TKI治疗还导致IGF-1和IGFBP-3的血液水平降低。幼年大鼠模型预测了达沙替尼和博舒替尼的这种副作用。因此，应定期监测接受TKI治疗的CML儿科患者的生长和GH相关参数。
Abstract Background: Long-term treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) exerts off-target effects on bone growth by either impaired growth hormone (GH) action or osseous modelling impairment. Methods: Body height and the GH-related parameters insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3(IGFBP-3) were determined repetitively 3-monthly over 2 years in 21 pediatric CML-patients on standardized imatinib treatment. In an animal model 4-week-old male Wistar rats were exposed over 10 weeks to imatinib, dasatinib, or bosutinib at varying concentrations via the drinking water. Blood was collected at prepubertal age, pubertal age, and at adult age, respectively, and animals’ serum levels of IGFBP-3 were measured. Results: Independent from treatment duration patients exhibited IGF-1 and IGFBP-3 levels almost exclusively in the very low range when compared to age-matched references. No clear pattern of rising or falling IGF-1 and IGFBP-3 levels was observed. In rats, compared to controls, serum IGFBP-3 was significantly lowered for all TKIs tested, at all concentrations applied, and at all ages under investigation. Conclusion: Besides direct off-target effects on the growing skeleton, TKI treatment also results in lowered blood levels of IGF-1 and IGFBP-3. A juvenile rat model predicts this side effect for dasatinib and bosutinib. Thus, growth and GH- related parameters should be monitored regularly in pediatric patients with CML on TKIs.