Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth

Cancer Gene Therapy volume 14, pages 19–29 (2007)Cite this article

Abstract

Pancreatic cancer is one of the most aggressive and devastating human malignancies. There is an urgent need for more effective therapy for patients with advanced disease. In this context, genetic therapy potentially represents a rational new approach to treating pancreatic cancer, which could provide an adjunct to conventional options. Because of the promise of recombinant SV40 vectors, we tested their ability to deliver a transgene, and to target a transcript, so as to inhibit pancreatic tumors growth in vivo. BxPC3 and Capan-1 cells were efficiently transduced using SV40 vectors without selection, as compared to synthetic vectors PEI. SV40 vectors were as efficient as adenoviral vectors, and provided long-term transgene expression. Next, we devised a SV40-derived, targeted gene therapy approach of pancreatic cancer, by combining hTR tumor-specific promoter with sst2 somatostatin receptor tumor-suppressor gene. In vitro cell proliferation was strongly impaired following administration of SV(hTR-sst2). SV40-derived sst2-mediated antiproliferative effect was dependent on the local production of somatostatin. In vivo, intratumoral gene transfer of sst2 using rSV40 vectors resulted in a marked inhibition of Capan-1 tumor progression, and proliferation. These results represent the initial steps toward a novel approach to the gene therapy of pancreatic cancer using SV40 as a vector.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Safioleas MC, Moulakakis KG . Pancreatic cancer today. Hepatogastroenterology 2004; 51: 862–868.

    PubMed  Google Scholar 

  2. Jemal A, Thomas A, Murray T, Thun M . Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23–47.

    Article  PubMed  Google Scholar 

  3. Rosewicz S, Wiedenmann B . Pancreatic carcinoma. Lancet 1997; 349: 485–489.

    Article  CAS  PubMed  Google Scholar 

  4. Jafari M, Abbruzzese JL, Goldstein D, Carroll S, Apte M, Keogh G . Pancreatic cancer: future outlook, promising trials, newer systemic agents, and strategies from the Gastrointestinal Intergroup Pancreatic Cancer Task Force Modern management of pancreatic carcinoma. Surg Oncol Clin N Am 2004; 13: 751–760.

    Article  PubMed  Google Scholar 

  5. Kulke MH . Metastatic pancreatic cancer. Curr Treat Options Oncol 2002; 3: 449–457.

    Article  PubMed  Google Scholar 

  6. Bardeesy N, DePinho RA . Pancreatic cancer biology and genetics. Nat Rev Cancer 2002; 2: 897–909.

    Article  CAS  PubMed  Google Scholar 

  7. Tsai JY, Iannitti DA, Safran H . Combined modality therapy for pancreatic cancer. Semin Oncol 2003; 30: 71–79.

    Article  CAS  PubMed  Google Scholar 

  8. Blaszkowsky L . Treatment of advanced and metastatic pancreatic cancer. Front Biosci 1998; 3: E214–E225.

    Article  CAS  PubMed  Google Scholar 

  9. McClane SJ, Chirmule N, Burke CV, Raper SE . Characterization of the immune response after local delivery of recombinant adenovirus in murine pancreas and successful strategies for readministration. Hum Gene Ther 1997; 8: 2207–2216.

    Article  CAS  PubMed  Google Scholar 

  10. McClane SJ, Hamilton TE, Burke CV, Raper SE . Functional consequences of adenovirus-mediated murine pancreatic gene transfer. Hum Gene Ther 1997; 8: 739–746.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang N, Schroppel B, Chen D, Fu S, Hudkins KL, Zhang H et al. Adenovirus transduction induces expression of multiple chemokines and chemokine receptors in murine beta cells and pancreatic islets. Am J Transplant 2003; 3: 1230–1241.

    Article  CAS  PubMed  Google Scholar 

  12. Pearson AS, Koch PE, Atkinson N, Xiong M, Finberg RW, Roth JA et al. Factors limiting adenovirus-mediated gene transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999; 5: 4208–4213.

    CAS  PubMed  Google Scholar 

  13. Strayer DS, Cordelier P, Kondo R, Liu B, Matskevich AA, McKee HJ et al. What they are, how they work and why they do what they do? The story of SV40-derived gene therapy vectors and what they have to offer. Curr Gene Ther 2005; 5: 151–165.

    Article  CAS  PubMed  Google Scholar 

  14. Benali N, Cordelier P, Calise D, Pages P, Rochaix P, Nagy A et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238. Proc Natl Acad Sci USA 2000; 97: 9180–9185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Buscail L, Saint-Laurent N, Chastre E, Vaillant JC, Gespach C, Capella G et al. Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Res 1996; 56: 1823–1827.

    CAS  PubMed  Google Scholar 

  16. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res 1999; 59: 551–557.

    CAS  PubMed  Google Scholar 

  17. Zhao JQ, Hoare SF, McFarlane R, Muir S, Parkinson EK, Black DM et al. Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene 1998; 16: 1345–1350.

    Article  CAS  PubMed  Google Scholar 

  18. 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  PubMed  PubMed Central  Google Scholar 

  19. Nyberg-Hoffman C, Shabram P, Li W, Giroux D, Aguilar-Cordova E . Sensitivity and reproducibility in adenoviral infectious titer determination. Nat Med 1997; 3: 808–811.

    Article  CAS  PubMed  Google Scholar 

  20. Strayer DS . Gene therapy using SV40-derived vectors: what does the future hold? J Cell Physiol 1999; 181: 375–384.

    Article  CAS  PubMed  Google Scholar 

  21. Arad U, Ben-Nun-Shaul O, El-Latif MA, Nissim O, Oppenheim A . A new packaging cell line for SV40 vectors that eliminates the generation of T-antigen-positive, replication-competent recombinants. Virology 2002; 304: 155–159.

    Article  CAS  PubMed  Google Scholar 

  22. Cordelier P, Morse B, Strayer DS . Targeting CCR5 with siRNAs: using recombinant SV40-derived vectors to protect macrophages and microglia from R5-tropic HIV. Oligonucleotides 2003; 13: 281–294.

    Article  CAS  PubMed  Google Scholar 

  23. Strayer DS . SV40-based gene therapy vectors: turning an adversary into a friend. Curr Opin Mol Ther 2000; 2: 570–578.

    CAS  PubMed  Google Scholar 

  24. Strayer DS, Lamothe M, Wei D, Milano J, Kondo R . Generation of recombinant SV40 vectors for gene transfer. Methods Mol Biol 2001; 165: 103–117.

    CAS  PubMed  Google Scholar 

  25. Rohr UP, Wulf MA, Stahn S, Steidl U, Haas R, Kronenwett R . Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. J Virol Methods 2002; 106: 81–88.

    Article  CAS  PubMed  Google Scholar 

  26. Vera M, Prieto J, Strayer DS, Fortes P . Factors influencing the production of recombinant SV40 vectors. Mol Ther 2004; 10: 780–791.

    Article  CAS  PubMed  Google Scholar 

  27. Shi L, Ho J, Norling LA, Roy M, Xu Y . A real time quantitative PCR-based method for the detection and quantification of simian virus 40. Biologicals 1999; 27: 241–252.

    Article  CAS  PubMed  Google Scholar 

  28. Gibbs RA . DNA amplification by the polymerase chain reaction. Anal Chem 1990; 62: 1202–1214.

    Article  CAS  PubMed  Google Scholar 

  29. Buscail L, Esteve JP, Saint-Laurent N, Bertrand V, Reisine T, O'Carroll AM et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci USA 1995; 92: 1580–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  PubMed  Google Scholar 

  31. Rauly I, Saint-Laurent N, Delesque N, Buscail L, Esteve JP, Vaysse N et al. Induction of a negative autocrine loop by expression of sst2 somatostatin receptor in NIH 3T3 cells. J Clin Invest 1996; 97: 1874–1883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vernejoul F, Faure P, Benali N, Calise D, Tiraby G, Pradayrol L et al. Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. Cancer Res 2002; 62: 6124–6131.

    CAS  PubMed  Google Scholar 

  33. Carrere N, Vernejoul F, Souque A, Asnacios A, Vaysse N, Pradayrol L et al. Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells. Hum Gene Ther 2005; 16: 1175–1193.

    Article  CAS  PubMed  Google Scholar 

  34. Delesque N, Buscail L, Esteve JP, Saint-Laurent N, Muller C, Weckbecker G et al. sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells. Cancer Res 1997; 57: 956–962.

    CAS  PubMed  Google Scholar 

  35. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2015.

    Article  CAS  PubMed  Google Scholar 

  36. Bilsland AE, Anderson CJ, Fletcher-Monaghan AJ, McGregor F, Evans TR, Ganly I et al. Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Oncogene 2003; 22: 370–380.

    Article  CAS  PubMed  Google Scholar 

  37. Gu J, Andreeff M, Roth JA, Fang B . hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity. Gene Therapy 2002; 9: 30–37.

    Article  CAS  PubMed  Google Scholar 

  38. Huang X, Lin T, Gu J, Zhang L, Roth JA, Stephens LC et al. Combined TRAIL and Bax gene therapy prolonged survival in mice with ovarian cancer xenograft. Gene Therapy 2002; 9: 1379–1386.

    Article  CAS  PubMed  Google Scholar 

  39. Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP . The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters. Gene Therapy 2001; 8: 568–578.

    Article  CAS  PubMed  Google Scholar 

  40. Plumb JA, Bilsland A, Kakani R, Zhao J, Glasspool RM, Knox RJ et al. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Oncogene 2001; 20: 7797–7803.

    Article  CAS  PubMed  Google Scholar 

  41. Aoki K, Yoshida T, Sugimura T, Terada M . Liposome-mediated in vivo gene transfer of antisense K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity. Cancer Res 1995; 55: 3810–3816.

    CAS  PubMed  Google Scholar 

  42. Hatanaka K, Suzuki K, Miura Y, Yoshida K, Ohnami S, Kitade Y et al. Interferon-alpha and antisense K-ras RNA combination gene therapy against pancreatic cancer. J Gene Med 2004; 6: 1139–1148.

    Article  CAS  PubMed  Google Scholar 

  43. Ndoye A, Merlin JL, Leroux A, Dolivet G, Erbacher P, Behr JP et al. Enhanced gene transfer and cell death following p53 gene transfer using photochemical internalisation of glucosylated PEI-DNA complexes. J Gene Med 2004; 6: 884–894.

    Article  CAS  PubMed  Google Scholar 

  44. Brummelkamp TR, Bernards R, Agami R . Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2: 243–247.

    Article  CAS  PubMed  Google Scholar 

  45. Buchler P, Reber HA, Ullrich A, Shiroiki M, Roth M, Buchler MW et al. Pancreatic cancer growth is inhibited by blockade of VEGF-RII. Surgery 2003; 134: 772–782.

    Article  PubMed  Google Scholar 

  46. Chen LM, Le HY, Qin RY, Kumar M, Du ZY, Xia RJ et al. Reversal of the phenotype by K-rasval12 silencing mediated by adenovirus-delivered siRNA in human pancreatic cancer cell line Panc-1. World J Gastroenterol 2005; 11: 831–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Noro T, Miyake K, Suzuki-Miyake N, Igarashi T, Uchida E, Misawa T et al. Adeno-associated viral vector-mediated expression of endostatin inhibits tumor growth and metastasis in an orthotropic pancreatic cancer model in hamsters. Cancer Res 2004; 64: 7486–7490.

    Article  CAS  PubMed  Google Scholar 

  48. Ugai S, Shimozato O, Yu L, Wang YQ, Kawamura K, Yamamoto H et al. Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects. Cancer Gene Ther 2003; 10: 771–778.

    Article  CAS  PubMed  Google Scholar 

  49. McClane SJ, Hamilton TE, DeMatteo RP, Burke C, Raper SE . Effect of adenoviral early genes and the host immune system on in vivo pancreatic gene transfer in the mouse. Pancreas 1997; 15: 236–245.

    Article  CAS  PubMed  Google Scholar 

  50. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, O'Malley KL et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994; 8: 148–154.

    Article  CAS  PubMed  Google Scholar 

  51. Shi W, Teschendorf C, Muzyczka N, Siemann DW . Adeno-associated virus-mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo. Cancer Gene Ther 2002; 9: 513–521.

    Article  CAS  PubMed  Google Scholar 

  52. Cordelier P, Van Bockstaele E, Calarota SA, Strayer DS . Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV. Mol Ther 2003; 7: 801–810.

    Article  CAS  PubMed  Google Scholar 

  53. Strayer DS . SV40 as an effective gene transfer vector in vivo. J Biol Chem 1996; 271: 24741–24746.

    CAS  PubMed  Google Scholar 

  54. Strayer DS . Gene delivery to human hematopoietic progenitor cells to address inherited defects in the erythroid cellular lineage. J Hematother Stem Cell Res 1999; 8: 573–574.

    Article  CAS  PubMed  Google Scholar 

  55. Strayer DS . Effective gene transfer using viral vectors based on SV40. Methods Mol Biol 2000; 133: 61–74.

    CAS  PubMed  Google Scholar 

  56. Strayer DS, Kondo R, Milano J, Duan LX . Use of SV40-based vectors to transduce foreign genes to normal human peripheral blood mononuclear cells. Gene Therapy 1997; 4: 219–225.

    Article  CAS  PubMed  Google Scholar 

  57. Strayer DS, Milano J . SV40 mediates stable gene transfer in vivo. Gene Therapy 1996; 3: 581–587.

    CAS  PubMed  Google Scholar 

  58. Strayer DS, Zern MA . Gene delivery to the liver using simian virus 40-derived vectors. Semin Liver Dis 1999; 19: 71–81.

    Article  CAS  PubMed  Google Scholar 

  59. Guillermet J, Saint-Laurent N, Rochaix P, Cuvillier O, Levade T, Schally AV et al. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc Natl Acad Sci USA 2003; 100: 155–160.

    Article  CAS  PubMed  Google Scholar 

  60. Liu B, Daviau J, Nichols CN, Strayer DS . In vivo gene transfer into rat bone marrow progenitor cells using rSV40 viral vectors. Blood 2005; 106: 2655–2662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sauter BV, Parashar B, Chowdhury NR, Kadakol A, Ilan Y, Singh H et al. A replication-deficient rSV40 mediates liver-directed gene transfer and a long-term amelioration of jaundice in gunn rats. Gastroenterology 2000; 119: 1348–1357.

    Article  CAS  PubMed  Google Scholar 

  62. Duan YY, Wu J, Zhu JL, Liu SL, Ozaki I, Strayer DS et al. Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors. Gastroenterology 2004; 127: 1222–1232.

    Article  CAS  PubMed  Google Scholar 

  63. Strayer D, Branco F, Zern MA, Yam P, Calarota SA, Nichols CN et al. Durability of transgene expression and vector integration: recombinant SV40-derived gene therapy vectors. Mol Ther 2002; 6: 227–237.

    Article  CAS  PubMed  Google Scholar 

  64. Pipas JM . Common and unique features of T antigens encoded by the polyomavirus group. J Virol 1992; 66: 3979–3985.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schirmbeck R, von der Weth A, Deppert W . Structural requirements for simian virus 40 replication and virion maturation. J Virol 1993; 67: 894–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Baiker A, Maercker C, Piechaczek C, Schmidt SB, Bode J, Benham C et al. Mitotic stability of an episomal vector containing a human scaffold/matrix-attached region is provided by association with nuclear matrix. Nat Cell Biol 2000; 2: 182–184.

    Article  CAS  PubMed  Google Scholar 

  67. Rochaix P, Delesque N, Esteve JP, Saint-Laurent N, Voight JJ, Vaysse N et al. Gene therapy for pancreatic carcinoma: local and distant antitumor effects after somatostatin receptor sst2 gene transfer. Hum Gene Ther 1999; 10: 995–1008.

    Article  CAS  PubMed  Google Scholar 

  68. Buscail L, Pages P, Berthelemy P, Fourtanier G, Frexinos J, Escourrou J . Role of EUS in the management of pancreatic and ampullary carcinoma: a prospective study assessing resectability and prognosis. Gastrointest Endosc 1999; 50: 34–40.

    Article  CAS  PubMed  Google Scholar 

  69. Costentin L, Pages P, Bouisson M, Berthelemy P, Buscail L, Escourrou J et al. Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic diseases. Pancreatology 2002; 2: 17–25.

    Article  CAS  PubMed  Google Scholar 

  70. Kern SE . Molecular genetic alterations in ductal pancreatic adenocarcinomas. Med Clin North Am 2000; 84: 691–695 xi.

    Article  CAS  PubMed  Google Scholar 

  71. Korc M . Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 1998; 7: 25–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was in part supported by grants from la Ligue Nationale Contre Le Cancer (PC, BL-3 laboratory), la Fondation pour la Recherche Médicale (FM), la Région Midi-Pyrénées, and Cancéropôle GSO (BL-3 laboratory).

Author information

Authors and Affiliations

  1. INSERM U531, Institut Louis Bugnard, IFR31, Toulouse, France

    P Cordelier, C Bienvenu, H Lulka, F Marrache, M Bouisson, N Vaysse, L Pradayrol & L Buscail

  2. Department of Hematology, Molecular Biology and Cellular Medicine, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    A Openheim

  3. Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    D S Strayer

Authors
  1. P Cordelier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Bienvenu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Lulka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Marrache
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Bouisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Openheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D S Strayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Vaysse
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Pradayrol
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Buscail
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Cordelier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cordelier, P., Bienvenu, C., Lulka, H. et al. Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth. Cancer Gene Ther 14, 19–29 (2007). https://doi.org/10.1038/sj.cgt.7700987

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700987

Keywords

This article is cited by

Search

Advanced search

Quick links