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Suppression of ovarian cancer growth via systemic administration with liposome-encapsulated adenovirus-encoding endostatin

Cancer Gene Therapy volume 17, pages 49–57 (2010)Cite this article

Abstract

Gene therapy using adenoviral vector containing the endostatin gene is a promising strategy for advanced cancers. However, host immune response to adenovirus and the lack of the requisite coxsackie-adenovirus receptor (CAR) in many primary cells limit the in vivo application. Liposome-complexed adenoviral vectors have proven to be useful for enhancing gene delivery in target cells that lack adenoviral receptors and avoiding a neutralizing antibody response. Here, we investigated antitumor effects of intravenous administration with PEG-PE cationic liposome-encapsulated recombinant human endostatin adenovirus (Ad-hEndo) on CAR-negative ovarian cancer. Electron micrography (EM) showed that these liposomes efficiently encapsulated the vectors, allowing CAR-independent adenovector transduction. The results showed that the complex enhanced transfection efficiency of recombinant adenovirus. Prolonged systemic administration was performed in immunocompetent mice and did not induce significant antibody response. The antitumor effect with PEG-PE cationic liposome encapsulated with Ad-hE (Ad-hE/lipo) was evaluated in the human ovarian cancer model. Systemic administration was well tolerated and resulted in marked suppression of tumor growth in an established ovarian cancer model, which was associated with a decreased number of micro-vessels and increased apoptosis of tumor cells. Our study shows that PEG-PE cationic liposome-encapsulated Ad-hE (Ad-hE/Lipo) can be administrated intravenously and lastingly to inhibit angiogenesis, thus showing promising clinical application.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43–66.

    Article  Google Scholar 

  2. Folkman J . Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.

    Article  CAS  Google Scholar 

  3. Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L . Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 1999; 59: 4770–4775.

    CAS  PubMed  Google Scholar 

  4. Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJ . Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst 1998; 90: 447–454.

    Article  CAS  Google Scholar 

  5. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–285.

    Article  Google Scholar 

  6. Dhanabal M, Volk R, Ramchandran R, Simons M, Sukhatme VP . Cloning, expression, and in vitro activity of human endostatin. Biochem Biophys Res Commun 1999; 258: 345–352.

    Article  CAS  Google Scholar 

  7. Dixelius J, Cross M, Matsumoto T, Sasaki T, Timpl R, Claesson-Welsh L . Endostatin regulates endothelial cell adhesion and cytoskeletal organization. Cancer Res 2002; 62: 1944–1947.

    CAS  PubMed  Google Scholar 

  8. Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B et al. Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J Biol Chem 2002; 277: 16464–16469.

    Article  CAS  Google Scholar 

  9. Boehm T, Folkman J, Browder T, O’Reilly MS . Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390: 404–407.

    Article  CAS  Google Scholar 

  10. Holmgren L, O’Reilly MS, Folkman J . Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995; 1: 149–153.

    Article  CAS  Google Scholar 

  11. O’Reilly MS, Holmgren L, Chen C, Folkman J . Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689–692.

    Article  Google Scholar 

  12. Crystal RG . The body as a manufacturer of endostatin. Nat Biotechnol 1999; 17: 336–337.

    Article  CAS  Google Scholar 

  13. Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T et al. Adenovirus-mediated calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer: bifunctional therapeutic effects on peritoneal cell layer and cancer cells. Clin Cancer Res 2006; 12: 5216–5223.

    Article  CAS  Google Scholar 

  14. Russell W . Adenovirus gene therapy for ovarian cancer. J Natl Cancer Inst 2002; 94: 706–707.

    Article  Google Scholar 

  15. Crystal RG, McElvaney NG, Rosenfeld MA, Chu CS, Mastrangeli A, Hay JG et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 1994; 8: 42–51.

    Article  CAS  Google Scholar 

  16. Dummer R, Hassel JC, Fellenberg F, Eichmuller S, Maier T, Slos P et al. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004; 104: 1631–1638.

    Article  CAS  Google Scholar 

  17. Sterman DH, Recio A, Vachani A, Sun J, Cheung L, DeLong P et al. Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 2005; 11: 7444–7453.

    Article  CAS  Google Scholar 

  18. Li HL, Li S, Shao JY, Lin XB, Cao Y, Jiang WQ et al. Pharmacokinetic and pharmacodynamic study of intratumoral injection of an adenovirus encoding endostatin in patients with advanced tumors. Gene Therapy 2008; 15: 247–256.

    Article  CAS  Google Scholar 

  19. Harvey BG, Maroni J, O’Donoghue KA, Chu KW, Muscat JC, Pippo AL et al. Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther 2002; 13: 15–63.

    Article  CAS  Google Scholar 

  20. Shirakawa T, Terao S, Hinata N, Tanaka K, Takenaka A, Hara I et al. Long-term outcome of phase I/II clinical trial of Ad-OC-TK/VAL gene therapy for hormone-refractory metastatic prostate cancer. Hum Gene Ther 2007; 18: 1225–1232.

    Article  CAS  Google Scholar 

  21. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–885.

    Article  CAS  Google Scholar 

  22. Brody SL, Metzger M, Danel C, Rosenfeld MA, Crystal RG . Acute responses of non-human primates to airway delivery of an adenovirus vector containing the human cystic fibrosis transmembrane conductance regulator cDNA. Hum Gene Ther 1994; 5: 821–836.

    Article  CAS  Google Scholar 

  23. Kaplan JM, St George JA, Pennington SE, Keyes LD, Johnson RP, Wadsworth SC et al. Humoral and cellular immune responses of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2. Gene Therapy 1996; 3: 117–127.

    CAS  PubMed  Google Scholar 

  24. Jooss K, Ertl HC, Wilson JM . Cytotoxic T-lymphocyte target proteins and their major histocompatibility complex class I restriction in response to adenovirus vectors delivered to mouse liver. J Virol 1998; 72: 2945–2954.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yotnda P, Chen DH, Chiu W, Piedra PA, Davis A, Templeton NS et al. Bilamellar cationic liposomes protect adenovectors from preexisting humoral immune responses. Mol Ther 2002; 5: 233–241.

    Article  CAS  Google Scholar 

  26. Steel JC, Cavanagh HM, Burton MA, Abu-Asab MS, Tsokos M, Morris JC et al. Increased tumor localization and reduced immune response to adenoviral vector formulated with the liposome DDAB/DOPE. Eur J Pharm Sci 2007; 30: 398–405.

    Article  CAS  Google Scholar 

  27. Raja-Walia R, Webber J, Naftilan J, Chapman GD, Naftilan AJ . Enhancement of liposome-mediated gene transfer into vascular tissue by replication deficient adenovirus. Gene Therapy 1995; 2: 521–530.

    CAS  PubMed  Google Scholar 

  28. Qiu C, De Young MB, Finn A, Dichek DA . Cationic liposomes enhance adenovirus entry via a pathway independent of the fiber receptor and alpha(v)-integrins. Hum Gene Ther 1998; 9: 507–520.

    Article  CAS  Google Scholar 

  29. Steel JC, Cavanagh HM, Burton MA, Kalle WH . Microsphere-liposome complexes protect adenoviral vectors from neutralising antibody without losses in transfection efficiency, in-vitro. J Pharm Pharmacol 2004; 56: 1371–1378.

    Article  CAS  Google Scholar 

  30. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  Google Scholar 

  31. Chillon M, Lee JH, Fasbender A, Welsh MJ . Adenovirus complexed with polyethylene glycol and cationic lipid is shielded from neutralizing antibodies in vitro. Gene Therapy 1998; 5: 995–1002.

    Article  CAS  Google Scholar 

  32. Buller RE, Runnebaum IB, Karlan BY, Horowitz JA, Shahin M, Buekers T et al. A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther 2002; 9: 553–566.

    Article  CAS  Google Scholar 

  33. Alvarez RD, Gomez-Navarro J, Wang M, Barnes MN, Strong TV, Arani RB et al. Adenoviral-mediated suicide gene therapy for ovarian cancer. Mol Ther 2000; 2: 524–530.

    Article  CAS  Google Scholar 

  34. Hemminki A, Belousova N, Zinn KR, Liu B, Wang M, Chaudhuri TR et al. An adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression. Mol Ther 2001; 4: 223–231.

    Article  CAS  Google Scholar 

  35. Cripe TP, Dunphy EJ, Holub AD, Saini A, Vasi NH, Mahller YY et al. Fiber knob modifications overcome low, heterogeneous expression of the coxsackievirus-adenovirus receptor that limits adenovirus gene transfer and oncolysis for human rhabdomyosarcoma cells. Cancer Res 2001; 61: 2953–2960.

    CAS  PubMed  Google Scholar 

  36. Raschperger E, Thyberg J, Pettersson S, Philipson L, Fuxe J, Pettersson RF . The coxsackie- and adenovirus receptor (CAR) is an in vivo marker for epithelial tight junctions, with a potential role in regulating permeability and tissue homeostasis. Exp Cell Res 2006; 312: 1566–1580.

    Article  CAS  Google Scholar 

  37. Kreuzer J, Denger S, Reifers F, Beisel C, Haack K, Gebert J et al. Adenovirus-assisted lipofection: efficient in vitro gene transfer of luciferase and cytosine deaminase to human smooth muscle cells. Atherosclerosis 1996; 124: 49–60.

    Article  CAS  Google Scholar 

  38. Sung MW, Lee SG, Yoon SJ, Lee HJ, Heo DS, Kim KH et al. Cationic liposome-enhanced adenoviral gene transfer in a murine head and neck cancer model. Anticancer Res 2000; 20: 1653–1656.

    CAS  PubMed  Google Scholar 

  39. Fasbender A, Zabner J, Chillon M, Moninger TO, Puga AP, Davidson BL et al. Complexes of adenovirus with polycationic polymers and cationic lipids increase the efficiency of gene transfer in vitro and in vivo. J Biol Chem 1997; 272: 6479–6489.

    Article  CAS  Google Scholar 

  40. Lee SG, Yoon SJ, Kim CD, Kim K, Lim DS, Yeom YI et al. Enhancement of adenoviral transduction with polycationic liposomes in vivo. Cancer Gene Ther 2000; 7: 1329–1335.

    Article  CAS  Google Scholar 

  41. Byk T, Haddada H, Vainchenker W, Louache F . Lipofectamine and related cationic lipids strongly improve adenoviral infection efficiency of primitive human hematopoietic cells. Hum Gene Ther 1998; 9: 2493–2502.

    Article  CAS  Google Scholar 

  42. Lee EM, Hong SH, Lee YJ, Kang YH, Choi KC, Choi SH et al. Liposome-complexed adenoviral gene transfer in cancer cells expressing various levels of coxsackievirus and adenovirus receptor. J Cancer Res Clin Oncol 2004; 130: 169–177.

    Article  CAS  Google Scholar 

  43. Natsume A, Mizuno M, Ryuke Y, Yoshida J . Cationic liposome conjugation to recombinant adenoviral vector reduces viral antigenicity. Jpn J Cancer Res 2000; 91: 363–367.

    Article  CAS  Google Scholar 

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Acknowledgements

Grant support was provided by National 973 Basic Research Program of China (2006CB504303).

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Author notes

  1. L Yang, L Wang and Y-s Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Biotherapy, West China Hospital, and School of life Science, Sichuan University, Gaoxin District, Chengdu, Sichuan, PRC

    L Yang, X-q Su, L Wang, X-c Chen, D Li, S-t Luo, H-s Shi, L-j Chen & Y-s Wang

  2. Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, PRC

    L Wang

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Correspondence to Y-s Wang.

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Yang, L., Wang, L., Su, Xq. et al. Suppression of ovarian cancer growth via systemic administration with liposome-encapsulated adenovirus-encoding endostatin. Cancer Gene Ther 17, 49–57 (2010). https://doi.org/10.1038/cgt.2009.47

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