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Folate-linked nanoparticle-mediated suicide gene therapy in human prostate cancer and nasopharyngeal cancer with herpes simplex virus thymidine kinase

Cancer Gene Therapy volume 12, pages 796–809 (2005)Cite this article

Abstract

For targeted gene delivery to human prostate cancer LNCaP and PC-3 cells and nasopharyngeal cancer KB cells, we developed a folate-linked nanoparticle (NP-F), and evaluated the potential of NP-F-mediated suicide gene therapy in the cells and xenografts with herpes simplex virus thymidine kinase (HSV-tk) and connexin 43 (Cx43). An NP-F-plasmid DNA complex (NP-F nanoplex) showed high DNA transfection efficiency in KB, LNCaP and PC-3 cells. Cell growth inhibition in the presence of ganciclovir (GCV) was enhanced with HSV-tk and Cx43 genes in LNCaP cells. In suicide gene therapy, the tumor growths of KB and LNCaP xenografts were significantly inhibited when an NP-F nanoplex of the HSV-tk gene, and HSV-tk and Cx43 genes, respectively, was injected intratumorally and GCV was administered intraperitoneally. These findings suggested that the NP-F is a potential target vector in prostate and nasopharyngeal cancer for suicide gene therapy.

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References

  1. Gao X, Porter AT, Grignon DJ, et al. Diagnostic and prognostic markers for human prostate cancer. Prostate. 1997;31:264–281.

    Article  CAS  PubMed  Google Scholar 

  2. Ellis WJ, Vessella RL, Buhler KR, et al. Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23. Clin Cancer Res. 1996;2:1039–1048.

    CAS  PubMed  Google Scholar 

  3. Mabjeesh NJ, Zhong H, Simons JW . Gene therapy of prostate cancer: current and future directions. Endocr Relat Cancer. 2002;9:115–139.

    Article  CAS  PubMed  Google Scholar 

  4. Yoshimura I, Suzuki S, Tadakuma T, Hayakawa M . Suicide gene therapy on LNCaP human prostate cancer cells. Int J Urol. 2001;8:S5–S8.

    Article  CAS  PubMed  Google Scholar 

  5. Hall SJ, Mutchnik SE, Yang G, et al. Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer. Cancer Gene Ther. 1999;6:54–63.

    Article  CAS  PubMed  Google Scholar 

  6. Fillat C, Carrio M, Cascante A, Sangro B . Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther. 2003;3:13–26.

    Article  CAS  PubMed  Google Scholar 

  7. Mesnil M, Piccoli C, Tiraby G, et al. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA. 1996; 93:1831–1835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tsai H, Werber J, Davia MO, et al. Reduced connexin 43 expression in high grade, human prostatic adenocarcinoma cells. Biochem Biophys Res Commun. 1996;227:64–69.

    Article  CAS  PubMed  Google Scholar 

  9. Habermann H, Ray V, Habermann W, Prins GS . Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer. J Urol. 2002;167: 655–660.

    Article  PubMed  Google Scholar 

  10. Campbell IG, Jones TA, Foulkes WD, Trowsdale J . Folate-binding protein is a marker for ovarian cancer. Cancer Res. 1991;51:5329–5338.

    CAS  PubMed  Google Scholar 

  11. Wu M, Gunning W, Ratnam M . Expression of folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol Biomarkers Prev. 1999;8:775–782.

    CAS  PubMed  Google Scholar 

  12. Ni S, Stephenson SM, Lee RJ . Folate receptor targeted delivery of liposomal daunorubicin into tumor cells. Anticancer Res. 2002;22:2131–2135.

    CAS  PubMed  Google Scholar 

  13. Reddy JA, Abburi C, Hofland H, et al. Folate-targeted, cationic liposome-mediated gene transfer into disseminated peritoneal tumors. Gene Therapy. 2002;9:1542–1550.

    Article  CAS  PubMed  Google Scholar 

  14. Hofland HE, Masson C, Iginla S, et al. Folate-targeted gene transfer in vivo. Mol Ther. 2002;5:739–744.

    Article  CAS  PubMed  Google Scholar 

  15. Ward CM . Folate-targeted non-viral DNA vectors for cancer gene therapy. Curr Opin Mol Ther. 2000;2:182–187.

    CAS  PubMed  Google Scholar 

  16. Holm J, Hansen SI, Hoier-Madsen M . High-affinity folate binding in human prostate. Biosci Rep. 1993;13:99–105.

    Article  CAS  PubMed  Google Scholar 

  17. Hattori Y, Maitani Y . Enhanced in vitro DNA transfection efficiency by novel folate-linked nanoparticles in human prostate cancer and oral cancer. J Control Rel. 2004;97:173–183.

    Article  CAS  Google Scholar 

  18. Miyauchi M, Yoshida Y, Tada Y, et al. Expression of herpes simplex virus-thymidine kinase gene controlled by a promoter region of the midkine gene confers selective cytotoxicity to ganciclovir in human carcinoma cells. Int J Cancer. 2001;91:723–727.

    Article  CAS  PubMed  Google Scholar 

  19. Turek JJ, Leamon CP, Low PS . Endocytosis of folate–protein conjugates: ultrastructural localization in KB cells. J Cell Sci. 1993;106:423–430.

    CAS  PubMed  Google Scholar 

  20. Agbaria R, Candotti F, Kelley JA, et al. Biosynthetic ganciclovir triphosphate: its isolation and characterization from ganciclovir-treated herpes simplex thymidine kinase-transduced murine cells. Biochem Biophys Res Commun. 2001;289:525–530.

    Article  CAS  PubMed  Google Scholar 

  21. Kim TW, Chung H, Kwon IC, et al. Optimization of lipid composition in cationic emulsion as in vitro and in vivo transfection agents. Pharm Res. 2001;18:54–60.

    Article  CAS  PubMed  Google Scholar 

  22. Lee RJ, Low PS . Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J Biol Chem. 1994;269:3198–3204.

    CAS  PubMed  Google Scholar 

  23. Pinto JT, Suffoletto BP, Berzin TM, et al. Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. Clin Cancer Res. 1996;2:1445–1451.

    CAS  PubMed  Google Scholar 

  24. Silver DA, Pellicer I, Fair WR, et al. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81–85.

    CAS  PubMed  Google Scholar 

  25. Rajasekaran SA, Anilkumar G, Oshima E, et al. A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol Biol Cell. 2003;14:4835–4845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hamel W, Magnelli L, Chiarugi VP, Israel MA . Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res. 1996;56:2697–2702.

    CAS  PubMed  Google Scholar 

  27. Mehta PP, Perez-Stable C, Nadji M, et al. Suppression of human prostate cancer cell growth by forced expression of connexin genes. Dev Genet. 1999;24:91–110.

    Article  CAS  PubMed  Google Scholar 

  28. Contreras JE, Saez JC, Bukauskas FF, Bennett MV . Gating and regulation of connexin 43 (Cx43) hemichannels. Proc Natl Acad Sci USA. 2003;100:11388–11393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Musil LS, Goodenough DA . Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J Cell Biol. 1991;115: 1357–1374.

    Article  CAS  PubMed  Google Scholar 

  30. Govindarajan R, Zhao S, Song XH, et al. Impaired trafficking of connexins in androgen-independent human prostate cancer cell lines and its mitigation by alpha-catenin. J Biol Chem. 2002;277:50087–50097.

    Article  CAS  PubMed  Google Scholar 

  31. Lawrence JM, Petitti DB, Watkins M, et al. Trends in serum folate after food fortification. Lancet. 1999;354:915–916.

    Article  CAS  PubMed  Google Scholar 

  32. Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA. 1994;91:8302–8306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Kazuhiro Kubo (NOF Corporation, Tokyo, Japan) for supplying amino-PEG-DSPE. This project was supported in part by a grant from the Promotion and Mutual Aid Corporation for Private Schools of Japan, and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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  1. Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, 142-8501, Tokyo, Japan

    Yoshiyuki Hattori & Yoshie Maitani

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  1. Yoshiyuki Hattori
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  2. Yoshie Maitani
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Correspondence to Yoshie Maitani.

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Hattori, Y., Maitani, Y. Folate-linked nanoparticle-mediated suicide gene therapy in human prostate cancer and nasopharyngeal cancer with herpes simplex virus thymidine kinase. Cancer Gene Ther 12, 796–809 (2005). https://doi.org/10.1038/sj.cgt.7700844

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