切换至 "中华医学电子期刊资源库"
高级检索
中华口腔医学研究杂志(电子版)

中华口腔医学研究杂志(电子版) ›› 2020, Vol. 14 ›› Issue (05) : 325 -329. doi: 10.3877/cma.j.issn.1674-1366.2020.05.009

所属专题： 口腔医学； 文献；

综述

安罗替尼的研究现状及其应用于晚期口腔鳞状细胞癌的治疗前景
楚晨1, 孙艳1,†(), 尚伟2, 张晓春3, 葛胜优2   
  1. 1. 青岛大学附属医院口腔内科　266000；青岛大学口腔医学院　266000
    2. 青岛大学口腔医学院　266000；青岛大学附属医院口腔颌面外科　266000
    3. 青岛大学附属医院肿瘤精准医学中心　266000
  • 收稿日期:2020-02-21 出版日期:2020-10-01
  • 通信作者: 孙艳

The current states of anlotinib and its prospect in advanced oral squamous cell carcinoma

Chen Chu1, Yan Sun1,†(), Wei Shang2, Xiaochun Zhang3, Shengyou Ge2   

  1. 1. Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China; School of Stomatology of Qingdao University, Qingdao 266000, China
    2. School of Stomatology of Qingdao University, Qingdao 266000, China; Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
    3. Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
  • Received:2020-02-21 Published:2020-10-01
  • Corresponding author: Yan Sun
  • About author:
    Corresponding author: Sun Yan, Email:
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

楚晨, 孙艳, 尚伟, 张晓春, 葛胜优. 安罗替尼的研究现状及其应用于晚期口腔鳞状细胞癌的治疗前景[J]. 中华口腔医学研究杂志(电子版), 2020, 14(05): 325-329.

Chen Chu, Yan Sun, Wei Shang, Xiaochun Zhang, Shengyou Ge. The current states of anlotinib and its prospect in advanced oral squamous cell carcinoma[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2020, 14(05): 325-329.

晚期口腔鳞状细胞癌（OSCC）患者生存期短，预后较差。由于手术效果不佳、耐药性、不良反应等原因，亟需更安全有效的新型化疗药物以提高晚期OSCC患者生存质量。安罗替尼（anlotinib）是我国自主研发的一种口服多靶点小分子酪氨酸激酶抑制剂，能够与多种血管生成因子受体靶向结合，抑制肿瘤血管生成，干扰肿瘤细胞增殖等生物学行为，有望成为多种晚期恶性肿瘤治疗药物。本文对安罗替尼的作用机制、研究现状及其应用于晚期OSCC术后化疗的治疗前景等进行分析综述。

关键词: 癌，鳞状细胞, 血管内皮生长因子类, 安罗替尼, 血管生成, 化疗

Patients with advanced oral squamous cell carcinoma often show short survival time and poor prognosis. Because of the poor efficacy of surgery, drug resistance and adverse events etc., the quality of life of these patients are required to improved by novel drugs with safety and efficacy. Anlotinib is a domestic small-molecule tyrosine kinase inhibitor, which has been presently regarded as a potential medicine for multiple advanced malignances. It targets multiple angiogenetic factor receptors to suppress the angiogenesis and inhibit partial functions of tumor cells. This review will focus on the mechanism, research status of anlotinib and its potential efficacy in advanced oral squamous cell carcinoma.

Key words: Carcinoma, squamous cell, Vasculare endothelial growth factors, Anlotinib, Angiogenesis, Chemotherapy
图1 安罗替尼作用机制[5]
表1 有关安罗替尼治疗晚期恶性肿瘤的临床试验
临床试验注册号 研究阶段 治疗方案顺序 对照组 人数 PFS[月，中位数(95% CI)] OS[月，中位数(95% CI)] ORR(%) 治疗相关
调整剂量人数(%) 死亡人数(%)
晚期非小细胞肺癌 ? ? ? ? ? ? ? ? ?
? NCT01924195[18] Ⅱ期 3线及以上 安慰剂 117 4.8(3.5 ~ 6.4)VS 1.2(0.7 ~ 1.6), P<0.001 9.3(6.8 ~ 15.1)VS 6.3(4.3 ~ 10.5), P = 0.232 10.0 VS 0.0,P = 0.028 10.0 0.0
? NCT02388919[19] Ⅲ期 3线及以上 安慰剂 439 5.4(4.4 ~ 5.6)VS 1.4(1.1 ~ 1.5), P<0.001 9.6(8.2 ~ 10.6)VS 6.3(5.0 ~ 8.1), P = 0.002 9.2 VS 0.7,P<0.001 8.9 -
晚期软组织肉瘤 ? ? ? ? ? ? ? ? ?
? NCT01878448[20] Ⅱ期 NR - 166 5.6(4.4 ~ 7.7) 12.0(11.0 ~ 16.0) 13.0 14.5 0.0
晚期髓样甲状腺癌 ? ? ? ? ? ? ? ? ?
? NCT01874873[22] Ⅱ期 NR - 58 - - 56.9 20.7 -
转移性肾细胞癌 ? ? ? ? ? ? ? ? ?
? NCT02072031[24] Ⅱ期 1线 Sunitinib 133 17.5 VS 16.6,P>0.05 30.9 VS 30.5,P>0.05 30.3 VS 27.9,P>0.05 7.8 VS 16.3，P = 0.14 -
表2 安罗替尼与其他酪氨酸酶抑制剂（TKI）比较
药品 不同点 相似点
安罗替尼 1.对VEGFR-2/3选择性较强，抑制肿瘤血管生成能力较强 1.作用机制相似，与VEGFR等血管生成因子受体结合，抑制肿瘤血管生成2.结合靶点较多，干扰多条信号通路，不良反应（高血压、手足综合征等）较多
2.不良反应大多可缓解，腹泻发生率相对较低
3.易发生血脂升高、甘油三酯升高，需监测血压、血脂等指标
索拉菲尼、舒尼替尼等 1.与VEGFR结合能力相对较弱，抑制肿瘤血管生成能力较弱
2.腹泻发生率相对较高
3.血脂升高、甘油三酯升高发生率相对较低
[1]
Cheraghlou S, Schettino A, Zogg CK，et al. Changing prognosis of oral cancer：An analysis of survival and treatment between 1973 and 2014[J]. Laryngoscope，2018，128(12): 2762-2769. DOI: 10.1002/lary.27315.
[2]
Hsieh MY, Chen G, Chang DC，et al. The Impact of Metronomic Adjuvant Chemotherapy in Patients with Advanced Oral Cancer [J]. Ann Surg Oncol，2018，25(7): 2091-2097. DOI: 10.1245/s10434-018-6497-3.
[3]
金晶，叶茂昌，王来平，等. TPF方案诱导化疗口腔癌后Ⅳ度骨髓抑制的临床分析[J].上海口腔医学，2014，23(2): 219-223.
[4]
尚伟，郑家伟.口腔及口咽癌新版TNM分期与NCCN诊治指南部分解读[J].中国口腔颌面外科杂志，2018，16(6): 533-546. DOI: 10.19438/j.cjoms.2018.06.010.
[5]
Shen G, Zheng F, Ren D，et al. Anlotinib：a novel multi-targeting tyrosine kinase inhibitor in clinical development[J]. J Hematol Oncol，2018，11(1): 120. DOI: 10.1186/s13045-018-0664-7.
[6]
Nowak-Sliwinska P, Alitalo K, Elizabeth A，et al. Consensus guidelines for the use and interpretation of angiogenesis assays [J]. Angiogenesis，2018，21(3): 425-532. DOI: 10.1007/s10456-018-9613-x.
[7]
Ochiya T, Takenaga K, Endo H. Silencing of S100A4，a metastasis-associated protein，in endothelial cells inhibits tumor angiogenesis and growth[J]. Angiogenesis，2014，17(1): 17-26. DOI: 10.1007/s10456-013-9372-7.
[8]
Zirlik K, Duyster J. Anti-Angiogenics：Current Situation and Future Perspectives[J]. Oncol Res Treat，2018，41(4): 166-171. DOI: 10.1159/000488087.
[9]
Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited：Is there a role for combinations with immunotherapy？[J]. Angiogenesis，2017，20(2): 185-204. DOI: 10.1007/s10456-017-9552-y.
[10]
Graham K, Unger E. Overcoming tumor hypoxia as a barrier to radiotherapy，chemotherapy and immunotherapy in cancer treatment[J]. International Journal Of Nanomedicine，2018，13: 6049-6058. DOI: 10.2147/IJN.S140462.
[11]
He C, Wu T, Hao Y. Anlotinib induces hepatocellular carcinoma apoptosis and inhibits proliferation via Erk and Akt pathway[J]. Biochem Biophys Res Commun，2018，503(4): 3093-3099. DOI: 10.1016/j.bbrc.2018.08.098.
[12]
Liang L, Hui K, Hu C，et al. Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells[J]. J Exp Clin Cancer Res，2019，38(1): 71. DOI: 10.1186/s13046-019-1093-3.
[13]
Xie C, Wan X, Quan H，et al. Preclinical characterization of anlotinib，a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor[J]. Cancer Sci，2018，109(4): 1207-1219. DOI: 10.1111/cas.13536.
[14]
Lin B, Song X, Yang D，et al. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2，PDGFRbeta and FGFR1[J]. Gene，2018，654: 77-86. DOI: 10.1016/j.gene.2018.02.026.
[15]
Ruan X, Shi X, Dong Q，et al. Antitumor effects of anlotinib in thyroid cancer[J]. Endocr Relat Cancer，2019，26(1): 153-164. DOI: 10.1530/ERC-17-0558.
[16]
Sun Y, Niu W, Du F，et al. Safety，pharmacokinetics，and antitumor properties of anlotinib，an oral multi-target tyrosine kinase inhibitor，in patients with advanced refractory solid tumors[J]. J Hematol Oncol，2016，9(1): 105. DOI: 10.1186/s13045-016-0332-8.
[17]
Miller KD, Nogueira L, Mariotto AB，et al. Cancer treatment and survivorship statistics，2019[J]. CA Cancer J Clin，2019，69(5): 363-385. DOI: 10.3322/caac.21565.
[18]
Han B, Li K, Zhao Y，et al. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer：a multicentre，randomised phase Ⅱ trial（ALTER0302）[J]. Br J Cancer，2018，118(5): 654-661. DOI: 10.1038/bjc.2017.478.
[19]
Han B, Li K, Wang Q，et al. Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer：The ALTER 0303 Phase 3 Randomized Clinical Trial[J]. JAMA Oncol，2018，4(11): 1569-1575. DOI: 10.1001/jamaoncol.2018.3039.
[20]
Chi Y, Fang Z, Hong X，et al. Safety and Efficacy of Anlotinib，a Multikinase Angiogenesis Inhibitor，in Patients with Refractory Metastatic Soft-Tissue Sarcoma[J]. Clin Cancer Res，2018，24(21): 5233-5238. DOI: 10.1158/1078-0432.CCR-17-3766.
[21]
Du L, Wang Y, Sun X，et al. Thyroid cancer：trends in incidence，mortality and clinical-pathological patterns in Zhejiang Province，Southeast China[J]. BMC Cancer，2018，18(1): 291. DOI: 10.1186/s12885-018-4081-7.
[22]
Sun Y, Du F, Gao M，et al. Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer[J]. Thyroid，2018，28(11): 1455-1461. DOI: 10.1089/thy.2018.0022.
[23]
Miyake H, Matsushita Y, Watanabe H，et al. Significance of introduction of alternative dosing schedule for sunitinib during first-line treatment of patients with metastatic renal cell carcinoma[J]. Med Oncol，2018，35(10): 133. DOI: 10.1007/s12032-018-1195-3.
[24]
Zhou AP, Bai Y, Song Y，et al. Anlotinib Versus Sunitinib as First-Line Treatment for Metastatic Renal Cell Carcinoma：A Randomized PhaseⅡ Clinical Trial[J]. Oncologist，2019，24(8): e702-e708. DOI: 10.1634/theoncologist.2018-0839.
[25]
Miao C, Cao J, Wang Y，et al. Effects of VEGF and VEGFR polymorphisms on the outcome of patients with metastatic renal cell carcinoma treated with sunitinib：a systematic review and meta-analysis[J]. Oncotarget，2017，8(40): 68854-68862. DOI: 10.18632/oncotarget.19924.
[26]
Si X, Zhang L, Wang H，et al. Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer：Experiences in ALTER-0303[J]. Thorac Cancer，2019，10(3): 551-556. DOI: 10.1111/1759-7714.12977.
[27]
Lee SH, Bang YJ, Mainwaring P，et al. Sunitinib in metastatic renal cell carcinoma：an ethnic Asian subpopulation analysis for safety and efficacy[J]. Asia Pac J Clin Oncol，2014，10(3): 237-245. DOI: 10.1111/ajco.12163.
[28]
Cheng AL, Kang YK, Chen Z，et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma：a phaseⅢ randomised，double-blind，placebo-controlled trial[J]. Lancet Oncol，2009，10(1): 25-34. DOI: 10.1016/s1470-2045(08)70285-7.
[29]
Jiang L, Xiao J. 2-phenylethynesulfonamide inhibits growth of oral squamous cell carcinoma cells by blocking the function of heat shock protein 70[J]. Biosci Rep，2020，40(3): BSR2020 0079. DOI: 10.1042/BSR20200079.
[30]
Thavarool SB, Muttath G, Nayanar S，et al. Improved survival among oral cancer patients：findings from a retrospective study at a tertiary care cancer centre in rural Kerala，India[J]. World J Surg Oncol，2019，17(1): 15. DOI: 10.1186/s12957-018-1550-z.
[31]
Petti S, Scully C. How many individuals must be screened to reduce oral cancer mortality rate in the Western context？A challenge[J]. Oral Dis，2015，21(8): 949-954. DOI: 10.1111/odi.12372.
[32]
Minhas S, Kashif M, Altaf W，et al. Concomitant-chemoradiotherapy-associated oral lesions in patients with oral squamous-cell carcinoma[J]. Cancer Biol Med，2017，14(2): 176-182. DOI: 10.20892/j.issn.2095-3941.2016.0096.
[33]
Srivastava S, Mohammad S, Gupta S，et al. Chemoprotective effect of nanocurcumin on 5-fluorouracil-induced-toxicity toward oral cancer treatment[J]. Natl J Maxillofac Surg，2018，9(2): 160-166. DOI: 10.4103/njms.NJMS_27_18.
[34]
Patil VM, Noronha V, Joshi A，et al. PhaseⅠ/Ⅱ Study of Palliative Triple Metronomic Chemotherapy in Platinum-Refractory/Early-Failure Oral Cancer[J]. J Clin Oncol，2019，37(32): 3032-3041. DOI: 10.1200/JCO.19.01076.
[35]
Hamauchi S, Yokota T, Mizumachi T，et al. Safety and efficacy of concurrent carboplatin or cetuximab plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin[J]. Int J Clin Oncol，2019，24(5): 468-475. DOI: 10.1007/s10147-018-01392-9.
[36]
Hwang-Bo J, Park JH, Bae MG，et al. Recombinant canstatin inhibits VEGF-A-induced lymphangiogenesis and metastasis in an oral squamous cell carcinoma SCC-Ⅶ animal model[J]. Cancer Med，2016，5(10): 2977-2988. DOI: 10.1002/cam4.866.
[37]
Lin X, Khalid S, Qureshi MZ，et al. VEGF mediated signaling in oral cancer[J]. Cell Mol Biol（Noisy-le-grand），2016，62(14): 64-68. DOI: 10.14715/cmb/2016.62.14.11.
[38]
Pianka A, Knösel T, Probst FA，et al. Vascular endothelial growth factor receptor isoforms：are they present in oral squamous cell carcinoma？[J]. J Oral Maxillofac Surg，2015，73(5): 897-904. DOI: 10.1016/j.joms.2014.12.030.
[39]
Lin YW, Huang ST, Wu JC，et al. Novel HDGF/HIF-1alpha/VEGF axis in oral cancer impacts disease prognosis[J]. BMC Cancer，2019，19(1): 1083. DOI: 10.1186/s12885-019-6229-5.
[40]
Xie X, Wang Z, Chen F，et al. Roles of FGFR in oral carcinogenesis[J]. Cell Prolif，2016，49(3): 261-269. DOI: 10.1111/cpr.12260.
[41]
Ong HS, Gokavarapu S, Tian Z，et al. PDGFRA mRNA overexpression is associated with regional metastasis and reduced survival in oral squamous cell carcinoma[J]. J Oral Pathol Med，2018，47(7): 652-659. DOI: 10.1111/jop.12713.
[42]
Chu C, Shang W, Sun Y，et al. Anlotinib is effective in patients with advanced oral cancer？[J]. Med Hypotheses，2020，137: 109578. DOI: 10.1016/j.mehy.2020.109578.
[43]
Syed YY. Anlotinib：First Global Approval[J]. Drugs，2018，78(10): 1057-1062. DOI: 10.1007/s40265-018-0939-x.
[44]
Sánchez-Danés A, Blanpain C. Deciphering the cells of origin of squamous cell carcinomas[J]. Nat Rev Cancer，2018，18(9): 549-561. DOI: 10.1038/s41568-018-0024-5.
[45]
Deng Y, Zhong ZY, Tan XR，et al. Satisfactory short-term outcome after anlotinib and docetaxel chemotherapy in tongue cancer with N3 cervical lymph node metastasis：A case report [J]. Clin Case Rep，2019，7(10): 1923-1927. DOI: 10.1002/ccr3.2390.
[46]
牛志成，何东伟，汪治宇.抗血管生成药物联合免疫检查点抑制剂治疗恶性肿瘤的研究进展[J].中国肿瘤生物治疗杂志，2019，26(9): 1012-1018. DOI: 10.3872/j.issn.1007-385x.2019.09.013.
[47]
Larkins E, Blumenthal GM, Yuan WS，et al. FDA Approval Summary：Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy[J]. Oncologist，2017，22(7): 873-878. DOI: 10.1634/theoncologist.2016-0496.
[1] 洪玮, 叶细容, 刘枝红, 杨银凤, 吕志红. 超声影像组学联合临床病理特征预测乳腺癌新辅助化疗完全病理缓解的价值[J]. 中华医学超声杂志（电子版）, 2024, 21(06): 571-579.
[2] 赵阳, 肖迎聪, 巨艳, 党晓智, 蔡林利, 薛文欣, 李洋, 肖瑶, 郭妤绮, 宋宏萍. 自动乳腺超声联合免疫组化早期预测乳腺癌新辅助化疗病理完全缓解的临床价值[J]. 中华医学超声杂志（电子版）, 2024, 21(04): 361-369.
[3] 杨焕, 马靓, 沈俊, 董丽丽, 孙文雯. 乳腺癌新辅助化疗患者支持性照顾需求与症状群及应对方式的相关性[J]. 中华乳腺病杂志(电子版), 2024, 18(04): 224-230.
[4] 别瑶, 曹志斌, 辛静, 王健楠, 惠宗光. 应用基质血管成分细胞治疗糖尿病足溃疡的研究进展[J]. 中华损伤与修复杂志(电子版), 2024, 19(05): 453-456.
[5] 汤宏涛, 何坤. 中晚期肝细胞癌介入治疗的进展及前景[J]. 中华普通外科学文献(电子版), 2024, 18(04): 305-308.
[6] 许杰, 李亚俊, 冯义文. SOX新辅助化疗后腹腔镜胃癌D2根治术与常规根治术治疗进展期胃癌的近期随访比较[J]. 中华普外科手术学杂志(电子版), 2024, 18(06): 647-650.
[7] 马立伟, 贾志强, 陈午盛, 邵明亮, 刘琼, 段玉松. CalliSpheres载药微球联合碘化油治疗肝癌的临床研究[J]. 中华普外科手术学杂志(电子版), 2024, 18(04): 369-372.
[8] 达热拜·热达提, 刘林, 赵为民, 孟涛, 雷程, 金博, 毕建军, 李新宇, 王海江. 中低位直肠癌新辅助放化疗后侧方淋巴结清扫术的临床观察[J]. 中华普外科手术学杂志(电子版), 2024, 18(04): 415-418.
[9] 宋小飞, 巫嘉文, 孙阳. 输尿管开口周围膀胱黏膜预离断联合早期膀胱灌注化疗在上尿路尿路上皮癌根治术中的应用[J]. 中华腔镜泌尿外科杂志(电子版), 2024, 18(05): 479-484.
[10] 张桂萍, 丘勇林, 湛绮婷, 孙乐栋. 晚期非小细胞肺癌血清Ape1/Ref-1对放射性肺损伤发生的预测意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 519-523.
[11] 张昊, 潘卫东. 胰腺癌新辅助化疗后可切除性评估现状及进展[J]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 629-633.
[12] 王军华, 王锐炫. 胰腺癌新辅助化疗现状和治疗策略[J]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 640-643.
[13] 李永政, 孟煜凡, 樊知遥, 展翰翔. 胰腺神经内分泌肿瘤新辅助治疗研究进展[J]. 中华肝脏外科手术学电子杂志, 2024, 13(04): 481-486.
[14] 张梦婷, 穷拉姆, 色珍, 李逸群, 德庆旺姆. 西藏地区藏族乳腺癌新辅助化疗的真实世界研究[J]. 中华临床医师杂志(电子版), 2024, 18(05): 441-446.
[15] 赵阳, 肖迎聪, 巨艳, 党晓智, 蔡林利, 薛文欣, 李洋, 肖瑶, 郭妤绮, 宋宏萍. 基于自动乳腺超声的列线图模型早期预测HER-2阳性乳腺癌新辅助化疗病理完全缓解的临床价值[J]. 中华临床医师杂志(电子版), 2024, 18(04): 355-362.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号