Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5.
Toxicol Appl Pharmacol. 2010 Apr 15;244(2):190-5. doi: 10.1016/j.taap.2009.12.032. Epub 2010 Jan 4.
The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large-scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes. The tyrosine kinase selectivity scores, but not the serine-threonine kinase scores, were highly correlated with the myocyte damaging effects of the TKIs. Additionally, we showed that damage to myocytes gave a good rank order correlation with clinical cardiotoxicity. Finally, strength of TKI binding to colony-stimulating factor 1 receptor (CSF1R) was highly correlated with myocyte damage, thus possibly implicating this kinase in contributing to TKI-induced cardiotoxicity.
新型抗癌酪氨酸激酶抑制剂（TKI）的应用彻底改变了某些癌症的治疗方法。然而，其中一些药物的使用会导致心脏毒性。最近获得的针对 9 种已获 FDA 批准的酪氨酸激酶抑制剂中的 7 种与 317 种激酶的结合的大规模分析数据，使我们能够将激酶抑制剂结合选择性评分与 TKI 对新生大鼠心肌细胞的损伤相关联。酪氨酸激酶选择性评分，但不是丝氨酸-苏氨酸激酶评分，与 TKI 的心肌细胞损伤效应高度相关。此外，我们表明，心肌细胞损伤与临床心脏毒性具有良好的秩相关。最后，TKI 与集落刺激因子 1 受体（CSF1R）的结合强度与心肌细胞损伤高度相关，因此该激酶可能与 TKI 诱导的心脏毒性有关。
