Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2012, Vol. 32 Issue (07): 37-42    
研究报告     
FAPα酶激活式靶向抗肿瘤前药: Z-GP-Dox对斑马鱼的毒性评价
马伟峰1, 杨飞华1, 赵海山2, 杜军3, 蔡绍晖2
1. 南方医科大学公共卫生与热带医学学院 广州 510515;
2. 暨南大学药学院 广州 510632;
2. 中山大学药学院 广州 510275
Toxicity Evaluation of a FAPα-activated Targeting Anticancer Prodrug Z-GP-Dox in Zebrafish
MA Wei-feng1, YANG Fei-hua1, ZHAO Hai-shan2, DU Jun3, CAI Shao-hui2
1. School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China;
2. College of Pharmacy Jinan University, Guangzhou 510632, China;
3. College of Pharmacy SunYat-Sen University, Guangzhou 510275, China
 全文: PDF(718 KB)   HTML
摘要: 目的:考察新设计合成的一种FAPα酶激活式靶向抗肿瘤新药甘脯酰阿霉素(Z-GP-Dox)对斑马鱼的毒性作用。方法:以阿霉素作为对照,用不同浓度的Z-GP-Dox处理4月龄的成年斑马鱼及其受精后24h(24hpf)的胚胎,观测其死亡率,并通过显微镜观察Z-GP-Dox对斑马鱼胚胎发育的影响,从形态学和电生理学方面评价其对斑马鱼心脏的毒性作用。结果:Dox对照组的斑马鱼死亡率具有明显的浓度依赖性,而经酰化修饰的前药Z-GP-Dox处理组的斑马鱼死亡率相对较低。Dox可导致斑马鱼胚胎发育严重畸形,心脏功能受损;而相同浓度的前药Z-GP-Dox处理组的胚胎发育基本正常,幼鱼的心脏形态和心率与空白对照组差异不显著。然而,当Z-GP-Dox被FAPα酶解后,其毒性则明显增强,与Dox对照组的毒性相当。结论:与Dox相比,经结构改造的前药Z-GP-Dox对斑马鱼的毒性显著降低,且具有FAPα酶激活式靶向释放特性。
关键词: 阿霉素甘脯酰阿霉素斑马鱼毒性    
Abstract: Objective: To investigate the toxicity in zebrafish of Z-GP-Dox, a novel FAPα-catalyzed activation targeted anticancer drug designed and synthesized previously. Methods: The mortality of 4-month-old zebrafish and the development of 24hpf (hours post fertilization) embryos were observed after treatment of Z-GP-Dox in different concentrations. The toxic effects of Z-GP-Dox on the zebrafish heart were evaluated with morphological and electrophysiological changes. Doxorubicin was set as a control. Results: The mortality rate of zebrafish in Dox control group showed significant does-dependent manner, while the mortality rate of the structural acylated modification prodrug Z-GP-Dox treated group was much lower. Dox induced malformations of zebrafish embryos and impaired heart function in juvenile. While at the same concentration, there was no significant difference between the Z-GP-Dox treatment group and blank control group in the heart shape and heart rate of the juvenile. When the Z-GP-Dox was hydrolysised by FAPα, its toxicity significantly increased and almost equal to the Dox. Conclusion: When compared with Dox, prodrug Z-GP-Dox toxicity was reduced significantly in zebrafish with characteristics of FAPα enzyme activated targeting release.
Key words: Doxorubicin    Z-GP-Doxorubicin    Zebrafish    Toxicity
收稿日期: 2012-03-22 出版日期: 2012-07-25
ZTFLH:  Q786  
基金资助: 国家自然科学基金(30973565,81101732);高等学校博士学科点专项科研基金(20104433120013)资助项目
通讯作者: 蔡绍晖     E-mail: csh5689@sina.cn
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
马伟峰
杨飞华
赵海山
杜军
蔡绍晖

引用本文:

马伟峰, 杨飞华, 赵海山, 杜军, 蔡绍晖. FAPα酶激活式靶向抗肿瘤前药: Z-GP-Dox对斑马鱼的毒性评价[J]. 中国生物工程杂志, 2012, 32(07): 37-42.

MA Wei-feng, YANG Fei-hua, ZHAO Hai-shan, DU Jun, CAI Shao-hui. Toxicity Evaluation of a FAPα-activated Targeting Anticancer Prodrug Z-GP-Dox in Zebrafish. China Biotechnology, 2012, 32(07): 37-42.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/        https://manu60.magtech.com.cn/biotech/CN/Y2012/V32/I07/37

[1] Trouet A, Passioukov A, Van derpoorten K, et al. Extracellularly tumor-activated prodrugs for the selective chemotherapy of cancer: application to doxorubicin and preliminary in vitro and in vivo studies. Cancer Res, 2001, 61 (7):2843-2846.
[2] Cheng J D, Dunbrack R L Jr, Valianou M, et al. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res, 2002, 62 (16):4767-4772.
[3] Rooseboom M, Commandeur J N, Vermeulen N P. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev, 2004, 56 (1): 53-102.
[4] Eimon P M, Rubinstein A L. The use of in vivo zebrafish assays in drug toxicity screening. Expert Opin Drug Metab Toxicol, 2009, 5(4):393-401.
[5] Sukardi H, Chng H T, Chan E C, et al. Zebrafish for drug toxicity screening: bridging the in vitro cell-based models and in vivo mammalian models. Expert Opin Drug Metab Toxicol, 2011, 7(5):579-589.
[6] Westerfield M. The Zebrafish Book: a guide for the laboratory use of zebrafish (Danio rerio). 5th edition. Eugene: University of Oregon Press, 2007. http://zfin.org/zf_info/zfbook /zfbk.html.
[7] Baurain R, Masquelier M, Deprez-De Campeneere D, et al. Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity on L1210 leukemic cells in vitro and in vivo. J Med Chem, 1980, 23 (11):1171-1174.
[8] Ravel D, Dubois V, Quinonero J, et al. Preclinical toxicity, toxicokinetics, and antitumoral efficacy studies of DTS-201, a tumor-selective peptidic prodrug of doxorubicin. Clin Cancer Res, 2008, 14 (4):1258-1265.
[9] Khong H T, Restifo N P. Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol, 2002, 3 (11):999-1005.
[10] Fassnacht M, Lee J, Milazzo C, et al. Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clin Cancer Res, 2005, 11 (15):5566-5571.
[11] Scott A M, Wiseman G, Welt S, et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res, 2003, 9 (5):1639-1647.
[12] Lee J, Fassnacht M, Nair S, et al. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res, 2005, 65 (23):11156-11163.
[13] Loeffler M, Kruger J A, Niethammer A G, et al. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest, 2006, 116 (7):1955-1962.
[14] Yang F, Chen Z, Pan J, et al. An integrated microfluidic array system for evaluating toxicity and teratogenicity of drugs on embryonic zebrafish developmental dynamics. Biomicrofluidics, 2011, 5(2):024115.
[1] 欧梦莹,王晓政,林双君,关统伟,林宜锦. 链黑菌素研究进展 *[J]. 中国生物工程杂志, 2019, 39(7): 100-107.
[2] 韦璇, 郝雅荞, Susanna Leong Su Jan, 吴言, 柳叶飞, 赵洪新. Saccharomyces cerevisiaeYarrowia lipolytica对自由饱和脂肪酸的选择性吸收及胞内积累特性研究[J]. 中国生物工程杂志, 2017, 37(2): 63-73.
[3] 周忠厅, 张权, 王胜涛, 蔡颖, 中西秀树, 尹健. 共价连接BODIPY光敏剂的聚合物纳米胶束及其靶向光动力疗效的研究[J]. 中国生物工程杂志, 2017, 37(10): 33-41.
[4] 桑维维, 常亚男, 李娟. 微流控芯片对乳腺癌细胞MDA-MB-231的捕获及再培养研究[J]. 中国生物工程杂志, 2015, 35(6): 46-53.
[5] 刘彦礼, 牛荣成, 杨芬, 朱文慧, 林俊堂. 金葡菌类肠毒素K原核表达载体构建及其生物学活性分析[J]. 中国生物工程杂志, 2015, 35(12): 45-50.
[6] 陈丽, 曹莹. PKA对斑马鱼前肾发育的影响及其机制研究[J]. 中国生物工程杂志, 2014, 34(10): 41-48.
[7] 苏燕南, 薛正莲, 陈涛, 马琦亚. 粘质沙雷氏菌PL-06磷脂酶A1基因大肠杆菌优化表达[J]. 中国生物工程杂志, 2013, 33(7): 36-42.
[8] 吴俊, 严新, 邵荣, 段菁华. 阿霉素-姜黄素聚氰基丙烯酸正丁酯复方纳米粒的研制及逆转MCF-7/ADR细胞多药耐药的研究[J]. 中国生物工程杂志, 2013, 33(5): 35-43.
[9] 王姝, 朱远茂, 蔡红, 马磊, 史鸿飞, 吕闯, 董秀梅, 高欲燃, 薛飞. 牛病毒性腹泻病毒E2蛋白单克隆抗体的制备及初步鉴定[J]. 中国生物工程杂志, 2013, 33(4): 40-45.
[10] 郭春芳, 张阳德, 王吉伟, 潘一峰, 廖明媚, 王宁. 载阿霉素柔性脂质体的性质及体外抗肿瘤效应[J]. 中国生物工程杂志, 2013, 33(3): 9-14.
[11] 徐义刚, 李丹丹, 刘忠梅, 崔丽春, 李苏龙. 产肠毒性大肠杆菌DPO-PCR检测方法的建立与应用[J]. 中国生物工程杂志, 2013, 33(11): 75-80.
[12] 牛秋红 董冰雪 黄思良 惠丰立 柯涛 张林. 松材线虫生防细菌的筛选、鉴定及其毒性因子的初步研究[J]. 中国生物工程杂志, 2010, 30(08): 76-81.
[13] 张静 刘环 周晶 刘建华. 通过断裂内含肽介导的反式剪接合成大的蛋白[J]. 中国生物工程杂志, 2009, 29(12): 74-78.
[14] 邱胜红 黄思超 蔡绍晖. 斑马鱼在抗肿瘤血管生成研究中的应用[J]. 中国生物工程杂志, 2009, 29(10): 98-101.
[15] 薛芳1,成志勇2,杨琳1,李世辉3,张颖1,潘崚1. 白血病耐药细胞系U937/ADR的建立及其生物学性状[J]. 中国生物工程杂志, 2009, 29(07): 17-21.