Sun X, Layton J E, Elefanty A, Lieschke G J
Cytokine Biology Laboratory, Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, The Royal Melbourne Hospital, Victoria, Australia.
Blood. 2001 Apr 1;97(7):2008-15. doi: 10.1182/blood.v97.7.2008.
STI571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145(abl) and its oncogenic derivative p210(bcr-abl). AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210(bcr-abl)-expressing factor-independent derivatives. STI571 was a more potent inhibitor of (3)H-thymidine incorporation in p210(bcr-abl)-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210(bcr-abl)-expressing derivatives. Assays performed with and without growth factor demonstrated that STI571 but not AG957 reversed the p210(bcr-abl)-driven factor independence of cell lines. p210(bcr-abl)-expressing cells were less sensitive to AG490 than to AG957 or STI571. However, for p210(bcr-abl)-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between STI571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of STI571 that reversed the p210(bcr-abl) factor-independent phenotype, STI571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) STI571 is a more potent and more selective inhibitor of a p210(bcr-abl)-dependent phenotype than AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory effect on p210(bcr-abl)-driven proliferation; and (3) the combination of p210(bcr-abl)-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells. (Blood. 2001;97:2008-2015)
STI571（原名CGP57148）和AG957是蛋白酪氨酸激酶（PTK）p145（abl）及其致癌衍生物p210（bcr - abl）的小分子抑制剂。AG490是PTK Janus激酶2（JAK2）的抑制剂。此前尚未有这些抑制剂的直接比较报道，因此本研究比较了它们对依赖因子的FDC - P1、32D和MO7e细胞及其表达p210（bcr - abl）的不依赖因子衍生物的作用。在表达p210（bcr - abl）的细胞中，STI571对[3H]胸腺嘧啶掺入的抑制作用比AG957更强，并且在对亲本细胞系的抑制作用与其对表达p210（bcr - abl）的衍生物的作用之间表现出更好的区分度。在有和没有生长因子的情况下进行的测定表明，STI571而非AG957可逆转细胞系中由p210（bcr - abl）驱动的不依赖因子状态。表达p210（bcr - abl）的细胞对AG490的敏感性低于对AG957或STI571的敏感性。然而，对于来自所有3种细胞系的表达p210（bcr - abl）的克隆，在STI571与无独立抑制作用的AG490浓度之间显示出协同抑制作用。用AG957处理抑制核酸合成与细胞数量减少、活力降低以及小的固缩凋亡细胞有关。在能够逆转p210（bcr - abl）不依赖因子表型的STI571浓度下，STI571处理与生长因子剥夺共同作用足以诱导细胞凋亡。本研究得出结论，对于所研究的细胞系，（1）与AG957相比，STI571是对p210（bcr - abl）依赖表型更有效且更具选择性的抑制剂；（2）AG490与STI571协同作用以增强其对p210（bcr - abl）驱动的增殖的抑制作用；（3）抑制p210（bcr - abl）酪氨酸激酶与撤回生长因子信号相结合足以诱导转化细胞的凋亡死亡（《血液》，2001年；97：2008 - 2015）
