Purpose: 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. Experimental Design: 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. Results: 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. Ad MSLNCR Ad5/3 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). Conclusions: The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLN-CRAd5/3 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. © 2008 American Association for Cancer Research.
CITATION STYLE
Tsuruta, Y., Pereboeva, L., Breidenbach, M., Rein, D. T., Wang, M., Alvarez, R. D., … Curiel, D. T. (2008). A fiber-modified mesothelin promoter-based conditionally replicating adenovirus fortreatment of ovarian cancer. Clinical Cancer Research, 14(11), 3582–3588. https://doi.org/10.1158/1078-0432.CCR-07-5053
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