阿帕替尼联合曲妥珠单抗对胃癌细胞的协同增敏作用

目的观察阿帕替尼联合曲妥珠单抗杀伤胃癌NCI-N87细胞的协同增敏作用并探讨可能作用机制。方法CCK-8法检测空白对照组、曲妥珠单抗组(0.1、1、10μg/ml)、阿帕替尼组(1μmol/L)及曲妥珠单抗(0.1、1、10μg/ml)+阿帕替尼(1μmol/L)组对NCI-N87细胞的增殖抑制作用,流式细胞术检测NCI-N87细胞凋亡,Western blotting检测HER-2、VEGFR2、Bax、Bcl-2蛋白表达。结果CCK-8检测提示曲妥珠单抗、阿帕替尼能够抑制NCI-N87细胞增殖,在一定浓度范围内作用呈浓度依赖性和时间依赖性(P<0.01);q值计算提示曲妥珠单抗与阿帕替尼具有协同抑制NCI-N87细胞增殖的作用。流式细胞术检测显示联合组NCI-N87胃癌细胞凋亡较单药组明显升高(P<0.05),其中空白对照组、阿帕替尼组(1μmol/L)、曲妥珠单抗(0.1μg/ml)组及曲妥珠单抗(0.1μg/ml)+阿帕替尼(1μmol/L)组的凋亡率分别为(3.0±1.28)%、(5.8±1.63)%、(8.0±3.92)%和(21.6±6.85)%。曲妥珠单抗+阿帕替尼组与空白对照组、曲妥珠单抗及阿帕替尼单药组比较,HER-2蛋白表达显著下调(P<0.05);曲妥珠单抗+阿帕替尼组与空白对照组比较,Bcl-2蛋白表达、Bcl-2/Bax比值明显降低(P<0.01)。结论阿帕替尼联合曲妥珠单抗可能通过下调HER-2蛋白及调控凋亡相关蛋白Bcl-2、Bax的表达,协同抑制NCI-N87细胞增殖和促进细胞凋亡。     

阿帕替尼治疗晚期及术后复发肺肉瘤样癌的疗效分析

目的探索阿帕替尼治疗晚期及术后复发肺肉瘤样癌的疗效。方法收集2016年6月至2019年8月Ⅲ~Ⅳ期及术后复发的肺肉瘤样癌患者21例,口服阿帕替尼(250~425 mg/d)治疗,30 d为1个疗程,观察并分析疗效及评价安全性。结果21例患者中,完全缓解(CR)为0,部分缓解(PR)为14.3%(3例),稳定(SD)为33.3%(7例),疾病进展(PD)为52.4%(11例);客观反应率(ORR)为13.3%(3例),疾病控制率(DCR)为47.6%(10例)。中位总生存期(mOS)为4.6个月,中位无进展生存期(mPFS)为1.0个月。病灶≥6 cm(或≥5 cm)较<6 cm(或<5 cm)平均OS明显缩短,差异有统计学意义(P<0.05);术后分期Ⅰ~Ⅱ期较Ⅲ~Ⅳ期平均OS明显延长(P<0.05)。位于中央的病灶较周围的病灶平均OS明显缩短,差异有统计学意义(P<0.01)。性别、年龄(>60岁,≤60岁)、吸烟史(是/否)对疗效影响差异无统计学意义。常见不良反应包括高血压38.1%(8例)、蛋白尿23.8%(5例)、手足综合征28.6%(6例)、腹泻28.6(6例)、骨髓抑制38.1%(8例)。结论阿帕替尼治疗晚期及术后复发肺肉瘤样癌具有一定疗效,不良反应可控,病灶大小、位置及分期可能是疗效的独立影响因素。     

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27−32.91; 95% CI 3.64−6.22) and 14.70 (range, 0.27−32.91; 95% CI 0.27−43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p<0.05) and mOS (24.03 vs. 6.07 months, p<0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.     

First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy

Gastric carcinoma (GC) is a common gastrointestinal malignancy with high incidence and mortality worldwide, and most patients are diagnosed in the late stages of disease. Palliative chemotherapy provides a survival benefit for patients with inoperable advanced GC. However, elderly patients who are unable to tolerate chemotherapy had worse prognosis due to lack of effective treatment. Herein we reported a Chinese elderly GC patient using next generation sequencing (NGS)-based tumor DNA analysis. Valuable gene variants of vascular endothelial growth factor (VEGF) A gene amplification were detected. Additionally, a novel NOTCH1-BPHL fusion has been identified. He received antiangiogenic drug apatinib and showed both good clinical and radiographic response, but eventually died of non-cancer related cause, with progression free survival time (PFS) and overall survival time (OS) up to 9.53 months. This was the first GC case with apatinib usage as first-line treatment under the guidance of NGS gene profiling.     

Apatinib as an alternative therapy for advanced hepatocellular carcinoma

Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma(HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.     

Apatinib induces apoptosis of breast cancer cells by redistribution of Fas into lipid rafts

Apatinib, an oral anti-angiogenic agent, has been shown to have anti-cancer effects for several cancer cell types. However, little is known about the direct anti-tumor activity of apatinib for breast cancer cells. Herein, the direct effect of apatinib on breast cancer cells and its mechanism of action were assessed. Cell viability was measured with a Cell Counting Kit-8. Cell apoptosis was assessed by flow cytometry. The expression of caspase-8 and the cleavage of poly ADP ribose polymerase were assessed by Western blotting analysis. Lipid rafts and Fas distribution were determined by immunofluorescence microscopy. Apatinib suppressed breast cancer cell proliferation in a dose-dependent manner. Furthermore, apatinib enhanced the aggregation of lipid rafts and the redistribution of Fas into lipid rafts. Pretreatment with methyl-β-cyclodextrin, a cholesterol-sequestering agent, significantlyreversed Fas redistribution and apatinib-induced apoptosis.In conclusion, these results demonstrated that apatinib induced apoptosis of breast cancer cells partially through recruitment of Fas into lipid rafts.     

阿帕替尼治疗晚期乳腺癌20例

目的 研究阿帕替尼治疗晚期乳腺癌的临床疗效及预后。方法 2015年5月至2017年6月皖北煤电集团总医院及宿州市立医院经病理学确诊的44例乳腺癌病人中20例口服阿帕替尼,24例行姑息对症支持治疗,比较两组总生存期、无进展生存期、疗效及对口服阿帕替尼不良反应的观察。结果 阿帕替尼组病人的中位总生存期(14个月)及中位无进展生存期(11个月)均长于姑息治疗组(6个月,4个月),两组差异有统计学意义(Kaplan-Meier法,P<0.05);阿帕替尼组病人的疾病控制率(85%)远高于姑息治疗组(46%),两组差异有统计学意义(χ² =14.204,P=0.003);口服阿帕替尼治疗中,不良反应多为1[KG-*3]～2级,治疗过程中无因为不能耐受不良反应而停止阿帕替尼靶向治疗。结论 阿帕替尼治疗一线、二线及三线治疗失败的晚期乳腺癌有较好的临床疗效及生存获益,不良反应可控制,值得临床上广泛应用。     

阿帕替尼通过阻断VEGF通路增强胃癌放疗疗效

目的:探讨血管内皮生长因子(VEGF)受体2酪氨酸激酶抑制剂阿帕替尼对胃癌细胞株SGC-7901放疗疗效的影响及其可能机制。方法:试验设对照组、阿帕替尼组、单纯放疗组与联合组。CCK-8法检测细胞活力,流式细胞术分析细胞凋亡比例与细胞周期,免疫荧光染色观察细胞核内γ-H_2AX的表达,Western blot法检测细胞增殖和凋亡相关蛋白。结果:与阿帕替尼组或单纯放疗组相比,阿帕替尼联合X射线显著降低SGC-7901细胞的生长活力(P0.01),增殖相关蛋白p-PLCγ1和p-ERK1/2的水平下降;细胞凋亡比例明显升高(P0.01),凋亡相关蛋白PARP、cleaved caspase-9和cleaved caspase-3蛋白水平上调,Bcl-2表达下降;SGC-7901细胞核内γ-H_2AX焦点淬灭延迟,表明阿帕替尼干扰放射线诱导的DNA双链断裂的修复;SGC-7901 G_2期细胞比例显著增高(P0.01)。结论:阿帕替尼通过阻断VEGF通路增加胃癌细胞对X射线照射的敏感性。     

Apatinib Plus Chemotherapy Shows Clinical Activity in Advanced NSCLC: A Retrospective Study

Apatinib is an oral TKI with antiangiogenic properties, and it is currently approved for the treatment of advanced gastric cancer in China. This agent has also been tested in other human solid tumors, including non-small cell lung cancer (NSCLC). Since the combination of chemotherapy and an antiangiogenic agent has been shown to be a feasible strategy in NSCLC, it is conceivable that a similar approach combining apatinib with chemotherapy may yield clinical activity. With this in mind, we investigated the efficiency of apatinib in combination with pemetrexed or docetaxel in advanced NSCLC. We treated a total of 20 patients with metastatic NSCLC adenocarcinoma with apatinib in combination with either pemetrexed or docetaxel from January 2016 to March 2017. The performance status of these patients was 0 or 1. All of these patients had been previously treated with two or more lines of treatment and had experienced disease progression prior to study enrollment. The overall objective response rate (ORR) was 30%, with 6 patients who had partial response (PR), 10 patients who had stable disease (SD), and 4 patients who had progressive disease (PD). The main adverse events were skin rash, hypertension, palmar–plantar erythrodysesthesia syndrome, diarrhea, and fatigue. Nearly 30% of patients required interruption of treatment as a result of toxicity. Our study demonstrated that apatinib combined with systemic cytotoxic chemotherapy has clinical efficacy in patients with disease-refractory metastatic NSCLC and provides evidence for further studies investigating apatinib-based combination regimens.     

Efficacy and safety of apatinib treatment for advanced progressive head and neck squamous cell carcinoma北大核心CSCD

Objective: To evaluate the efficacy and safety of apatinib combined with individualized chemoradiotherapy for advanced progressive head and neck squamous cell carcinoma (HNSCC). Methods: A retrospectively analysis was performed by using the clinical data of 44 patients with advanced progressive HNSCC who were admitted in the First Affiliated Hospital of Zhengzhou University from 2017 to 2018. All patients were treated with apatinib 500 mg once a day until the disease progressed. During the treatment period, if the patient was intolerant to the toxicity of the drug, the dose of apatinib was reduced to 250 mg once a day. At the same time, all patients were treated with individualized radiotherapy or chemotherapy. Intensity modulated radiation therapy (IMRT) was used for the recurrent or metastatic lesions. The chemotherapy regimen was synchronous platinum + fluorouracil or paclitaxel + platinum or paclitaxel + fluorouracil + platinum. The clinical efficacy and adverse reactions were observed. Results: Among 44 patients with advanced progressive HNSCC, there was no complete remission, 9 (20.45%) patients with partial remission, 22 (50.00%) patients with stable disease, and 13 (29.55%) patients with disease progression. The objective response rate was 20.45%, the disease control rate was 70.45%, and the median progression-free time was 5 months (95% confidence interval: 3.26-6.74). All patients were well tolerated to apatinib without any grade 3 or 4 adverse events. The most common adverse reactions were oral ulcers in 29 (65.91%) cases, liver function abnormalities in 16 (36.36%) cases, and headache in 13 (29.55%) cases. Conclusion: The application of apatinib combind with individualized radiotherapy or chemotherapy for the patients with advanced progressive HNSCC is feasible, and its safety is controllable. © 2019 by TUMOR All rights reserved.