Replicating adenoviral vector-mediated transfer of a heat-inducible double suicide gene for gene therapy

被引:33
|
作者
Lee, YJ
Galoforo, SS
Battle, P
Lee, H
Corry, PM
Jessup, JM
机构
[1] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA
[3] William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI 48073 USA
[4] Univ Ulsan, Sch Med, Dept Microbiol, Seoul, South Korea
[5] Univ Texas, Hlth Sci Ctr, Dept Surg, San Antonio, TX 78284 USA
关键词
heat shock promoter; p53; mutant; HSV-TK; E. coli CD; adenoviral vector; cytopathic effect;
D O I
10.1038/sj.cgt.7700310
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Tumor cells that express a fusion gene of Escherichia coli cytosine deaminase (CD) and herpes simplex virus type I thymidine kinase (TK) sequences activate and are subsequently killed by the nontoxic prodrugs 5-fluorocytosine and ganciclovir. We have previously developed a recombinant adenovirus containing the CD - TK fusion gene controlled by the human inducible heat shock protein 70 promoter so that heat at 41 degreesC for I hour induces therapeutic gene expression. This adenovirus effectively transduces heat-inducible expression of the CD-TK gene into human prostate carcinoma cells. However, because a limited number of cells in a tumor can actually be infected, we created a replicating adenoviral vector to increase CD-TK gene expression. This vector is a replication-competent, E1B-attenuated adenoviral vector containing the hsp70 promoter-driven CD-TK gene (Ad.E1A(+)HS-CDTK). When human prostate adenocarcinoma DU-145 cells (mutant p53) were infected with the virus at a multiplicity of infection (MOI) of I or 10, the viral replication was detected within 2 days at both MOIs. Similar results were observed in human colorectal carcinoma CX-I cells. When DU-145 cells were infected with the virus at an MOI of 10, incubated for 24 hours, heated at 41 degreesC for 4 hours and then harvested 20 hours later, Western blot analysis demonstrated that this virus successfully produced viral EIA proteins and heat shock stimulated the CD-TK gene expression by 12.3-fold. In addition, Ad.E1A(+)HS-CDTK effectively suppressed cell proliferation by viral cytopathic, effect). Unlike with a replication-incompetent virus (Ad.HS-CDTK), the cytopathic effect of the virus and cytotoxicity in the presence of the prodrugs were still observed even at low MOI (MOI=1.0).
引用
收藏
页码:397 / 404
页数:8
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