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Enhanced efficiency and specificity of ovarian cancer gene therapy in rats with a novel nonviral gene delivery system (GE7) via intraovarian artery perfusion approach

Cancer Gene Therapy volume 12, pages 810–817 (2005)Cite this article

Abstract

Transfer of the herpes simplex virus type I-thymidine kinase gene, followed by the administration of ganciclovir (HSV1-tk/GCV) into ovarian cancer-derived cell line either in vitro or transplanted into nude mice has been shown to provide a potential strategy for the gene therapy of ovarian cancer. We investigated the antitumor effects of HSV1-tk/GCV strategy with a chemically induced rat ovarian cancer model and a tumor-selective gene delivery by a novel nonviral gene delivery system (GE7) through the ovarian artery and tail vein. We demonstrated the expression of a reporter gene, β-gal gene, as well as HSV1-tk gene in tumors and other organs, evaluated the overall antitumor effects after the GCV treatment and analyzed the tumor cell cycle phase distribution. Via the ovarian artery route, the expressions of β-gal and HSV1-tk in tumors were significantly stronger than those expressed in such organs as the hearts, livers, spleens, lungs and kidneys. However, no β-gal and HSV1-tk were detected in the tumor tissues when administrated via the tail vein, and little was found in other organs. The cell cycle analysis showed that the total S-phase of tumor cells in the test intra-arterial treatment group was considerably higher than that of the controls. The weight of the tumor tissues in the group treated by the intra-arterial route (4.06±2.12 g) was much less than the group treated intravenously (18.25±8.34 g) (P<.01). These findings indicated that the administration of GE7/HSV1-tk complex via the ovarian artery route could be a promising avenue of future human ovarian cancer treatment.

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References

  1. Song JS, Kim HP, Yoon WS, et al. Adenovirus-mediated suicide gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter induced apoptosis of ovarian cancer cell line. Biosci Biotechnol Biochem. 2003;67:2344–2350.

    Article  CAS  PubMed  Google Scholar 

  2. Kong BH, Wang WX, Liu CS, Ma DX, Qu X . Tegument viral protein 22 enhanced cell-killing effect of the herpes simplex virus thymidine kinase/ganciclovir system on ovarian cancer in vivo. Zhonghua Fu Chan Ke Za Zhi. 2003;38:195–198.

    PubMed  Google Scholar 

  3. Selvakumaran M, Bao R, Crijns AP, Connolly DC, Weinstein JK, Hamilton TC . Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element. Cancer Res. 2001;61:1291–1295.

    CAS  PubMed  Google Scholar 

  4. Alvarez RD, Gomez-Navarro J, Wang M, et al. Adenoviral-mediated suicide gene therapy for ovarian cancer. Mol Ther. 2000;2:524–530.

    Article  CAS  PubMed  Google Scholar 

  5. Almadrones LA . Treatment advances in ovarian cancer. Cancer Nurs. 2003;26 (6 Suppl):16S–20S.

    PubMed  Google Scholar 

  6. See HT, Kavanagh JJ, Hu W, Bast RC . Targeted therapy for epithelial ovarian cancer: current status and future prospects. Int J Gynecol Cancer. 2003;13:701–734.

    Article  CAS  PubMed  Google Scholar 

  7. Kirby TO, Curiel DT, Alvarez RD . Gene therapy for ovarian cancer: progress and potential. Hematol Oncol Clin North Am. 2003;17:1021–1050.

    Article  PubMed  Google Scholar 

  8. Rancourt C, Bergeron C, Lane D, Garon G, Piche A . Delivery of herpes simplex thymidine kinase bystander effect by engineered human mesothelial cells for the treatment of ovarian cancer. Cytotherapy. 2003;5:509–522.

    Article  CAS  PubMed  Google Scholar 

  9. Collinet P, Lanvin D, Vereecque R, Quesnel B, Querleu D . Gene therapy and ovarian cancer: update of clinical trials. J Gynecol Obstet Biol Reprod (Paris). 2000;29:532–537.

    CAS  Google Scholar 

  10. Alvarez RD, Curiel DT . A phase I study of recombinant adenovirus vector-mediated intraperitoneal delivery of herpes simplex virus thymidine kinase (HSV-TK) gene and intravenous ganciclovir for previously treated ovarian and extraovarian cancer patients. Hum Gene Ther. 1997;8:597–613.

    Article  CAS  PubMed  Google Scholar 

  11. Bauknecht T, Meinhold-Heerlein I . Gene therapy of ovarian cancer. Curr Womens Health Rep. 2002;2:39–46.

    PubMed  Google Scholar 

  12. Soda Y, Tani K, Bai Y, et al. A novel Maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2004 Mar 23 [Epub ahead of print].

  13. Zhu ZB, Makhija SK, Lu B, et al. Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter. Gene Ther. 2004;11:645–648.

    Article  CAS  PubMed  Google Scholar 

  14. Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L . EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell. 2002;1:445–457.

    Article  CAS  PubMed  Google Scholar 

  15. Bandera CA, Tsui HW, Mok SC, Tsui FW . Expression of cytokines and receptors in normal, immortalized, and malignant ovarian epithelial cell lines. Anticancer Res. 2003;23:3151–3157.

    CAS  PubMed  Google Scholar 

  16. Liu X, Tian P, Yu Y, Yao M, Cao X, Gu J . Enhanced antitumor effect of EGF R-targeted p21WAF-1 and GM-CSF gene transfer in the established murine hepatoma by peritumoral injection. Cancer Gene Ther. 2002;9:100–108.

    Article  CAS  PubMed  Google Scholar 

  17. Alper O, Bergmann-Leitner ES, Bennett TA, Hacker NF, Stromberg K, Stetler-Stevenson WG . Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J Natl Cancer Inst. 2001;93:1375–1384.

    Article  CAS  PubMed  Google Scholar 

  18. Nagao K, Hisatomi H, Hirata H, et al. Expression of molecular marker genes in various types of normal tissue: implication for detection of micrometastases. Int J Mol Med. 2002;10:307–310.

    CAS  PubMed  Google Scholar 

  19. Shao ZM, Nguyen M, Alpaugh ML, O'Connell JT, Barsky SH . The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis. Exp Cell Res. 1998;241:394–403.

    Article  CAS  PubMed  Google Scholar 

  20. Alpaugh ML, Tomlinson JS, Shao ZM, Barsky SH . A novel human xenograft model of inflammatory breast cancer. Cancer Res. 1999;59:5079–5084.

    CAS  PubMed  Google Scholar 

  21. Sekiya S, Endoh N, Kikuchi Y, et al. In vivo and in vitro studies of experimental ovarian adenocarcinoma in rats. Cancer Res. 1979;39:1108–1112.

    CAS  PubMed  Google Scholar 

  22. Kim KK, Shim JC, Kim JR . Overexpression of p21, cyclin E and decreased expression of p27 in DMBA (7, 12-dimethylbenzanthracene)-induced rat ovarian carcinogenesis. Pathol Int. 2003;53:291–296.

    Article  CAS  PubMed  Google Scholar 

  23. Seymour LW, Fisher KD, Green NK, et al. Adenovirus retargeting and systemic delivery. Ernst Schering Res Found Workshop. 2003;43:107–114.

    CAS  Google Scholar 

  24. Benigni A, Tomasoni S, Lutz J, Amuchastegui S, Capogrossi MC, Remuzzi G . Nonviral and viral gene transfer to the kidney in the context of transplantation. Nephron. 2000;85:307–316.

    Article  CAS  PubMed  Google Scholar 

  25. Tian PK, Ren SJ, Ren CC, Yao M, Gu JR . A novel receptor — targeted gene delivery system for gene therapy. Sci Chin. 1998;28:554–558.

    Google Scholar 

  26. Chun-Hong M, Wen-Sheng S, Pei-Kun T, et al. A novel HBV antisece RNA gene delivery system targeting hepatocellular carcinoma. World J Gastroenterol. 2003;9:463–467.

    Article  Google Scholar 

  27. Nagy HJ, Panis Y, Fabre M, Klatzmann D, Houssin D, Soubrane O . Suicide gene therapy of ovarian cancer: an experimental study in rats using retroviral-mediated transfer of herpes simplex virus thymidine kinase gene. Anticancer Res. 2000;20:4633–4638.

    CAS  PubMed  Google Scholar 

  28. Sugiyama T, Nishida T, Kumagai S, et al. Combination treatment with cisplatin and schizophyllan for 7,12-dimethylbenz(a)anthracene-induced rat ovarian adenocarcinoma. J Obstet Gynaecol. 1995;21:521–527.

    Article  CAS  Google Scholar 

  29. Laurema A, Heikkila A, Keski-Nisula L, et al. Transfection of oocytes and other types of ovarian cells in rabbits after direct injection into uterine arteries of adenoviruses and plasmid/liposomes. Gene Therapy. 2003;10:580–584.

    Article  CAS  PubMed  Google Scholar 

  30. Sadahiro S, Suzuki T, Ishikawa K, et al. Prophylactic hepatic arterial infusion chemotherapy for the prevention of liver metastasis in patients with colon carcinoma: a randomized control trial. Cancer. 2004;100:590–597.

    Article  CAS  PubMed  Google Scholar 

  31. Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 1986;46:5276–5281.

    CAS  PubMed  Google Scholar 

  32. Moolten FL, Vonderhaar BK, Mroz PJ . Transduction of the herpes thymidine kinase gene into premalignant murine mammary epithelial cells renders subsequent breast cancers responsive to ganciclovir therapy. Hum Gene Ther. 1996;7:1197–1204.

    Article  CAS  PubMed  Google Scholar 

  33. Kwong YL, Chen SH, Kosai K, Finegold MJ, Woo SL . Adenoviral-mediated suicide gene therapy for hepatic metastases of breast cancer. Cancer Gene Ther. 1996;3:339–344.

    CAS  PubMed  Google Scholar 

  34. Deharvengt S, Wack S, Uhring M, Aprahamian M, Hajri A . Suicide gene/prodrug therapy for pancreatic adenocarcinoma by E. coli purine nucleoside phosphorylase and 6-methylpurine 2′-deoxyriboside. Pancreas. 2004;28:E54–E64.

    Article  PubMed  Google Scholar 

  35. Jones RK, Pope IM, Kinsella AR, Watson AJ, Christmas SE . Combined suicide and granulocyte-macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity. Cancer Gene Ther. 2000;7:1519–1528.

    Article  CAS  PubMed  Google Scholar 

  36. Kharbanda S, Emoto Y, Kisaki H, Saleem A, Kufe D . 1-beta-D-arabinofuranosylcytosine activates serine/threonine protein kinases and c-jun gene expression in phorbol ester-resistant myeloid leukemia cells. Mol Pharmacol. 1994;46:67–72.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 200011, Shanghai, P.R. China

    Wei Jiang & Cong-Jian Xu

  2. Department of Surgery, Cancer Hospital, Fudan University, 200032, Shanghai, P.R. China

    Zhi-Min Shao

  3. Experimental Animal Center, Fudan University, 200032, Shanghai, P.R. China

    Wen-Jiang Zhou

  4. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02138, USA

    Bin Ye

  5. National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, 200032, Shanghai, P.R. China

    Pei-Kun Tian, Jin-De Zhu & Jian-Ren Gu

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  1. Wei Jiang
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Correspondence to Cong-Jian Xu.

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Jiang, W., Xu, CJ., Shao, ZM. et al. Enhanced efficiency and specificity of ovarian cancer gene therapy in rats with a novel nonviral gene delivery system (GE7) via intraovarian artery perfusion approach. Cancer Gene Ther 12, 810–817 (2005). https://doi.org/10.1038/sj.cgt.7700845

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