Tsuruta Yuko, Pereboeva Larisa, Breidenbach Martina, Rein Daniel T, Wang Minghui, Alvarez Ronald D, Siegal Gene P, Dent Paul, Fisher Paul B, Curiel David T
Division of Human Gene Therapy, Department of Medicine, Obstetrics and Gynecology, The University of Alabama at Birmingham, 901 19th Street South, BMR2-508, Birmingham, AL 35294-2180, USA.
Clin Cancer Res. 2008 Jun 1;14(11):3582-8. doi: 10.1158/1078-0432.CCR-07-5053.
Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenoviruses (CRAd) may contain tumor-specific promoters that restrict virus replication to cancer cells. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter-based CRAd in a murine model of ovarian cancer, using noninvasive in vivo imaging.
We constructed a mesothelin promoter-based CRAd with a chimeric Ad5/3 fiber (AdMSLNCRAd5/3) that contains an Ad5 tail, Ad5 shaft, and an Ad3 knob. Previously, a chimeric Ad5/3 fiber has shown improved infectivity in many ovarian cancer cells. Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of AdMSLNCRAd5/3 in a murine model, bioluminescence imaging of tumor luciferase activity and survival analysis were done.
AdMSLNCRAd5/3 achieved up to a 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all human ovarian cancer cells, compared with wild-type Ad5. AdMSLNCRAd5/3 significantly inhibited tumor growth as confirmed by in vivo imaging (P < 0.05). Survival with AdMSLNCRAd5/3 was significantly enhanced when compared with no virus or with a wild-type Ad5-treated group (P < 0.05).
The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLNCRAd5/3 showed that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have applied in vivo imaging that has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment.
最近，病毒疗法已被提议作为卵巢癌的一种新治疗方法。条件性复制腺病毒（CRAd）可能包含肿瘤特异性启动子，可将病毒复制限制在癌细胞中。间皮素是一种细胞表面糖蛋白，在卵巢癌中过表达，但在正常卵巢组织中不表达。本研究的目的是使用非侵入性体内成像技术，探讨基于间皮素启动子的CRAd在卵巢癌小鼠模型中的治疗效用。
我们构建了一种基于间皮素启动子的CRAd，其具有嵌合的Ad5/3纤维（AdMSLNCRAd5/3），包含Ad5尾部、Ad5杆部和Ad3头部。此前，嵌合的Ad5/3纤维已在许多卵巢癌细胞中显示出改善的感染性。在一组卵巢癌细胞系中评估了病毒复制和溶瘤作用。为了测试AdMSLNCRAd5/3在小鼠模型中的溶瘤疗效，进行了肿瘤荧光素酶活性的生物发光成像和生存分析。
与野生型Ad5相比，AdMSLNCRAd5/3在所有人类卵巢癌细胞中实现了高达10000倍的更高细胞杀伤效果和高达120倍的更高病毒复制水平。体内成像证实，AdMSLNCRAd5/3显著抑制了肿瘤生长（P<0.05）。与未感染病毒或野生型Ad5治疗组相比，AdMSLNCRAd5/3治疗后的生存率显著提高（P<0.05）。
AdMSLNCRAd5/3强大的复制、溶瘤和体内治疗疗效表明，这种CRAd是治疗卵巢癌的一个有前景的候选药物。重要的是，我们应用了体内成像技术，能够在CRAd治疗后对肿瘤生长进行重复和纵向测量。
