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International Journal of Ophthalmology(English edition) 2023年第9期16卷 1450-1455页

作者： Wei Fang Jing Zhai Zhen-Bin Qian Hai-Dong Li Meng-Di Wang Li-Jun Shen The Eye Hospital of Wenzhou Medical University School of Opthalmology&OptometryWMUZhejiang Eye HospitalHangzhou 310000Zhejiang ProvinceChina

AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in ***:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a *** samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after ***-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous ***:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both *** the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third *** nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several ***:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.

关键词： retinal vein occlusion nintedanib tyrosine kinase inhibitor basic fibroblast growth factor vascular endothelial growth factor rabbit model

tyrosine kinase inhibitor for Treatment of Adult AIIogeneic Hematopoietic Stem Cell Transplantation Candidate with Philadelphia-Positive Acute Lymphoblastic Leukemia

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Chinese Medical Journal 2017年第2期130卷 127-129页

作者： Lu Wang Dai-Hong Liu Department of Hematology Chinese People's Liberation Army General Hospital Beijing 100082 China

Philadelphia-positive acute lymphoblastic leukemia （Ph＋ ALL） accounts for approximately 25-33% of all adult ALL cases. Its prognosis was dismal until the introduction of tyrosine kinase inhibitors （TKls） in clinical applications. TKIs combined with chemotherapy resulted in higher rates of complete remission （CR） and complete molecular remission （CMR） compared with chemotherapy alone. However, allogeneic stem cell transplantation （allo-SCT） has been considered the only potentially curative option once the patient achieves CR. There are still questions that remain unanswered regarding the use of TKis prior to or after alIo-SCT. Imatinib was the first TKI used for induction and maintenance therapy in combination with chemotherapy. What is its optimal dosage and how long should it be maintained＇？

关键词： Acute Lymphoblastic Leukemia Allogeneic Transplantation tyrosine kinase inhibitor

Phase I trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer

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Chinese Medical Journal 2011年第13期124卷 1933-1938页

作者： WANG Hart-ping ZHANG Li WANG Yin-xiang TAN Fen-lai XIA Ying REN Guan-jun HU Pei JIANG Ji WANG Meng-zhao XIAO Yi Department of Respiratory Medicine Peking Union Medical College HospitalPeking Union Medical College & Chinese Academy of MedicalSciences Beijing 100730 China Center of Clinical Pharmacology Peking Union Medical College HospitalPeking Union Medical College & Chinese Academy of MedicalSciences Beijing 100730 China Zhejiang Beta Pharma Inc. Hangzhou Zhejiang 100176 China

Background The preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the EGFR, block the EGFR related signal, thereby inhibit the growth of tumor cell. The objective of this study was to investigate the safety, tolerability and dose-related biologic effects of icotinib in patients with non-small cell lung cancer （NSCLC） in a Chinese patient population. Methods This was an open-label, phase I, dose escalation, safety/tolerability trial of oral icotinib （100 to 400 mg）, administered twice per day for 28-continuous-day cycles until disease progression or undue toxicity. Results Forty patients with stage IIIB （15%） or IV （85%） NSCLC were included in the study. They had mainly adenocarcinoma （85%）, with a performance status （PS） of 0 （45%） or 1 （55%） and less than half the patients （45%） had histories of smoking and all were pretreated by at least one regimen of chemotherapy. Patients were assigned to three dose levels of 150 mg b.i.d, 200 mg b.i.d, or 125 mg t.i.d. The follow-up periods ranged from 5 to 80 weeks. Adverse events were found in 35% patients, most of which were mild and reversible. The adverse events mainly occurred in the first 4 weeks and included rash （25%）, diarrhea, nausea and abdominal distention. One definite interstitial lung disease （ILD） was found in a patient in the dose of 200 mg b.i.d. According to an 8-week assessment, one （2.5%） patient receiving 150 mg gained complete response （CR） that persisted for 44 weeks, seven （17.50%） patients had partial remission （PR）, and 18 （45%） patients had stable disease （SD）. The objective response including CR＋PR was 20%. The median time of progression-free survival for the 40 patients was 20 weeks （range： 12 to 32 weeks）. The response was not affected by pathological type, history of smoking, or numbers of previous therapeutic regimens. No relationship between dose, r

关键词： icotinib epidermal growth factor receptor tyrosine kinase inhibitor tolerability safety

inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization

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International Journal of Ophthalmology(English edition) 2014年第2期7卷 220-225页

作者： Halil Ibrahim Onder Mesut Erdurmus Yasin Yücel Bucak Hüseyin Simavli Murat Oktay Ahmet Sahap Kukner Department of Ophthalmology Duzce University Medical Faculty Department of Ophthalmology Abant Izzet Baysal University Medical School Ophthalmology Clinic Izzet Baysal State Hospital Department of Pathology Duzce University Medical Faculty

AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were *** NV was induced by NaOH in the left eyes of each *** the establishment of alkali burn,the animals were randomized into five groups according to topical *** 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone *** the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging *** corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by ***:A statistically significant difference in the percent area of corneal NV was found among the groups(P0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(P<0.05).The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3,4 and 5 thanin Groups 1 and ***:Topical administration of regorafenib 1mg/mL is partly effective for preventing alkali-induced corneal NV in rats.

关键词： corneal neovascularization regorafenib tyrosine kinase inhibitor

Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses

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Cancer Drug Resistance 2018年第3期1卷 118-125页

作者： Natalia J.Gurule Lynn E.Heasley Department of Craniofacial Biology University of Colorado Anschutz Medical CampusAuroraCO 80045USA.

Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung *** kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage,but also a variety of adverse *** toxicities,hematological deficiencies,nausea,vomiting,diarrhea,and headache are among the most common,with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less *** normal epithelia,RTKs regulate tissue *** example,EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue *** studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell ***,blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this *** innate immune response within the tumor microenvironment(TME)involves increased antigen presentation and effector T cell recruitment that may participate in therapy *** TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for ***,early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events,especially pneumonitis,hepatitis,and pulmonary *** preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells,cancer cells,and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.

关键词： tyrosine kinase inhibitor receptor tyrosine kinase interferon inflammation tumor microenvironment epithelial tissue homeostasis

Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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Oncology Research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical Oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome tyrosine kinase inhibitor Gastrointestinal tumors miRNA

CARD11 serves as a therapeutic biomarker for the drug therapies of ccRCC

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BIOCELL 2024年第5期48卷 817-834页

作者： KAIWEN TIAN HANZHONG CHEN QIANQIAN WANG FENGLIAN JIANG CHUNXIANG FENG TENG LI XIAOYONG PU YANLIN TANG JIUMIN LIU Department of Urology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080China

Background:The incidence of clear cell renal cell carcinoma(ccRCC)is globally high;however,despite the introduction of innovative drug therapies,there remains a lack of effective biomarkers for evaluating treatment ***,Caspase recruiting domain-containing protein 11(CARD11)has garnered attention due to its significant association with tumor development and the immune ***:The expression of CARD11 mRNA and protein in ccRCC were analyzed by public database and *** focus of this study is on the epigenomic modifications of CARD11,its expression of ccRCC immunophenotype,and its correlation with response to immunotherapy and targeted ***,to investigate the mechanism of this molecule’s influence on different biological behaviors of cells,cell tests in vitro have been conducted to observe the impact of its expression ***:CARD11 expression was upregulated which may be mainly modified by body methylation and was correlated with poor prognosis in *** the tumor microenvironment of ccRCC,CARD11 expression was positively correlated with increased T lymphocyte infiltration and increased expression of inhibitory immune ***,ccRCC patients with high CARD11 expression had a better response to immunotherapy and targeted *** knockdown of CARD11 ultimately suppressed the proliferation,migration,and invasion capabilities of ccRCC cells while simultaneously enhancing tumor cell ***:We identified CARD11 as a novel therapeutic biomarker for immunotherapy and targeted therapy in ccRCC.

关键词： Clear cell renal cell carcinoma Tumor microenvironment CARD11 Immune checkpoint inhibitor tyrosine kinase inhibitor

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

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Frontiers of Medicine 2016年第4期10卷 383-388页

作者： Shuhang Wang Yongping Song Feifei Yan Delong Liu The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Peking University Cancer Hospital Beijing 100142 China Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University Zhengzhou 450008 China

The tyrosine kinase inhibitors （TKI） of the epidermal growth factor receptor （EGFR） are becoming the first line of therapy for advanced non-small cell lung cancer （NSCLC）. Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 （osimertinib; Tagrisso） is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

关键词： EGFR tyrosine kinase inhibitor AZD9291 EAI045

miR-30b and miR-30c expression predicted response to tyrosine kinase inhibitors as first line treatment in non-small cell lung cancer

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Chinese Medical Journal 2013年第23期126卷 4435-4439页

作者： GU Yan-fei ZHANG Hui SU Dan MO Min-li SONG Pan ZHANG Fang ZHANG Shu-cai Department of Oncology Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital Capital Medical University Beijing 101149 China Department of Pathology Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital Capital Medical University Beijing 101149 China School of Life Sciences Tsinghua University Beijing 100084 China Beijing ACCB Biotech Ltd. Beijing 100094 China Zhejiang Provincial Key Laboratory of Applied Enzymology Yangtze Delta Region Institute of Tsinghua University Jiaxing Zhejiang 314006 China Division of Life & Health Sciences Graduate School at ShenzhenTsinghua University Center for Biotech & Biomedicine

Background Aberrantly expressed microRNAs are a hallmark of cancer,and microRNA expression profiling is associated with tumor progression and response to chemotherapy,suggesting their potential application as prognostic and predictive *** role of microRNAs in lung cancer remains *** has been recently reported that epidermal growth factor receptor （EGFR） and hepatocyte growth factor receptor （MET） tyrosine kinase can regulate expression of specific microRNAs including miR-30b,miR-30c,miR-221,miR-222,miR-103 and miR-203,and induce tumorigenesis and gefitinib resistance in lung *** intend to study the role of miR-30b and miR-30c expression in predicting response to tyrosine kinase inhibitors （TKIs） in non-small cell lung cancer （NSCLC）.Methods We have therefore retrospectively examined expression of miR-30b miR-30c in 41 formalin fixed paraffin embedded tissue samples from NSCLC patients when TKIs were used as first line *** We found a significant correlation between expression of miR-30b and ***,miR-30b and miR-30c expression correlated with short-term ***-Meier analysis further revealed that the expression of miR-30b and miR-30c predicted progression free survival and the overall survival rate in the examined *** Our study identified miR-30b and miR-30c as useful prognostic predictors in NSCLC patients who underwent first line treatment with TKIs.

关键词： non-small cell lung cancer microRNA tyrosine kinase inhibitor epidermal growth factor receptor

A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy

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Bioactive Materials 2023年第9期27卷 337-347页

作者： Bin Xu Fanjun Zeng Jialong Deng Lintong Yao Shengbo Liu Hengliang Hou Yucheng Huang Hongyuan Zhu Shaowei Wu Qiaxuan Li Weijie Zhan Hongrui Qiu Huili Wang Yundong Li Xianzhu Yang Ziyang Cao Yu Zhang Haiyu Zhou Department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080PR China Department of General Practice Guangdong Provincial Geriatrics InstituteGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080PR China Department of Orthopedics Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080GuangdongChina The Second School of Clinical Medicine Southern Medical UniversityGuangzhou510515PR China Shantou University Medical College Shantou515063PR China Guangzhou University of Chinese Medicine Guangzhou510006PR China Guangzhou First People’s Hospital South China University of TechnologyGuangzhou510006PR China School of Biology and Biological Engineering South China University of TechnologyGuangzhou510006PR China School of Medicine South China University of TechnologyGuangzhou510006PR China School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International CampusGuangzhou511442PR China South China Sea Fisheries Research Institute Chinese Academy of Fishery SciencesKey Laboratory of South China Sea Fishery Resources Exploitation and UtilizationMinistry of Agriculture and Rural AffairsGuangzhou510300China

The abnormal activation of epidermal growth factor receptor(EGFR)drives the development of non-small cell lung cancer(NSCLC).The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR ***,free osimertinib administration exhibits an inadequate response in vivo,with only~3%patients demonstrating a complete clinical ***,we designed a biomimetic nanoparticle(CMNP^(@Osi))comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery,thereby supporting a dual-target strategy for enhancing osimertinib *** intravenous injection,CMNP^(@Osi)accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous *** is subsequently released into the cytoplasm,where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC ***,this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

关键词： Biomimetic nanoparticles Membrane targeting EGFR mutation tyrosine kinase inhibitor Intracellular drug delivery Clinical efficacy Non-small cell lung cancer