Inhibitory effects of the ultrasound‑targeted microbubble destruction‑mediated herpes simplex virus‑thymidine kinase/ganciclovir system on ovarian cancer in mice

Zhou,Xian‑Long; Shi,Yu‑Lu; Li,Xiong

doi:10.3892/etm.2014.1877

Inhibitory effects of the ultrasound‑targeted microbubble destruction‑mediated herpes simplex virus‑thymidine kinase/ganciclovir system on ovarian cancer in mice

Authors:
- Xian‑Long Zhou
- Yu‑Lu Shi
- Xiong Li
View Affiliations

Affiliations: Emergency Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China, Medical College of Wuhan University, Wuhan, Hubei 430072, P.R. China, Department of Ultrasound, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: August 4, 2014 https://doi.org/10.3892/etm.2014.1877
Pages: 1159-1163

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the effect of the ultrasound‑targeted microbubble destruction mediated (UTMD) herpes simplex virus‑thymidine kinase (HSV‑TK) and ganciclovir (GCV) system on ovarian cancer (OC). This study was conducted between June and December 2012 in the Animal Biosafety Level III Laboratory of Wuhan University. Mice with OC were randomly divided into four groups: i) HSV‑TK plus microbubbles (MBs) plus ultrasound (US) (n=15); ii) HSV‑TK plus US (n=15); iii) HSV‑TK (n=15); and iv) phosphate‑buffered saline (n=15). The inhibitory effect and survival time in the experimental groups were compared with those in the control group. The TK protein expression was detected by western blot analysis. Tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling and caspase‑3 activity analysis. The data showed that the efficiency of HSV‑TK gene transfection and the tumor inhibitory effects were significantly increased in the HSV‑TK plus MBs plus US group compared with those in the control group (P<0.01). UTMD‑mediated HSV‑TK treatment has also improved the rat survival rate (P<0.01). In conclusion, UTMD can effectively transfect the HSV‑TK gene into target tissues and exert a significant inhibitory effect on OC in mice.

View Figures

View References

1	Runnebaum IB and Stickeler E: Epidemiological and molecular aspects of ovarian cancer risk. J Cancer Res Clin Oncol. 127:73–79. 2001. View Article : Google Scholar : PubMed/NCBI
2	Lin HW, Tu YY, Lin SY, Su WJ, Lin WL, Lin WZ, Wu SC and Lai YL: Risk of ovarian cancer in women with pelvic inflammatory disease: a population-based study. Lancet Oncol. 12:900–904. 2011. View Article : Google Scholar : PubMed/NCBI
3	Rocconi RP, Numnum TM, Stoff-Khalili M, Makhija S, Alvarez RD and Curiel DT: Targeted gene therapy for ovarian cancer. Curr Gene Ther. 5:643–653. 2005. View Article : Google Scholar : PubMed/NCBI
4	Yap TA, Carden CP and Kaye SB: Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer. 9:167–181. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kimball KJ, Numnum TM, Rocconi RP and Alvarez RD: Gene therapy for ovarian cancer. Curr Oncol Rep. 8:441–447. 2006. View Article : Google Scholar
6	Rainov NG: A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 11:2389–2401. 2000. View Article : Google Scholar
7	Shand N, Weber F, Mariani L, Bernstein M, Gianella-Borradori A, Long Z, Sorensen AG and Barbier N: A phase 1–2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther. 10:2325–2335. 1999.
8	Aoi A, Watanabe Y, Mori S, Takahashi M, Vassaux G and Kodama T: Herpes simplex virus thymidine kinase-mediated suicide gene therapy using nano/microbubbles and ultrasound. Ultrasound Med Biol. 34:425–434. 2008. View Article : Google Scholar : PubMed/NCBI
9	Chen Z, Liang K, Liu J, Xie M, Wang X, Lü Q, Zhang J and Fang L: Enhancement of survivin gene downregulation and cell apoptosis by a novel combination: liposome microbubbles and ultrasound exposure. Med Oncol. 26:491–500. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kaur T, Slavcev RA and Wettig SD: Addressing the challenge: current and future directions in ovarian cancer therapy. Curr Gene Ther. 9:434–458. 2009. View Article : Google Scholar : PubMed/NCBI
11	Piscaglia F and Bolondi L: Italian Society for Ultrasound in Medicine and Biology (SIUMB) Study Group on Ultrasound Contrast Agents: The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol. 32:1369–1375. 2006. View Article : Google Scholar
12	Chen S, Shimoda M, Wang MY, Ding J, Noguchi H, Matsumoto S and Grayburn PA: Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Ther. 17:1411–1420. 2010. View Article : Google Scholar : PubMed/NCBI
13	Fujii H, Sun Z, Li SH, Wu J, Fazel S, Weisel RD, Rakowski H, Lindner J and Li RK: Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice. JACC Cardiovasc Imaging. 2:869–879. 2009. View Article : Google Scholar : PubMed/NCBI
14	Delalande A, Bureau MF, Midoux P, Bouakaz A and Pichon C: Ultrasound-assisted microbubbles gene transfer in tendons for gene therapy. Ultrasonics. 50:269–272. 2010. View Article : Google Scholar : PubMed/NCBI
15	Wang ZX, Wang ZG, Ran HT, Ren JL, Zhang Y, Li Q, Zhu YF and Ao M: The treatment of liver fibrosis induced by hepatocyte growth factor-directed, ultrasound-targeted microbubble destruction in rats. Clin Imaging. 33:454–61. 2009. View Article : Google Scholar : PubMed/NCBI
16	Zhou S, Li S, Liu Z, Tang Y, Wang Z, Gong J and Liu C: Ultrasound-targeted microbubble destruction mediated herpes simplex virus-thymidine kinase gene treats hepatoma in mice. J Exp Clin Cancer Res. 29:1702010. View Article : Google Scholar
17	Khaider NG, Lane D, Matte I, Rancourt C and Piché A: Targeted ovarian cancer treatment: the TRAILs of resistance. Am J Cancer Res. 2:75–92. 2012.PubMed/NCBI
18	Weberpals JI, Koti M and Squire JA: Targeting genetic and epigenetic alterations in the treatment of serous ovarian cancer. Cancer Genet. 204:525–535. 2011. View Article : Google Scholar : PubMed/NCBI
19	Chen Z, Xie M, Wang X, Lv Q and Ding S: Effects of lipid shell microbubble on ultrasound mediated EGFP gene delivery to transplanted tumors: initial experience. Chin-Ger J Clin Oncol. 7:424–428. 2008. View Article : Google Scholar
20	Liu P, Gao YH, Tan KB, Liu Z and Zuo S: Grey scale enhancement of rabbit liver and kidney by intravenous injection of a new lipid-coated ultrasound contrast agent. World J Gastroenterol. 10:2369–2372. 2004.PubMed/NCBI
21	Carson AR, McTiernan CF, Lavery L, Hodnick A, Grata M, Leng X, Wang J, Chen X, Modzelewski RA and Villanueva FS: Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. Ultrasound Med Biol. 37:393–402. 2011. View Article : Google Scholar : PubMed/NCBI
22	Meijering BD, Juffermans LJ, van Wamel A, Henning RH, Zuhorn IS, Emmer M, Versteilen AM, Paulus WJ, van Gilst WH, Kooiman K, de Jong N, Musters RJ, Deelman LE and Kamp O: Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation. Circ Res. 104:679–687. 2009. View Article : Google Scholar : PubMed/NCBI
23	Wang Y, Canine BF and Hatefi A: HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector. Nanomedicine. 7:193–200. 2011. View Article : Google Scholar : PubMed/NCBI
24	Nicholas TW, Read SB, Burrows FJ and Kruse CA: Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects. Histol Histopathol. 18:495–507. 2003.PubMed/NCBI
25	Mesnil M and Yamasaki H: Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 60:3989–3999. 2000.