Waller Cornelius F
Department of Hematology and Oncology, University of Freiburg Medical Center, Hugstetterstrasse 55, 79106, Freiburg, Germany.
Recent Results Cancer Res. 2010;184:3-20. doi: 10.1007/978-3-642-01222-8_1.
IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases.Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression.Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors (see Chaps. 7-9).
甲磺酸伊马替尼(格列卫,Glivec[瑞士巴塞尔诺华公司],以前称为STI571或CGP57148B)代表了一类新型抗癌药物,即所谓的小分子药物的范例。它们对一种已知是恶性表型建立和维持原因的特定分子靶点具有高度选择性。伊马替尼是一种合理设计的口服信号转导抑制剂,它特异性靶向几种蛋白酪氨酸激酶,Abl、Arg(Abl相关基因)、干细胞因子受体(c-KIT)、血小板衍生生长因子受体(PDGF-R)及其致癌形式,最显著的是Bcr-Abl。已证明伊马替尼在慢性髓性白血病(CML)和恶性胃肠道间质瘤(GIST)患者中具有显著的临床活性,从而获批用于治疗这些疾病。伊马替尼治疗一般耐受性良好,严重副作用发生率低。最常见的不良事件(AE)包括轻度至中度水肿、肌肉痉挛、腹泻、恶心、皮疹和骨髓抑制。已确定了几种耐药机制。已证明Bcr-Abl的克隆进化、扩增或过表达以及催化结构域、P环的突变和其他突变分别在对伊马替尼的原发性和继发性耐药中起作用。对耐药潜在机制的进一步了解已导致开发新的第二代酪氨酸激酶抑制剂(见第7 - 9章)。