Gross David J, Munter Gabriel, Bitan Menachem, Siegal Tali, Gabizon Alberto, Weitzen Ronny, Merimsky Ofer, Ackerstein Aliza, Salmon Asher, Sella Avishai, Slavin Shimon
Endocrinology and Metabolism Service, Department of Medicine, Hadassah University Hospital, P.O.B 12000, Jerusalem, Israel 91120.
Endocr Relat Cancer. 2006 Jun;13(2):535-40. doi: 10.1677/erc.1.01124.
Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.
甲磺酸伊马替尼（IM）是一种小分子物质，是ABL、血小板衍生生长因子受体（PDGFR-R）和干细胞配体受体（c-kit）酪氨酸激酶（TK）的选择性抑制剂。还发现IM可抑制慢性粒细胞白血病中产生的BCR/ABL融合蛋白的TK活性，对该疾病具有显著的临床活性。由于PDGF-R和c-kit在肿瘤发生中都具有假定作用，我们在一项关于IM治疗实体瘤患者的全面II期多中心研究框架内，研究了IM用于对传统疗法无反应且表达c-kit和/或PDGF-R的内分泌肿瘤患者的疗效和安全性。IM起始剂量为400毫克/天，1周内可能将剂量增至600毫克/天，若病情进展且无安全问题，可选择在长达12个月的时间内将剂量增至800毫克/天。2002年9月至2003年7月，招募了15例成年播散性内分泌肿瘤患者，具体如下：甲状腺髓样癌（MTC，n = 6）；肾上腺皮质癌（ACC，n = 4）；恶性嗜铬细胞瘤（嗜铬细胞瘤，n = 2）；类癌（无分泌功能，n = 2），神经内分泌肿瘤（NET，n = 1）。未观察到客观反应。MTC——4例患者疾病进展，2例患者因不良事件停药；ACC——3例患者疾病进展，1例患者因严重精神不良事件停药；嗜铬细胞瘤——2例患者疾病进展；类癌——1例患者病情稳定（6.5个月），1例患者疾病进展；NET——1例患者疾病进展。IM似乎对恶性内分泌肿瘤的治疗无效，在该患者群体中还会引起显著毒性。
