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本文引用的文献

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Herpes simplex virus thymidine kinase-mediated suicide gene therapy for hepatocellular carcinoma using HIV-1-derived lentiviral vectors.使用HIV-1衍生慢病毒载体的单纯疱疹病毒胸苷激酶介导的肝癌自杀基因疗法。
J Hepatol. 2004 Feb;40(2):291-7. doi: 10.1016/j.jhep.2003.10.019.
2
A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the alpha-fetoprotein promoter.在人类肝细胞癌中频繁表达的中期因子基因的启动子区域，激活自杀基因的效果与甲胎蛋白启动子一样有效。
Br J Cancer. 2003 Sep 15;89(6):1086-90. doi: 10.1038/sj.bjc.6601246.
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[Oncolytic viruses for genetic therapy of gastrointestinal tumors].用于胃肠道肿瘤基因治疗的溶瘤病毒
Z Gastroenterol. 2003 Jul;41(7):667-74. doi: 10.1055/s-2003-40543.
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Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.通过体外基因疗法对X连锁重症联合免疫缺陷进行持续矫正。
N Engl J Med. 2002 Apr 18;346(16):1185-93. doi: 10.1056/NEJMoa012616.
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Enhanced suicide gene effect by adenoviral transduction of a VP22-cytosine deaminase (CD) fusion gene.通过腺病毒转导VP22-胞嘧啶脱氨酶（CD）融合基因增强自杀基因效应。
Gene Ther. 2001 Nov;8(21):1654-64. doi: 10.1038/sj.gt.3301564.
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Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases.将腺病毒载体靶向肿瘤细胞并不能实现乳腺癌转移灶的有效转导。
Cancer Res. 2002 Feb 15;62(4):1063-8.
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Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas.胞嘧啶脱氨酶/5-氟胞嘧啶基因疗法产生的瘤内5-氟尿嘧啶对实验性人类胶质母细胞瘤有效。
Cancer Res. 2002 Feb 1;62(3):773-80.
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Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males.雄性小鼠经全身注射重组腺相关病毒2型（AAV-2）载体后载体序列的种系传递缺失。
Mol Ther. 2001 Dec;4(6):586-92. doi: 10.1006/mthe.2001.0491.
9
In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase.使用腺病毒介导的胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶融合基因转移进行结肠癌的体内基因治疗。
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Adenovirus-mediated gene transfer to orthotopic hepatocellular carcinomas in athymic nude mice.腺病毒介导的基因转移至无胸腺裸鼠原位肝细胞癌
Cancer Gene Ther. 2001 Aug;8(8):573-9. doi: 10.1038/sj.cgt.7700345.

双功能嵌合超CD自杀基因-YCD：YUPRT融合体在大鼠肝癌模型中具有高效性。

Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model.

作者信息

Graepler Florian, Lemken Marie-Luise, Wybranietz Wolfgang A, Schmidt Ulrike, Smirnow Irina, Gross Christine D, Spiegel Martin, Schenk Andrea, Graf Hansjörg, Lauer Ulrike A, Vonthein Reinhard, Gregor Michael, Armeanu Sorin, Bitzer Michael, Lauer Ulrich M

机构信息

Department of Internal Medicine I, Medical University Clinic Tübingen, Germany.

出版信息

World J Gastroenterol. 2005 Nov 28;11(44):6910-9. doi: 10.3748/wjg.v11.i44.6910.

DOI:10.3748/wjg.v11.i44.6910
PMID:16437592
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4717030/
Abstract

AIM

To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model.

METHODS

To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine (5-FC), we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase (YCD) and the yeast uracil phosphoribosyltransferase (YUPRT) gene.

RESULTS

In vitro stably transduced Morris rat hepatoma cells (MH) expressing the bifunctional SuperCD suicide gene (MH SuperCD) showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely (MH YCD) or the cytosine deaminase gene of bacterial origin (MH BCD), respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions (P<0.01) under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression (MH naive) showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness (SuperCD>> YCD>>BCD>>>negative control) was defined as a result of a direct in vivo comparison of all three suicide genes.

CONCLUSION

Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

摘要

目的

研究催化性能更优的基因导向酶前药治疗系统对大鼠肝癌模型的影响。

方法

为提高肝癌细胞对前药5-氟胞嘧啶（5-FC）的化学敏感性，我们构建了一个嵌合双功能SuperCD自杀基因，它是酵母胞嘧啶脱氨酶（YCD）和酵母尿嘧啶磷酸核糖转移酶（YUPRT）基因的融合体。

结果

体外稳定转导表达双功能SuperCD自杀基因的莫里斯大鼠肝癌细胞（MH）（MH SuperCD）与单独稳定表达YCD的MH细胞（MH YCD）或细菌来源的胞嘧啶脱氨酶基因的MH细胞（MH BCD）相比，在与5-FC孵育时细胞杀伤作用明显增强。在体内，皮下以及原位植入同基因ACI大鼠肝脏的MH SuperCD肿瘤在高剂量和低剂量全身应用5-FC时均显示出显著的肿瘤消退（P<0.01），而未转基因表达的MH肿瘤（MH naive）则迅速进展。通过对所有三种自杀基因进行直接体内比较，首次确定了体内自杀基因有效性的顺序（SuperCD>> YCD>>BCD>>>阴性对照）。

结论

双功能SuperCD自杀基因表达在大鼠肝癌模型中非常有效，从而显著提高了治疗指数以及氟胞嘧啶对肝细胞癌的杀伤效果。