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World Journal of Clinical Cases 2023年第9期11卷 2104-2109页

作者： Shuai Dong Yang-Chun Xu Yuan-Chen Zhang Jian-Xin Xia Yan Mou Department of Dermatology The Second Hospital of Jilin UniversityChangchun 130041Jilin ProvinceChina

BACKGROUND Renal clear cell carcinoma(RCC)is a malignant tumor of the genitourinary system with a predilection for *** most common metastatic sites are the lung,liver,lymph nodes,contralateral kidney or adrenal gland,however,skin metastasis has only been seen in 1.0%-3.3%of *** most common site of skin metastasis is the scalp,and metastasis to the nasal ala region is *** SUMMARY A 55-year-old man with clear cell carcinoma of the left kidney was treated with pembrolizumab and axitinib for half a year after surgery and was found to have a red mass on his right nasal ala for 3 *** skin lesion of the patient grew rapidly to the size of 2.0 cm×2.0 cm×1.2 cm after discontinuation of targeted drug therapy due to the coronavirus disease 2019 *** patient was finally diagnosed with skin metastasis of RCC in our *** patient refused to undergo surgical resection and the tumor shrank rapidly after resuming target therapy for 2 *** It is rare for an RCC to metastasize to the skin of the nasal ala *** tumor size change of this patient before and after treatment with targeted drugs shows the effectiveness of combination therapy for skin metastasis.

关键词： Skin metastasis Renal clear cell carcinoma Pembrolizumab axitinib Case report

Efficacy and Safety of axitinib as First-Line Therapy in Japanese Patients with Metastatic Renal Cell Carcinoma

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Journal of Cancer Therapy 2015年第8期6卷 670-678页

作者： Takeshi Namekawa Satoshi Fukasawa Atsushi Komaru Masayuki Kobayashi Takayuki Ohzeki Yosuke Sato Junryo Rii Hirotsugu Uemura Tomohiko Ichikawa Takeshi Ueda Prostate Center and Division of Urology Chiba Cancer Center Chiba Japan Department of Urology Kinki University Hospital Osaka Japan Department of Urology Graduate School of Medicine Chiba University Chiba Japan

Previous study reported that patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib for metastatic renal cell carcinoma (mRCC). In this study, we reviewed our experience of axitinib as a first-line therapy for mRCC in Japanese patients, focusing on its efficacy and safety. We retrospectively assessed 26 patients treated with axitinib as a first-line therapy for mRCC from July 2010 to July 2014 at Chiba Cancer Center and Kinki University Hospital. Observation period was 24.6 ± 18.3 months. The objective response rate was 50.0%, and the median progression-free survival was 27.5 months. Overall survival was not estimable. Common grade 3 adverse events were hypertension in 19 patients and proteinuria in 5 patients. axitinib demonstrated significant efficacy as a first-line therapy in Japanese patients with mRCC. Careful monitoring and management of the adverse effects may help to control its toxicities.

关键词： axitinib Renal Cell Carcinoma First Line

A liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma: development, validation and application to a pharmacokinetic study

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Journal of Chinese Pharmaceutical Sciences 2016年第5期25卷 342-350页

作者：马元亨李健苏清虹陈文君卢炜周田彦北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室北京100191 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

In the present study, a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma was developed, validated, and applied to a pharmacokinetic study. Plasma samples were pre-treated by protein precipitation with acetonitrile spiked with erlotinib as an internal standard. The chromatographic separation was accomplished by using a reversed phase C18 column （50 mm×2 mm, 5 μm） with a simple mobile phase system composed of methanol and water （60：40, v/v） at an isocratic flow rate of 0.4 mL/min. The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization and multiple reaction monitoring was employed to select both axitinib and erlotinib in the positive ion mode. The calibration curves were linear （r〉0.99） ranging from 1 to 1000 ng/mL, and the lowest level of this range was the lower limit of quantification. The intra- and inter-day precision were 7.7%-12.0%, and the accuracies ranged from 88.6% to 110.4%. This method was successfully applied to a preclinical pharmacokinetic study on female nu/nu nude mice administrated with a single oral dose of axitinib at 120 mg/kg, and the pharmacokinetics was characterized by a one-compartment model with first-order absorption.

关键词： axitinib LC-MS/MS Nude mice Pharmacokinetics

抗癌药物axitinib的重氮衍生物的合成及光控活性研究

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抗癌药物axitinib的重氮衍生物的合成及光控活性研究

作者：魏娜湘潭大学

学位级别：硕士

抗癌药物常见的毒副作用主要包括恶心、呕吐、便秘、腹泻、口腔炎、食欲不振、脱发,降低其毒副作用的方法主要包括采用靶向药物、免疫治疗药物、前体药物、缓释制剂、控释给药系统及靶向给药系统,但是靶向药物难以研制,药物修饰导致活... 详细信息

抗癌药物常见的毒副作用主要包括恶心、呕吐、便秘、腹泻、口腔炎、食欲不振、脱发,降低其毒副作用的方法主要包括采用靶向药物、免疫治疗药物、前体药物、缓释制剂、控释给药系统及靶向给药系统,但是靶向药物难以研制,药物修饰导致活性降低。2016年诺贝尔化学奖得主Feringa BL于2014年首次提出的光药物学（Photopharmacology）概念,光药物学是指用光来远程、可逆控制药物分子的结构进而控制药物活性,使药物在活性态和非活性态之间转变。光药物学可以用光控制体内特定部位的药物活性选择性地激活或丧失,为降低药物的毒副作用提供了一种新思路。阿西替尼（axitinib）是由辉瑞公司研发的一种小分子酪氨酸激酶抑制剂,2012年上市,用于其他药物治疗无效的晚期肾癌,作用靶点主要为血管内皮细胞生长因子受体VEGFR1-3。axitinib含类二苯乙烯结构,具有反式与顺式两种构型,其中反式结构为稳定构型即临床应用的活性构型。由于其类二苯乙烯结构受光作用易发生结构环化失活等缺点,不易用光来控制其活性变化或用于酪氨酸激酶抑制剂分子开关。目前应用广泛的偶氮苯光开关,具有顺反式构型偶极矩差别大、相对较高的光稳态和量子产率、快速光异构化、光漂白现象较少等优点。为获得长波长控制、半衰期长的目标化合物,达到可逆光控药物活性目的,本论文对axitinib光学性质及顺反式构型活性差异进行了研究,并用氮氮双键替代axitinib结构中的碳碳双键,用含取代基的苯环或五元吡咯环替代吡啶环,设计合成了十个目标化合物。本论文取得的主要结果如下:（1）通过重氮化反应,得到十个结构新颖的化合物,并用高分辨质谱、核磁氢谱（1HNMR）、核磁碳谱（13CNMR）确定其结构。（2）利用紫外分光光度计测试了 axitinib及目标化合物的光学性质,其中所有的目标化合物最大吸收波长均比axitinib红移,所有目标化合物的半衰期均比axitinib短,目标化合物中取代基苯环α位都被甲氧基占据的化合物及N-甲基五元吡咯环类化合物半衰期相对较长。（3）VEGFR-2酶抑制活性实验结果表明,黑暗实验组中（化合物大部分处于反式构型）,五元吡咯环取代化合物大都展示出了较好的酶抑制活性,IC50为100～300 nM。光照实验结果表明,axitinib顺反式异构体活性表现出了明显差异,IC50差值高达48倍,但axitinib衍生物由于半衰期太快,未表现出活性差异。（4）HUVEC细胞增殖抑制实验结果表明,黑暗实验组中,重氮盐分子与五元吡咯环α位相连的化合物活性优于axitinib。光照实验组中,axitinib及其他衍生物光照前后活性几乎无差别,重氮盐分子与N-甲基五元吡咯环α位相连的化合物光照前后活性差别显著。

关键词：光药物学 axitinib 偶氮衍生物酶活性细胞活性光学性质

多靶点酪氨酸激酶抑制剂axitinib抑制人肝癌SNU-423细胞生长机制的研究

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多靶点酪氨酸激酶抑制剂Axitinib抑制人肝癌SNU-423细胞生长机制...

作者：田九博山西医科大学

学位级别：硕士

目的:1、检测axitinib对肝癌细胞增殖,细胞周期和细胞凋亡的影响,并初步揭示其中复杂的分子机制。2、为axitinib作为临床上治疗此类肝癌细胞的辅助方案提供参考。同时,为设计和研发更有效的分子靶向药物提供实验依据。方法:1、MTT法筛选... 详细信息

目的:1、检测axitinib对肝癌细胞增殖,细胞周期和细胞凋亡的影响,并初步揭示其中复杂的分子机制。2、为axitinib作为临床上治疗此类肝癌细胞的辅助方案提供参考。同时,为设计和研发更有效的分子靶向药物提供实验依据。方法:1、MTT法筛选对axitinib敏感的肝癌细胞株。设置一定浓度梯度的axitinib,分别作用于BEL-7402细胞、SK-Hep1细胞、HepG2细胞、SNU-423细胞等肝癌细胞株,应用MTT法检测各类细胞的生存能力,通过分析比较,确定对axitinib敏感的细胞株。2、应用细胞克隆形成实验、Hoechst染色法、流式细胞术和Western blot分别检测不同浓度下的axitinib对SNU-423细胞增殖能力、细胞凋亡和细胞周期的影响。3、通过蛋白质印记实验初步探索axitinib影响SNU-423细胞株生存及增殖过程的分子机制。结果:1、通过对四种肝癌细胞株进行药敏检测,筛选出了对多靶点酪氨酸激酶抑制剂axitinib最为敏感的细胞株SNU-423。2、细胞克隆形成实验的结果显示,axitinib对SNU-423细胞的集落形成能力具有明显的抑制作用,且这种抑制作用呈现良好的浓度依赖关系。进而表明axitinib对SNU-423细胞的增殖具有较强抑制作用。3、细胞凋亡的检测结果表明,随着axitinib浓度的增加,相同视野下,处于凋亡过程的SNU-423细胞所占的比例也随之增大。而用Western blot对相关凋亡蛋白Cleaved Caspase-3及Bcl-2表达量的检测,同样表明,Cleaved Caspase-3蛋白的表达量随着axitinib浓度的增加,其蛋白条带的灰度也成正相关的增大;而Bcl-2蛋白的表达量随着axitinib浓度的增加显著地降低。总体而言,axitinib能够促进SNU-423细胞凋亡,且细胞的凋亡情况与药物浓度具有依赖关系。4、细胞周期的流式检测及相关周期蛋白Cyclin D1的Western blot检测结果表明,经不同浓度的axitinib处理后,SNU-423细胞的周期动力学出现显著的差异,其中被阻滞在G1期的细胞所占的比例随axitinib浓度的增加而增高。因此,axitinib能够引起SNU-423细胞的G1期阻滞。5、蛋白质印记实验结果表明,SNU-423细胞经不同浓度的axitinib作用后,细胞内的VEGFR2、p38 MAPK、Src和P-Src（Tyr527）、Akt和P-Akt（Thr308）、MEK1/2以及Erk1/2的表达量均未受到显著影响,这些蛋白的表达量均保持相对稳定。P-p38MAPK、P-Src（Tyr416）、P-Akt（Ser473）和P-MEK1/2这些蛋白的表达量与axitinib浓度梯度间呈现正相关性,即随着药物浓度的增大,蛋白的表达量也随之增高。在1μmol/L至10μmol/L实验组中,axitinib能够显著地抑制P-VEGFR2蛋白的表达,且随着药物浓度的增加VEGFR2的磷酸化显著性地降低。在1μmol/L和5μmol/L药物浓度实验组,P-Erk1/2的表达量相较于Control组而言,随药物浓度的增大而增高;而10μmol/L药物浓度实验组,P-Erk1/2的表达量相较于Control组而言则保持相对的稳定性。结论:1、多靶点酪氨酸激酶抑制剂axitinib对肝癌细胞株（BEL-7402细胞、SK-Hep1细胞、HepG2细胞、SNU-423细胞）的生存及增殖能力均存在不同程度的抑制作用。其中SNU-423细胞生存及增殖能力所受的抑制作用最强,对axitinib最为敏感。2、多靶点酪氨酸激酶抑制剂axitinib能够通过浓度依赖性的方式抑制SNU-423细胞增殖,促进细胞凋亡,诱导细胞G1期阻滞。3、axitinib可通过特定的信号分子促进p38 MAPK蛋白的磷酸化,进而激活p38MAPK蛋白相关信号通路,最终诱导SNU-423细胞完成caspases依赖性细胞凋亡过程。

关键词： axitinib SNU-423细胞 VEGFR2 细胞凋亡

axitinib对肿瘤干细胞样细胞的作用及其机制研究

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Axitinib对肿瘤干细胞样细胞的作用及其机制研究

血管内皮生长因子受体抑制剂——axitinib

2011医学科学前沿论坛第十二届全国肿瘤药理与化疗学术会议

作者：米彦军符立梧华南肿瘤学国家重点实验室

目的:肿瘤干细胞样细胞具有自我更新、无限增殖和多向分化潜能等干细胞特性,是肿瘤发生,复发和转移的根源。axitinib是-种口服小分子酪氨酸激酶抑制剂,可选择性抑制VEGFR-1,2,3、PDGFR和c-Kit的活性。本实验探讨axitinib是否可靶向肿瘤... 详细信息

目的:肿瘤干细胞样细胞具有自我更新、无限增殖和多向分化潜能等干细胞特性,是肿瘤发生,复发和转移的根源。axitinib是-种口服小分子酪氨酸激酶抑制剂,可选择性抑制VEGFR-1,2,3、PDGFR和c-Kit的活性。本实验探讨axitinib是否可靶向肿瘤干细胞样细胞增加传统化疗药物敏感性及其作用机制。方法:用Hoechst33342染色法分选A549中肿瘤干细胞样细胞(SP-A549)和非SP-A549(NSP-A549)细胞。MTT法检测axitinib及常用抗癌药物对将SP-A549和NSP-A549细胞的细胞毒作用,流式细胞术检测细胞凋亡变化。

关键词：肿瘤干细胞样细胞多药耐药 ABC transporters axitinib

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药学进展 2008年第4期32卷 186-188页

作者：孙大柠

近年来,在抗肿瘤药的研制中,靶向血管生成和血管内皮生长因子(VEGF)的药物已成为热点。一些抗VEGF的单克隆抗体,如治疗转移性结肠直肠癌的贝伐单抗(bevacizumb)和小分子、多靶向[包括靶向于VEGF受体(VEGFR)]的激酶抑制剂,如舒尼替尼(sun... 详细信息

近年来,在抗肿瘤药的研制中,靶向血管生成和血管内皮生长因子(VEGF)的药物已成为热点。一些抗VEGF的单克隆抗体,如治疗转移性结肠直肠癌的贝伐单抗(bevacizumb)和小分子、多靶向[包括靶向于VEGF受体(VEGFR)]的激酶抑制剂,如舒尼替尼(sunitinib)、索拉非尼(sorafenib)等陆续被批准上市。[第一段]

关键词： axitinib 血管内皮生长因子受体抑制剂抗癌

Chemotherapy,transarterial chemoembolization,and nephrectomy combined treated one giant renal cell carcinoma(T3aN1M1)associated with Xp11.2/TFE3:A case report

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World Journal of Clinical Cases 2022年第28期10卷 10180-10185页

作者： Peng Wang Xiao Zhang Shuo-Han Shao Fa Wu Fei-Zhou Du Jun-Feng Zhang Zhi-Way Zuo Rui Jiang Department of Radiology The General Hospital of Western Theater CommandChengdu 610083Sichuan ProvinceChina

BACKGROUND Renal cell carcinoma(RCC)with Xp11.2 translocation/TFE3 gene fusion is a rare and distinct subtype of RCC that is classified under tumors with translocation of the microphthalmia-associated transcriptional *** SUMMARY We report an adult case of Xp11.2 translocation advanced RCC with metastasis(T3a N1M1),after targeted treatment,alcohol ablation,and transarterial chemoembolization,who eventually underwent successful surgical *** recurrence or transfer was seen within one year,and the survival period was more than 3 years.A review of the relevant literature was conducted to improve our understanding of the pathogenesis,epidemiology,clinical manifestations,diagnosis,differential diagnosis,treatment,and other aspects of the *** Transarterial chemoembolization and ablation did not achieve the desired tumor reduction in this patient,but had a significant effect on reducing intraoperative bleeding and inhibiting tumor activity.

关键词： Xp11.2/TFE3 Renal Cell Carcinoma TACE axitinib Zoledronic Acid Targeted therapy Multimodal imaging Case report

Current and emerging therapies for first line treatment of metastatic clear cell renal cell carcinoma

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 532-550页

作者： Michael T.Serzan Michael B.Atkins Georgetown Lombardi Comprehensive Cancer Center WashingtonDC 20057USA.

The therapeutic landscape for advanced clear cell renal cell carcinoma(ccRCC)is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and *** this review,we discuss historical,current,and emerging first line treatment options for patients with advanced *** include data with single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors(TKIs):sunitinib,pazopanib and cabozantinib as well as the recently reported results for the combination of lenvatinib and everolimus(mTOR inhibitor).We also discuss results of the nivolumab anti-programmed cell death(PD-1)/ipilimumab(anti-cytotoxic T lymphocyte-associated antigen 4)combination as well as emerging front-line data with nivolumab and pembrolizumab(anti-PD-1)***,we review data supporting recent approvals of TKI and anti-PD-1 or anti-PD-Ligand 1(PD-L1)combinations(e.g.,axitinib/pembrolizumab,axitinib/avelumab and cabozantinib/nivolumab)and initial outcomes of lenvatinib(multi-kinase inhibitor)and *** many individual and combination treatment options and the lack of head-to-head comparisons,treatment selection will depend on the goals of therapy(endpoints)and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints.

关键词： Renal cell carcinoma nivolumab ipilimumab axitinib pembrolizumab avelumab biomarkers

Translating new data to the daily practice in second line treatment of renal cell carcinoma:The role of tumor growth rate

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World Journal of Clinical Oncology 2017年第2期8卷 100-105页

作者： Enrique Grande Olga Martínez-Sáez Pablo Gajate-Borau Teresa Alonso-Gordoa Medical Oncology Department Ramón y Cajal University Hospital

The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased in daily practice and now it is not uncommon to see patients surviving kidney cancer for more than four to five years. Once treatment fails with the first line targeted therapy, head to head comparisons have shown that cabozantinib, nivolumab and the combination of lenvatinib plus everolimus are more effective than everolimus alone and that axitinib is more active than sorafenib. Unfortunately, it is very unlikely that we will ever have prospective data comparing the activity of axitinib, cabozantinib, lenvatinib or nivolumab. It is frustrating to observe the lack of biomarkers that we have in this field, thus there is no firm recommendation about the optimal sequence of treatment in the second line. In the absence of reliable biomarkers, there are several clinical endpoints that can help physicians to make decisions for an individual patient, such as the tumor burden, the expected response rate and the time to achieve the response to each agent, the prior response to the agent administered, the toxicity profile of the different compounds and patient preference. Here, we propose the introduction of the tumor-growth rate(TGR) during first-line treatment as a new tool to be used to select the second line strategy in m RCC. The rapidness of TGR before the onset of the treatment reflects the variability between patients in terms of tumor growth kinetics and it could be a surrogate marker of tumor aggressiveness that may guide treatment decisions.

关键词： axitinib Everolimus Cabozantinib Kidney cancer Nivolumab Renal cell Sequence Second line Sorafenib Tumor-growth rate