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STI571是通过计算机辅助设计、人工合成的Abl激酶ATP结合位点竞争性抑制剂。体外试验证实:STI571高度选择性抑制Bcr-Abl、c-kit和PDGF受体酪氨酸激酶或底物蛋白的酪氨酸磷酸化而使其灭活;选择性抑制Bcr-Abl阳性细胞生长;诱导Bcr-Abl阳性细胞凋亡和分化;与IFN、DNR、Ara-C和HU有协同作用。对BCR-ABL基因转化小鼠有特异性的治疗作用。Ⅰ、Ⅱ期临床试验STI571治疗慢性期慢性粒细胞白血病(CML)效果显著,对CML急变和Ph~+急性白血病也有一定的疗效。白血病细胞对STI571体外耐药与靶基因扩增导致Bcr-Abl蛋白的过度表达有关,与P糖蛋白(Pgp)的过度表达也有关。体内耐药的机制与酸性糖蛋白(AGP)增加有关。
STI571 is a computer-aided, synthetic inhibitor of Abl kinase ATP binding site competition. In vitro experiments confirmed that: STI571 highly selective inhibition of Bcr-Abl, c-kit and PDGF receptor tyrosine kinase or substrate protein tyrosine phosphorylation and inactivation; selective inhibition of Bcr-Abl positive cell growth; Induced apoptosis and differentiation of Bcr-Abl positive cells and synergized with IFN, DNR, Ara-C and HU. BCR-ABL gene in mice has a specific therapeutic effect. Ⅰ, Ⅱ clinical trials STI571 treatment of chronic myelogenous leukemia (CML) effect is significant, CML acute and Ph ~ + acute leukemia also have some effect. Leukemia cells are associated with over-expression of Bcr-Abl protein in vitro and drug resistance of STI571 and target gene amplification, as well as overexpression of P-glycoprotein (Pgp). The mechanism of drug resistance in vivo is associated with an increase in acid glycoprotein (AGP).