甲磺酸伊马替尼:治疗胃肠道间质肿瘤。
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Croom KF,佩里CM
甲磺酸伊马替尼:治疗胃肠道间质肿瘤。
药。2003;63 (5):513 - 22;讨论523 - 4。
- PubMed ID
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12600228 (在PubMed]
- 文摘
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甲磺酸伊马替尼(伊马替尼)是一种口服接种的竞争性抑制剂酪氨酸激酶与设备相关的蛋白质(干细胞因子受体),ABL蛋白和血小板源生长因子受体。工具包酪氨酸激酶异常表达在胃肠道间质瘤(GIST),一种罕见的肿瘤,没有有效的系统性治疗。nonblind,随机,多中心研究,评估伊马替尼400或600毫克每天一次在147年先进的要点,患者证实部分反应实现54%的患者整体(中位随访时间是288天)。稳定的疾病是由28%的患者经历,1年生存率大约为88%。类似的响应率是在较小的报告,剂量递增研究,客观肿瘤反应是次要的端点。尽管几乎所有患者依据伊马替尼治疗经验丰富的不良事件,大多数事件是轻度或中度的性质。严重或严重不良事件发生在21%的病人在较大的研究中,和包括胃肠道肿瘤出血。控制的细胞过程,如细胞生长、分裂和死亡,包括信号转导,这通常涉及到的磷酸转移三磷酸腺苷(ATP)对底物蛋白质酪氨酸残基,通过酪氨酸激酶的酶。激活癌基因编码的蛋白质激酶的激酶可能导致生产不断活跃在缺乏正常的刺激,导致增加细胞增殖和/或减少细胞凋亡。癌症研究的一个主要焦点近年来识别致癌分子和信号转导途径中,为了发展特别是靶向药物。 One such drug is imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2-phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine kinases associated with platelet-derived growth factor (PDGF) receptors, the Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF] receptor). Imatinib was initially evaluated for the treatment of chronic myeloid leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been approved for the treatment of patients with advanced gastrointestinal stromal tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed. GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal cells. They are rare neoplasms, with between 5000 and 10 000 new cases being diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract but the stomach and small intestine are the most common sites. Symptoms depend on the site and size of the tumour, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumours may be asymptomatic. The diagnosis of GIST is made by immunohistochemical staining for CD117, a cell surface antigen on the extracellular domain of KIT, in conjunction with pathological examination of tissue with light microscopy. All GISTs may have some degree of malignant potential. They are unresponsive to standard chemotherapy and to radiotherapy, and the mainstay of treatment in the past has been surgery. However, recurrence rates are high, and there has been no effective systemic treatment for unresectable GIST or metastatic disease. For patients in whom complete resection is not possible, or in patients with metastatic or recurrent disease, the median duration of survival is 9-12 months, and 10-19 months, respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to 90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto-phosphorylation of tyrosine residues independent of ligand-receptor binding), leading to aberrant cell division and tumour growth. Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for evaluating its effects in GIST. Subsequent to initial evidence of the clinical efficacy of imatinib in a single patient with progressive, metastatic, CD117-positive GIST, formal studies of imatinib in this new indication were initiated. This article summarises the pharmacology, efficacy and tolerability profile of imatinib in the treatment of patients with advanced GIST.