Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses

被引:160
作者
Kanerva, A
Wang, MH
Bauerschmitz, GJ
Lam, JT
Desmond, RA
Bhoola, SM
Barnes, MN
Alvarez, RD
Siegal, GP
Curiel, DT
Hemminki, A [1 ]
机构
[1] Univ Alabama Birmingham, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Pathol, Div Human Gene Therapy, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Surg, Div Human Gene Therapy, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
[5] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA
[6] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
[7] Univ Alabama Birmingham, Dept Cell Biol & Surg, Birmingham, AL 35294 USA
[8] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA
关键词
cancer; gene therapy; ovarian cancer; adenovirus; pseudotyping; toxicity; biodistribution;
D O I
10.1006/mthe.2002.0599
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
Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ads tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ads capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ads.
引用
收藏
页码:695 / 704
页数:10
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