多靶点酪氨酸激酶抑制剂舒尼替尼的研究进展

近年来各种酪氨酸激酶抑制剂不断涌现,以酪氨酸激酶抑制剂为代表的分子靶向治疗已成为抗肿瘤研究的热点.舒尼替尼(sunitinib,商品名Sutent)是一种小分子多靶点酪氨酸激酶抑制剂,对血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR)、干细胞因子受体(C-Kit)等多种受体酪氨酸激酶具有抑制作用,已于2006年1月被美国FDA批准用于临床上晚期肾细胞癌(RCC)和对伊马替尼(ima-tinib)耐药和(或)治疗失败的胃肠道间质瘤(GIST)的治疗,并在其他多种肿瘤的临床试验中也显示显著抗肿瘤活性,文中综述了该药的临床前研究及临床研究进展.     

酪氨酸激酶抑制药的不良反应

目的 分析临床上常用酪氨酸激酶抑制药的不良反应, 总结其主要不良反应及构成比, 为临床合理应用该类药物提供参考依据. 方法 采集温州医学院附属第一医院2007年1月～2009年6月使用酪氨酸激酶抑制药治疗肿瘤的病例118例, 分析索拉非尼、伊马替尼、舒尼替尼、厄洛替尼、吉非替尼产生的不良反应. 结果 不良反应涉及皮肤及其附件72例, 消化系统38例, 五官26例, 呼吸系统12例, 神经系统10例, 泌尿系统、血液系统各3例, 循环系统2例.吉非替尼、索拉非尼致死亡各1例.结论 酪氨酸激酶抑制药治疗肿瘤有效, 但其不良反应应引起关注.     

舒尼替尼致重度血小板减少及甲状腺功能减低1例

<正>舒尼替尼(sunitinib)为一种口服多靶点酪氨酸激酶抑制剂,其作用靶点包括血小板衍生生长因子受体(PDGFRα、PDGFRβ)、血管内皮生长因子受体(VEGFR1、VEGFR2、VEGFR3)、干细胞因子受体(KIT)、Fms样酪氨酸激酶-3(FLT3)、1型集落刺激因子受体(CSF-1R)和神经胶质细胞系衍生的神经营养因子受体(RET)等,是目前治疗转移性肾透明细胞癌的标准一线方案。舒尼替尼主要不良反应包括乏力、腹泻、皮肤毒性     

舒尼替尼可延长晚期胰腺神经内分泌肿瘤患者的生存期

一项在晚期胰腺神经内分泌肿瘤患者中进行的Ⅲ期临床试验结果表明,舒尼替尼（sunitinib;商品名：Sutent,索坦）可延长受试者的肿瘤无进展生存期。舒尼替尼是由辉瑞公司研发的新型多靶点抗肿瘤药物,可抑制血小板衍生因子受体（PDGFR）、血管内皮生长因子受体（VEGFR）以及多种酪氨酸激酶,     

舒尼替尼致甲状腺功能减退的研究进展

舒尼替尼是一种口服多靶点受体酪氨酸激酶抑制剂,用于治疗转移性肾细胞癌和伊马替尼治疗失败或不耐受的转移性胃肠道间质瘤.舒尼替尼致甲状腺功能减退的发生率较高,症状不典型,包括乏力、心悸、畏寒、嗜睡等,易与肿瘤相关症状及舒尼替尼的其他常见不良反应混淆.舒尼替尼致甲状腺功能减退可能与破坏甲状腺腺体、抑制甲状腺过氧化物酶和损伤血管有关.服用舒尼替尼的患者需定期监测甲状腺功能,必要时给予甲状腺激素替代治疗.     

苹果酸舒尼替尼

苹果酸舒尼替尼(sunitinib malate)是由美国辉瑞公司开发的一种口服小分子多靶点酪氨酸激酶受体抑制剂.分别于2006年1月和2007年1月由美国FDA和欧洲EMEA批准上市,商品名为Sutent,为口服硬明胶胶囊制剂,用于治疗胃肠道间质肿瘤(GIST)和晚期肾细胞瘤.     

Bruton酪氨酸激酶抑制剂伊鲁替尼治疗B细胞恶性肿瘤的临床应用

Bruton酪氨酸激酶(bruton tyrosine kinase,BTK)是B细胞内一种非受体型酪氨酸激酶,介导了B细胞抗原受体(BCR)在内的一系列细胞通路,其异常活性与B细胞恶性肿瘤的发病密切相关。伊鲁替尼(ibrutinib)是一种高效选择性BTK抑制剂,能够在钠摩尔水平下抑制肿瘤细胞增殖。本文介绍了伊鲁替尼的药理学特点,并且综述了其治疗慢性淋巴细胞白血病、套细胞淋巴瘤等疾病的临床应用。     

多靶点酪氨酸激酶抑制剂舒尼替尼临床评价

苹果酸舒尼替尼是一种选择性多受体酪氨酸激酶抑制剂,具有抗肿瘤生长和抗血管生成作用.多中心随机双盲安慰剂对照研究显示,转移性和(或)不能切除的胃肠道间质瘤(GIST)在伊马替尼治疗失败后改用舒尼替尼(一日50mg,服用4周,间隔2周,一个治疗周期共为6周),结果与安慰剂组相比,至疾病进展时间和中位无进展生存期均延长,约为安慰剂组的4倍以上.初步评价显示,舒尼替尼作为晚期肾细胞癌(RCC)一线治疗用药比干扰素α更有效.     

舒尼替尼与头孢曲松钠合用诱发剥脱性皮炎性药疹1例

舒尼替尼是一种新型抗肿瘤药物(多靶点的小分子酪氨酸激酶抑制剂),该药物的主要不良反应是皮肤毒性,但多为1～2级。1例晚期非小细胞肺癌患者标准治疗失败后,在用舒尼替尼治疗期间,联用头孢曲松钠后,诱发剥脱性皮炎性药疹。     

新型多靶点蛋白激酶抑制剂——舒尼替尼

苹果酸舒尼替尼（Sunitinib malate／SUTENT／SU112481是美国辉瑞公司研制的新型多靶点的抗肿瘤药物，于2006年2月被美国食品与药品管理局批准上市，用于治疗胃肠间质肿瘤和晚期肾细胞癌。这是该机构首次批准能同时治疗2种适应证的抗肿瘤药物。同时，其也是第一个被欧盟批准为治疗转移性肾细胞癌（MRCC）一线用药的多靶点酪氨酸激酶受体抑制剂。     

Sunitinib malate for the treatment of solid tumours: a review of current clinical data

Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.     

Sunitinib malate for the treatment of solid tumours: a review of current clinical data

Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.     

Molecular basis for sunitinib efficacy and future clinical development

Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors.     

硫酸铵梯度法制备苹果酸舒尼替尼脂质体

目的:采用跨膜硫酸铵梯度法制备苹果酸舒尼替尼脂质体并对制备工艺进行考察。方法:采用混合离子交换树脂建立跨膜硫酸铵[ammonium sulfate,(NH4)2SO4]梯度制备苹果酸舒尼替尼脂质体;阳离子交换树脂分离-可见分光光度法测定苹果酸舒尼替尼脂质体的包封率,激光散射粒径分析仪测定苹果酸舒尼替尼脂质体的粒径。结果:苹果酸舒尼替尼脂质体包封率大于96%,平均粒径为107.5 nm。结论:以(NH4)2SO4梯度法制备的苹果酸舒尼替尼脂质体包封率较高,方法简便易行。     

Strategies to overcome resistance to targeted protein kinase inhibitors

Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR-ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr-Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.     

Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma.

PURPOSE: The role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma (mRCC) is reviewed. SUMMARY: Sunitinib malate is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors, FMS-like tyrosine kinase 3 (FLT3), c-KIT, and platelet-derived growth factor (PDGF), which give the drug its direct antitumor and antiangiogenic properties. Sunitinib is currently approved as a second-line treatment of mRCC in patients who have either not responded to or who are not eligible to receive interleukin-2. Clinical trials of sunitinib have found similar rates of partial response, disease stabilization, and progression-free survival. Sorafenib inhibits VEGF receptors, PDGF receptors, FLT3, RAF-1, and BRAF in vitro and has been shown to prevent the growth of tumors but not to reduce tumor size. Sorafenib has been proven to improve survival in a novel randomized discontinuation trial and a Phase III randomized, placebo-controlled trial. No studies have directly compared the effectiveness of sunitinib to sorafenib in the treatment of advanced renal cell carcinoma. Sunitinib and sorafenib share a similar mechanism of action and primarily target tumor angiogenesis by inhibiting a variety of tyrosine kinases; the agents have similar toxicity, with the exception of an increased risk of hypertension associated with the use of sorafenib. Sorafenib does not result in tumor shrinkage, but sunitinib significantly reduces tumor size. CONCLUSION: The tyrosine kinase inhibitors sorafenib and sunitinib offer improved outcomes for patients with mRCC, but they are far short of a cure. Despite the introduction of sorafenib and sunitinib, palliative care is still an acceptable treatment option for mRCC because of the disease's extremely poor prognosis.     

A comprehensive overview of targeted therapy in metastatic renal cell carcinoma

Chemotherapy and immunotherapy failed to deliver decisive results in the systemic treatment of metastatic renal cell carcinoma. Agents representing the current standards operate on members of the RAS signal transduction pathway. Sunitinib (targeting vascular endothelial growth factor), temsirolimus (an inhibitor of the mammalian target of rapamycin - mTOR) and pazopanib (a multi-targeted receptor tyrosine kinase inhibitor) are used in the first line of recurrent disease. A combination of bevacizumab (inhibition of angiogenesis) plus interferon α is also first-line therapy. Second line options include everolimus (another mTOR inhibitor) as well as tyrosine kinase inhibitors for patients who previously received cytokine. We review the results of clinical investigations focusing on survival benefit for these agents. Additionally, trials focusing on new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and monoclonal antibodies including velociximab are also discussed. In addition to published outcomes we also include follow-up and interim results of ongoing clinical trials. In summary, we give a comprehensive overview of current advances in the systemic treatment of metastatic renal cell carcinoma.     

HPLC法测定苹果酸舒尼替尼胶囊中主药的含量

目的:建立测定苹果酸舒尼替尼胶囊中主药含量的方法。方法:采用高效液相色谱法。色谱柱为Shimadzu C18,流动相为醋酸铵缓冲液(pH6.8)-乙腈(55:45),流速为1.0mL·min-1,检测波长为430nm,柱温为35℃。结果:苹果酸舒尼替尼检测浓度线性范围为5～25μg·mL-1(r=0.9997),平均回收率为99.65%,RSD=0.66%(n=9)。结论:该方法操作简便、准确性好、精密度高,可作为本品含量测定的方法。