修回日期: 2016-05-24
接受日期: 2016-06-03
在线出版日期: 2016-11-18
胃癌细胞药物抵抗的存在是导致治疗失败的重要原因. 胃癌对化疗药物、靶向药物都可以产生抵抗, 导致药物作用效果降低. 胃癌耐药的机制已研究多年并已取得很多研究成果, 但迄今没有有效的药物能用于临床对胃癌的耐药特性进行逆转. 因此在胃癌化疗药物及靶向药物耐药领域进行深入研究并实现胃癌耐药的有效逆转可能改善胃癌的预后, 有重要的现实意义. 为引起本领域研究者的重视, 本文对胃癌化疗耐药、靶向治疗耐药的机制进行了综述. 然后对胃癌耐药的研究现状进行了总结, 并对今后发展的方向进行了预测.
核心提要: 多种相关分子参与了胃癌对化疗药物及靶向药物的耐药形成, 深入了解胃癌耐药形成的机制对于改善胃癌药物治疗效果, 从而改善胃癌整体预后有重要意义.
引文著录: 李勇, 檀碧波. 胃癌耐药的研究现状及趋势. 世界华人消化杂志 2016; 24(32): 4330-4336
Revised: May 24, 2016
Accepted: June 3, 2016
Published online: November 18, 2016
Drug resistance of gastric cancer cells is one of the main reasons that lead to failure of chemotherapy in gastric cancer. Gastric cancer cells can be resistant to chemotherapeutic drugs and targeted drugs, which leads to poor therapeutic effects. Although the mechanisms of drug resistance of gastric cancer cells have long been investigated, no effective drug that can reverse the drug resistance of gastric cancer cells has been found. Therefore, it is important to reverse the drug resistance of gastric cancer cells to improve the prognosis of gastric cancer. In this paper, we review the mechanisms of drug resistance of gastric cancer cells to chemotherapeutic drugs and targeted drugs, summarize current situation for research of drug resistance of gastric cancer cells, and discuss the future development direction in this field.
- Citation: Li Y, Tan BB. Current situation and trend of research for drug resistance in gastric cancer. Shijie Huaren Xiaohua Zazhi 2016; 24(32): 4330-4336
- URL: https://www.wjgnet.com/1009-3079/full/v24/i32/4330.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i32.4330
胃癌是我国高发的恶性肿瘤, 进展快、预后差, 对人民健康危害极大. 虽经多年进展, 胃癌的治疗效果一直不能令人满意. 胃癌的治疗是综合治疗, 包括手术、化疗、放疗、生物治疗及近年来已逐渐在临床推广的靶向药物治疗. 由于胃癌患者就诊时多已处于进展期, 仅依靠手术很难达到根治. 因此, 其他治疗措施在胃癌综合治疗中还是有重要意义的. 这些治疗措施中最主要的是化疗, 在胃癌治疗中是除了手术之外最重要的措施, 但由于胃癌细胞对化疗药物存在多药耐药性(multiple drug resistance, MDR), 因而化疗的有效率并不理想. 近年来随着靶向药物不断应用于肿瘤治疗, 以HER-2等药物靶点检测结果为依据对胃癌进行靶向治疗的工作已在临床开始应用. 在应用过程中, 学者们同样发现靶向药物在胃癌治疗中也存在明显的耐药问题. 寻找有效措施逆转胃癌对化疗药物及靶向药物的耐药性对改善胃癌治疗效果有重要的意义. 本文根据近年来的研究报道, 对胃癌耐药的机制及相关逆转措施进行了总结及评价, 旨在引起研究者对胃癌耐药的关注并积极参与其中寻找解决问题的对策.
有关胃癌对化疗药物耐药形成的机制研究[1-3]已开展多年, 对部分耐药分子如P-糖蛋白(P-glycoprotein, P-gp)[4]、多药耐药蛋白-1(multidrug resistance protein-1, MRP-1)[5]、肺耐药蛋白[6]等的作用机制研究已取得很大进展, 但这些分子在胃癌化疗药物的耐药形成中发挥的作用是有限的. 胃癌常用的化疗药物为铂类药物、氟尿嘧啶类药物及紫杉类药物, 这些药物的耐药机制更为复杂, 而目前机制较为明确的耐药分子其相关药物多为蒽环类药物、生物碱类和鬼臼碱类药物, 这些药物在胃癌化疗中并不常用, 因而深入探讨铂类药物、氟尿嘧啶类药物及紫杉类药物的耐药机制对胃癌化疗更具有现实意义.
胃癌化疗常用的铂类化疗药物有顺铂(Cisplatin, CDDP)及奥沙利铂(Oxaliplatin, L-OHP), 这些药物为胃癌化疗的一线药物, 属于胃癌化疗的主要药物. 铂类药物主要作用于癌细胞的DNA, 导致DNA的功能发生障碍, 从而引起细胞死亡. 铂类药物的作用主要是诱导肿瘤细胞凋亡, 与凋亡有关的基因在铂类药物的作用过程中发挥了重要作用, 这些基因的表达表达变化在铂类药物耐药形成中发挥了重要作用. 在CDDP、L-OHP的作用机制中, 肿瘤细胞对药物诱导凋亡的效果会逐渐产生耐受, 因而出现MDR. 在此过程中, 已发现B淋巴细胞瘤-2(B-cell lymphoma-2, Bcl-2)、Bcl-2相关x蛋白(bcl-associated x protein, Bax)、生存素、凋亡抑制蛋白家族等均参与CDDP、L-OHP的耐药形成[7,8], 类似的基因相关报道目前已较为多见. 本课题组前期研究[9]发现锌指蛋白139(zinc finger protein 139, ZNF139)在胃癌耐药形成中发挥了重要作用. 近年来随着微小RNA(microRNA, miRNA)研究进展, 已发现miRNA-101[10]、miRNA-103/107[11]、miRNA-503[12]、miRNA-1271[13]、miRNA27a[14]等均在胃癌铂类药物耐药形成中发挥了作用. Li等[10]研究发现血管内皮生长因子-C(vascular endothelial growth factor-C, VEGF-C)是受miRNA-101直接调控的靶基因, 当miRNA-101表达增高时VEGF-C表达明显受到抑制, 此时CDDP作用后引起胃癌细胞株SGC7901的凋亡增多, 增强了CDDP的效果; 反之当miRNA-101表达受到抑制时, CDDP导致胃癌细胞株SGC7901的凋亡也明显减弱, 说明miRNA-101参与了胃癌细胞对CDDP得的耐药形成. 其他研究也得到了类似结果. Hong等[15]还对参与胃肠道癌的miRNA进行了总结综述. miRNA由于分子量小, 功能明确, 易于作为治疗的靶点而受到了关注. 最近受到关注的长链非编码RNA(Long non-coding RNA, lncRNA)也被证实与胃癌对铂类药物的耐药形成有关. lncRNA指不能翻译为蛋白的功能性RNA分子, 其长度超过200个核苷酸, 在多种生命活动中发挥了重要作用[16]. 研究表明lncRNA在胃癌铂类药物耐药过程中也发挥了重要作用. 研究已发现lncRNA PVT1[17]、AK022798[18]均参与了胃癌铂类药物耐药形成. Zhang等[17]的研究发现lncRNA PVT1在对CDDP存在抵抗的患者胃癌组织中及胃癌CDDP耐药细胞株BGC823/DDP和SGC7901/DDP中表达增高, 抑制lncRNA PVT1表达后CDDP对肿瘤细胞的杀伤作用明显增强. 这些研究为胃癌对铂类药物耐药形成的机制提供了新的思路及方向, 可能为胃癌铂类药物耐药逆转提供新的治疗靶点.
氟尿嘧啶类药物是胃癌化疗的另一类一线药物, 其基本药物为5-氟尿嘧啶(5-fluorouracil, 5-Fu). 5-Fu在体内的代谢产物可模拟尿嘧啶核苷酸, 影响蛋白质合成; 也可抑制胸苷酸合成酶, 阻断肿瘤细胞DNA复制而发挥作用. 自从20世纪50年代投入临床应用以来, 5-Fu一直是胃癌化疗最常用药物[19,20]. 在应用过程中, 已有多种同类的改进药物应用于胃癌患者的治疗, 这些药物包括替加氟、卡培他滨、替吉奥(S-1)等[21,22]. 这些药物延长了作用时间, 减轻了不良反应, 但基本原理与5-Fu是类似的. 氟尿嘧啶类药物在胃癌的治疗应用过程中同样也出现了明显的耐药现象. 关于氟尿嘧啶类药物耐药形成的机制, 目前发现胃癌细胞对氟尿嘧啶产生耐药的机制与MDR-1/P-gp、MRP-1、Bcl-2/Bax等基因有关[9], 还与环氧合酶-2[23]、p53通路[24]等多种基因的参与有关. 研究也发现胃癌细胞对氟尿嘧啶的耐药形成中miRNA、lncRNA同样发挥了作用. Xiong等[25]研究发现miRNA-197可逆转胃癌细胞株SGC7901对氟尿嘧啶的耐药性. Smid等[26]发现miRNA-150、miRNA-192、miRNA-224、miRNA-375、miRNA-342-3p等均与胃癌氟尿嘧啶类药物化疗效果有关. lncRNA HOTAIR、LEIGC被证实与胃癌氟尿嘧啶类药物化疗效果有关[27,28]. 这些研究表明, 胃癌对氟尿嘧啶类药物产生耐药的机制与铂类药物的耐药形成既有联系又有区别. 联系在于一些相同的基因、miRNA、lncRNA在胃癌对氟尿嘧啶类药物和铂类药物的耐药形成中均发挥了作用; 区别在于铂类药物的耐药与凋亡相关的通路关系密切, 而氟尿嘧啶类药物耐药形成的机制则更为复杂, 与经典耐药途径、p53通路、凋亡相关途径均有关系. 由于这两类药物常在同一化疗方案中出现, 因此寻找共同的耐药机制有可能对改善化疗效果有益.
紫杉类药物用于胃癌化疗的时间较短, 目前主要用于分期较晚的胃癌化疗[29]. 紫杉类药物杀伤癌细胞的主要机制在于影响细胞的有丝分裂, 从而对细胞的增殖能力产生抑制作用, 还可促进肿瘤细胞凋亡[30]. 紫杉类药物主要耐药相关机制已有一些报道. 有研究[31]发现β-tubulin、MAPT、生存素参与了胃癌细胞对紫杉醇的耐药形成; 还有研究[32]表明阻断VEGFR-1、VEGFR-2可以改善胃癌对紫杉醇的敏感性. 同样miRNA、lncRNA在胃癌对紫杉类药物的耐药形成中发挥了作用. 研究[14,33-35]发现miRNA27a、miRNA21、miRNA23a、miRNA-34c-5p都在胃癌紫杉耐药中发挥了作用, 可能成为逆转胃癌紫杉耐药的靶点. 对lncRNA的研究[36]表明, PVT1与胃癌紫杉醇耐药有关, 但相关研究还不多见, 具体机制也有待深入研究.
近年来靶向药物已用于临床胃癌的治疗并取得了一定效果. 用于胃癌治疗的靶向药物主要有以下几类: 针对人类表皮生长因子受体的靶向药物, 这类药物针对Her-2受体发挥作用, 以曲妥珠单抗(赫赛汀)为代表[41]; 抗表皮生长因子受体靶向治疗的药物, 此类药物以西妥昔单抗为代表[42]; 针对血管内皮生长因子(vascular endothelial growth factor, VEGF)的靶向药物, 以贝伐单抗为代表[43]; 针对VEGF的新型药物还有阿帕替尼[44]. 研究表明, 这些药物应用于晚期胃癌患者, 对延长生存期有一定效果. 另外还有针对c-MET靶向治疗药物(如Rilotumumab)[45]、针对mTOR通路的靶向药物(如依维莫司)[46], 但从临床实际来看, 这些药物的预期效果并不令人满意. 另外新近研究表明, 在此类药物的应用中同样出现了耐药现象. 如Yang等[47]研究发现胃癌细胞对曲妥珠单抗的耐药形成与IL-6/STAT3/Jagged-1/Notch正反馈回路的激活有关, 研究者认为应用Notch或STAT3抑制剂有可能延缓胃癌细胞对曲妥珠单抗的耐药形成. Zhang等[48]研究发现PTEN缺陷可作为进展期胃癌对曲妥珠单抗耐药的预测指标. 但目前这些研究基本都处于基础研究阶段, 相关成果应用于临床还有大量工作需要完成.
胃癌对药物的耐药形成给胃癌的综合治疗带来了很大困难, 严重影响了胃癌的治疗效果. 有关胃癌对化疗药物耐药的研究已开展多年, 一直是胃癌研究中的热点领域. 胃癌靶向药物耐药的研究在近年来也已受到关注. 关于胃癌耐药的机制研究已较为深入, 已发现许多基因及信号通路参与胃癌耐药性的形成, 且已找到一些药物在体外研究及体内实验中都取得了较好的逆转耐药的效果, 如本课题组研究发现粉防己碱能通过抑制ZNF139下调MDR-1、MRP-1的表达, 从而逆转胃癌耐药细胞MDR表型[49]. 其他研究发现苦参碱[50]、白藜芦醇[51]等也对逆转胃癌的耐药有效. 但迄今还没有在临床应用效果确切的药物对胃癌的耐药性进行逆转. 我国传统的中药及提取物在胃癌耐药性逆转中被证实具有一定效果, 中药用于胃癌耐药逆转已受到关注. 但这方面的研究也存在临床效果不确切的问题, 而且中药成分繁多, 作用机制复杂, 因而距临床大规模推广仍有许多工作需要完成. 由于种种困难存在, 胃癌的综合治疗效果并没有得到显著改善, 胃癌仍是威胁我国人民健康的主要疾病之一.
从目前胃癌预防及治疗的综合措施来看, 由于我国胃镜检查还不普及, 早期胃癌就诊率一直在总患者数的10%左右, 进展期胃癌达到90%[52]. 胃癌的手术方式及手术设备在近年来已有很大进步, 切除原发肿瘤已不再是胃癌手术的障碍. 但由于大多胃癌在较早的阶段已有转移存在, 手术很难达到彻底根治, 故围手术期药物的应用仍具有重要的意义. 因而在胃癌化疗药物及靶向药物耐药领域进行深入研究并实现胃癌耐药的有效逆转可能改善胃癌的预后, 有重要的现实意义.
对于胃癌耐药的逆转大多研究关注于化疗药物的耐药逆转, 迄今已有不少研究成果, 有一些药物已用于临床, 但其效果还不完全肯定. 如韩晓鹏等[53]应用塞来昔布联合FOL-FOX4方案治疗胃癌根治术后患者, 认为效果较单用化疗方案好, 能提高有效率, 且有助于减少复发转移. 但该研究为单中心研究, 入组患者较少, 具体的情况还有待证实. 胃癌靶向药物的耐药是近年来新近发现的现象, 对这些药物的耐药研究还不充分. 中医药对胃癌耐药的影响也已受到关注, 一些药物已被证实对胃癌耐药表型逆转有效. 但实际用于临床对于胃癌耐药逆转有效的药物迄今还没有大规模应用. 关于胃癌靶向药物耐药是近年来新出现的问题, 机制研究还不完善, 对耐药逆转的研究也不够深入. 中医药在包括胃癌在内的许多肿瘤的综合治疗中发挥了重要作用. 中医药治疗胃癌的重要机制在于中药对于胃癌细胞的耐药特征有良好的效果. 如已经发现人参皂甙可以通过调控一些与凋亡、耐药均有关的基因而促进胃癌细胞凋亡[54,55], 因而推测人参皂甙对逆转胃癌耐药有效, 但具体情况如何还有待大规模临床研究证实.
胃癌耐药是治疗中存在的较为棘手的问题, 其机制复杂, 相关研究是本领域的热点. 由于一直没有突破性进展, 所以研究仍在进展中. 但胃癌耐药的逆转对该病的综合治疗效果改善有重要意义, 因此深入研究胃癌耐药机制及逆转措施有重大的临床价值.
胃癌对化疗药物、靶向药物都可以产生抵抗, 这是胃癌治疗效果不理想的重要原因. 故本文对胃癌化疗耐药、靶向治疗耐药的机制进行了综述. 然后对胃癌耐药的研究现状进行了总结, 并对今后发展的方向进行了预测.
胃癌细胞对化疗药物或靶向药物的耐药形成是肿瘤复发转移的重要原因, 而目前还没有有效的措施能预防或逆转胃癌耐药. 因此, 探讨胃癌耐药形成的机制并寻找新药用于耐药逆转具有重要临床意义.
本文除了探讨常用化疗药物的耐药形成外, 还对近年来广受关注的靶向药物的耐药形成进行了分析; 在分析耐药形成机制时, 除了分析了耐药相关基因的作用外, 还对miRNA、lncRNA在胃癌耐药形成中的作用进行了分析. 这两点在其他文献中不多见.
本文对胃癌耐药形成的机制进行了较为广泛的分析和总结, 使相关领域的医师对胃癌耐药的现状能有较为全面的认识, 从而为临床应用提供一定理论依据.
多药耐药(MDR): MDR是指肿瘤细胞对一种抗肿瘤药产生耐药性的同时, 对其他结构不同、作用靶点相异的抗肿瘤药也产生交叉性耐药的现象. MDR包括原发性(先天性)耐药和继发性耐药.
李正荣, 副主任医师, 副教授, 南昌大学附属第一医院胃肠外科(普六病区)
本文论述较全面, 具有一定价值.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 河北省
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| 1. | Marin JJ, Al-Abdulla R, Lozano E, Briz O, Bujanda L, Banales JM, Macias RI. Mechanisms of Resistance to Chemotherapy in Gastric Cancer. Anticancer Agents Med Chem. 2016;16:318-334. [PubMed] [DOI] |
| 2. | Kuo HY, Yeh KH. Molecular-targeted therapy for chemotherapy-refractory gastric cancer: a case report and literature review. Anticancer Res. 2014;34:3695-3699. [PubMed] |
| 3. | Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, Fanetti G, Biondani P, Pellegrinelli A, Bossi I. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013;33:1257-1266. [PubMed] |
| 4. | Rocco A, Compare D, Liguori E, Cianflone A, Pirozzi G, Tirino V, Bertoni A, Santoriello M, Garbi C, D'Armiento M. MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells. Lab Invest. 2012;92:1407-1418. [PubMed] [DOI] |
| 5. | Ge J, Chen Z, Huang J, Chen J, Yuan W, Deng Z, Chen Z. Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer. PLoS One. 2014;9:e110293. [PubMed] [DOI] |
| 6. | Zhang KG, Qin CY, Wang HQ, Wang JX, Wang QM. The effect of TRAIL on the expression of multidrug resistant genes MDR1, LRP and GST-π in drug-resistant gastric cancer cell SGC7901/VCR. Hepatogastroenterology. 2012;59:2672-2676. [PubMed] [DOI] |
| 7. | Li Y, Tan BB, Zhao Q, Fan LQ, Liu Y, Hao YJ, Zhao XF. Tumor chemosensitivity is correlated with expression of multidrug resistance associated factors in variously differentiated gastric carcinoma tissues. Hepatogastroenterology. 2013;60:213-216. [PubMed] |
| 8. | Tan B, Li Y, Zhao Q, Fan L, Liu Y, Wang D, Zhao X. Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway. Cancer Gene Ther. 2014;21:526-531. [PubMed] [DOI] |
| 9. | Li Y, Tan BB, Zhao Q, Fan LQ, Liu Y, Wang D. Regulatory mechanism of ZNF139 in multi-drug resistance of gastric cancer cells. Mol Biol Rep. 2014;41:3603-3610. [PubMed] [DOI] |
| 10. | Li G, Yang F, Gu S, Li Z, Xue M. MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C. Mol Med Rep. 2016;13:572-578. [PubMed] [DOI] |
| 11. | Zhang Y, Qu X, Li C, Fan Y, Che X, Wang X, Cai Y, Hu X, Liu Y. miR-103/107 modulates multidrug resistance in human gastric carcinoma by downregulating Cav-1. Tumour Biol. 2015;36:2277-2285. [PubMed] [DOI] |
| 12. | Wang T, Ge G, Ding Y, Zhou X, Huang Z, Zhu W, Shu Y, Liu P. MiR-503 regulates cisplatin resistance of human gastric cancer cell lines by targeting IGF1R and BCL2. Chin Med J (Engl). 2014;127:2357-2362. [PubMed] |
| 13. | Yang M, Shan X, Zhou X, Qiu T, Zhu W, Ding Y, Shu Y, Liu P. miR-1271 regulates cisplatin resistance of human gastric cancer cell lines by targeting IGF1R, IRS1, mTOR, and BCL2. Anticancer Agents Med Chem. 2014;14:884-891. [PubMed] [DOI] |
| 14. | Huang D, Wang H, Liu R, Li H, Ge S, Bai M, Deng T, Yao G, Ba Y. miRNA27a is a biomarker for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer. J Cell Biochem. 2014;115:549-556. [PubMed] [DOI] |
| 15. | Hong L, Han Y, Yang J, Zhang H, Zhao Q, Wu K, Fan D. MicroRNAs in gastrointestinal cancer: prognostic significance and potential role in chemoresistance. Expert Opin Biol Ther. 2014;14:1103-1111. [PubMed] [DOI] |
| 16. | Li J, Meng H, Bai Y, Wang K. Regulation of lncRNA and Its Role in Cancer Metastasis. Oncol Res. 2016;23:205-217. [PubMed] [DOI] |
| 17. | Zhang XW, Bu P, Liu L, Zhang XZ, Li J. Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun. 2015;462:227-232. [PubMed] [DOI] |
| 18. | Hang Q, Sun R, Jiang C, Li Y. Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs. 2015;26:632-640. [PubMed] [DOI] |
| 19. | Pandey K, Dubey RS, Prasad BB. A Critical Review on Clinical Application of Separation Techniques for Selective Recognition of Uracil and 5-Fluorouracil. Indian J Clin Biochem. 2016;31:3-12. [PubMed] [DOI] |
| 20. | Wang WB, Yang Y, Zhao YP, Zhang TP, Liao Q, Shu H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World J Gastroenterol. 2014;20:15682-15690. [PubMed] [DOI] |
| 21. | Hirao A, Oiso N, Tsurutani J, Kimura M, Watatani M, Nakagawa K, Kawada A. Transient effectiveness of an oral 5-Fluorouracil derivative, s-1, for epirubicin, cyclophosphamide and Paclitaxel refractory skin metastases from possible occult breast cancer in a male. Case Rep Dermatol. 2011;3:42-48. [PubMed] [DOI] |
| 22. | Sato Y, Fujiwara T, Mine T, Shomura H, Homma S, Maeda Y, Tokunaga N, Ikeda Y, Ishihara Y, Yamada A. Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients. Cancer Sci. 2007;98:1113-1119. [PubMed] [DOI] |
| 23. | Qiu ZQ, Qiu ZR. Sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 expression. Asian Pac J Cancer Prev. 2015;16:3447-3450. [PubMed] [DOI] |
| 24. | Endo F, Nishizuka SS, Kume K, Ishida K, Katagiri H, Ishida K, Sato K, Iwaya T, Koeda K, Wakabayashi G. A compensatory role of NF-κB to p53 in response to 5-FU-based chemotherapy for gastric cancer cell lines. PLoS One. 2014;9:e90155. [PubMed] [DOI] |
| 25. | Xiong HL, Zhou SW, Sun AH, He Y, Li J, Yuan X. MicroRNA197 reverses the drug resistance of fluorouracilinduced SGC7901 cells by targeting mitogenactivated protein kinase 1. Mol Med Rep. 2015;12:5019-5025. [PubMed] [DOI] |
| 26. | Smid D, Kulda V, Srbecka K, Kubackova D, Dolezal J, Daum O, Kucera R, Topolcan O, Treska V, Skalicky T. Tissue microRNAs as predictive markers for gastric cancer patients undergoing palliative chemotherapy. Int J Oncol. 2016;48:2693-2703. [PubMed] [DOI] |
| 27. | Zhao W, Dong S, Duan B, Chen P, Shi L, Gao H, Qi H. HOTAIR is a predictive and prognostic biomarker for patients with advanced gastric adenocarcinoma receiving fluorouracil and platinum combination chemotherapy. Am J Transl Res. 2015;7:1295-1302. [PubMed] |
| 28. | Han Y, Ye J, Wu D, Wu P, Chen Z, Chen J, Gao S, Huang J. LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition. BMC Cancer. 2014;14:932. [PubMed] [DOI] |
| 29. | Izuishi K, Mori H. Recent Strategies for Treating Stage IV Gastric Cancer: Roles of Palliative Gastrectomy, Chemotherapy, and Radiotherapy. J Gastrointestin Liver Dis. 2016;25:87-94. [PubMed] [DOI] |
| 30. | Sakamoto J, Matsui T, Kodera Y. Paclitaxel chemotherapy for the treatment of gastric cancer. Gastric Cancer. 2009;12:69-78. [PubMed] [DOI] |
| 31. | He W, Zhang D, Jiang J, Liu P, Wu C. The relationships between the chemosensitivity of human gastric cancer to paclitaxel and the expressions of class III β-tubulin, MAPT, and survivin. Med Oncol. 2014;31:950. [PubMed] [DOI] |
| 32. | Hwang JE, Lee JH, Park MR, Kim DE, Bae WK, Shim HJ, Cho SH, Chung IJ. Blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in gastric cancer cells. Yonsei Med J. 2013;54:374-380. [PubMed] [DOI] |
| 33. | Jin B, Liu Y, Wang H. Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel. Cell Biochem Biophys. 2015;72:275-282. [PubMed] [DOI] |
| 34. | Liu X, Ru J, Zhang J, Zhu LH, Liu M, Li X, Tang H. miR-23a targets interferon regulatory factor 1 and modulates cellular proliferation and paclitaxel-induced apoptosis in gastric adenocarcinoma cells. PLoS One. 2013;8:e64707. [PubMed] [DOI] |
| 35. | Wu H, Huang M, Lu M, Zhu W, Shu Y, Cao P, Liu P. Regulation of microtubule-associated protein tau (MAPT) by miR-34c-5p determines the chemosensitivity of gastric cancer to paclitaxel. Cancer Chemother Pharmacol. 2013;71:1159-1171. [PubMed] [DOI] |
| 36. | Ding J, Li D, Gong M, Wang J, Huang X, Wu T, Wang C. Expression and clinical significance of the long non-coding RNA PVT1 in human gastric cancer. Onco Targets Ther. 2014;7:1625-1630. [PubMed] [DOI] |
| 37. | Teker F, Yilmaz B, Kemal Y, Kut E, Yucel I. Efficacy and safety of docetaxel or epirubicin, combined with cisplatin and fluorouracil (DCF and ECF), regimens as first line chemotherapy for advanced gastric cancer: a retrospective analysis from Turkey. Asian Pac J Cancer Prev. 2014;15:6727-6732. [PubMed] [DOI] |
| 38. | Wang W, Huang J, Tao Y, Lyu X, Yang L, Wu D, Tian Y. Phase II and UGT1A1 Polymorphism Study of Two Different Irinotecan Dosages Combined with Cisplatin as First-Line Therapy for Advanced Gastric Cancer. Chemotherapy. 2016;61:197-203. [PubMed] [DOI] |
| 39. | Kang YK, Chang HM, Yook JH, Ryu MH, Park I, Min YJ, Zang DY, Kim GY, Yang DH, Jang SJ. Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201). Br J Cancer. 2013;108:1245-1251. [PubMed] [DOI] |
| 40. | Shulman K, Haim N, Wollner M, Bernstein Z, Abdah-Bortnyak R, Bar-Sela G. Postoperative chemotherapy in gastric cancer, consisting of etoposide, doxorubicin and cisplatin, followed by radiotherapy with concomitant cisplatin: A feasibility study. Oncol Lett. 2012;3:1154-1158. [PubMed] |
| 41. | Gong J, Liu T, Fan Q, Bai L, Bi F, Qin S, Wang J, Xu N, Cheng Y, Bai Y. Optimal regimen of trastuzumab in combination with oxaliplatin/capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phase II trial. BMC Cancer. 2016;16:68. [PubMed] [DOI] |
| 42. | Shi M, Ji J, Wu J, Ma T, Liu Y, Zhou CF, Su Y, Ye ZB, Zhang J, Zhu ZG. Cetuximab combined with FOLFOX4 as the first-line treatment for advanced gastric cancer: report of 25 cases from a single institution. Hepatogastroenterology. 2012;59:1054-1058. [PubMed] [DOI] |
| 43. | Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-3976. [PubMed] [DOI] |
| 44. | Geng R, Li J. Apatinib for the treatment of gastric cancer. Expert Opin Pharmacother. 2015;16:117-122. [PubMed] [DOI] |
| 45. | Doshi S, Gisleskog PO, Zhang Y, Zhu M, Oliner KS, Loh E, Perez Ruixo JJ. Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer. Clin Cancer Res. 2015;21:2453-2461. [PubMed] [DOI] |
| 46. | Shen YC, Li CP, Yen CJ, Hsu C, Lin YL, Lin ZZ, Chen LT, Su WC, Chao Y, Yeh KH. Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer. Oncology. 2014;87:104-113. [PubMed] [DOI] |
| 47. | Yang Z, Guo L, Liu D, Sun L, Chen H, Deng Q, Liu Y, Yu M, Ma Y, Guo N. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6:5072-5087. [PubMed] [DOI] |
| 48. | Zhang X, Park JS, Park KH, Kim KH, Jung M, Chung HC, Rha SY, Kim HS. PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer. Oncology. 2015;88:76-85. [PubMed] [DOI] |
| 49. | 李 勇, 赵 群, 檀 碧波, 范 立侨, 刘 庆伟, 焦 志凯, 赵 雪峰, 郝 英杰. 粉防己碱对人胃癌耐药细胞锌指蛋白139、多药耐药基因表达的影响. 中国中西医结合杂志. 2014;34:66-70. |
| 50. | 李 海龙, 陈 兆峰, 刘 敏, 杨 雅丽, 王 晶, 吴 红彦. 苦参碱对胃癌SGC7901/DDP细胞耐药相关miRNA表达的影响和靶点分析. 中国老年学杂志. 2015;35:4746-4748. |
| 52. | Li Y, Zhao Q, Fan LQ, Tan BB, Zhang ZD, Liu Y. Analysis of lymph node dissection range-related factors for early gastric cancer operation. Hepatogastroenterology. 2013;60:971-974. [PubMed] [DOI] |
| 53. | 韩 晓鹏, 刘 宏斌, 李 洪涛, 朱 万坤, 苏 琳, 周 海存. 塞来昔布联合化疗对腹腔镜胃癌根治术患者的临床疗效. 中国现代普通外科进展. 2013;16:789-793. |
| 54. | Kim BJ, Nah SY, Jeon JH, So I, Kim SJ. Transient receptor potential melastatin 7 channels are involved in ginsenoside Rg3-induced apoptosis in gastric cancer cells. Basic Clin Pharmacol Toxicol. 2011;109:233-239. [PubMed] [DOI] |
| 55. | Jang HJ, Han IH, Kim YJ, Yamabe N, Lee D, Hwang GS, Oh M, Choi KC, Kim SN, Ham J. Anticarcinogenic effects of products of heat-processed ginsenoside Re, a major constituent of ginseng berry, on human gastric cancer cells. J Agric Food Chem. 2014;62:2830-2836. [PubMed] [DOI] |