Imatinib Mesylate
Imatinib Mesylate
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DOI：
10.1007/978-3-642-54490-3_1
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Waller, Cornelius F.
中科院分区：
文献类型：
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作者：
Waller, Cornelius F.
甲磺酸伊马替尼（Gleevec，Glivec [Novartis，巴塞尔，瑞士]，以前称为STI 571或CGP 57148 B）代表了一类新的抗癌剂，即所谓的小分子的范例。它们对已知是恶性表型建立和维持的原因的特定分子靶点具有高选择性。伊马替尼是一种合理设计的口服信号转导抑制剂，特异性靶向几种蛋白酪氨酸激酶，Abl，Arg（PDGF-R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，伊马替尼在慢性粒细胞白血病（CML）患者中具有显著的临床活性和恶性胃肠道基质肿瘤（GIST），导致其被批准用于治疗这些疾病。伊马替尼治疗通常耐受性良好，严重副作用的发生率低。最常见的不良反应包括轻度至中度水肿、肌肉痉挛、腹泻、恶心、皮疹和骨髓抑制。已经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环和其他突变分别在伊马替尼的原发性和继发性耐药中发挥作用。对耐药潜在机制的理解导致了新的第二代和第三代酪氨酸激酶抑制剂的开发（见达沙替尼，尼洛替尼，博舒替尼和泊那替尼章节）。
Imatinib mesylate (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, 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 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. Understanding of the underlying mechanisms of resistance has led to the development of new second- and third-generation tyrosine kinase inhibitors (see chapters on dasatinib, nilotinib, bosutinib, and ponatinib).