Pancreatic Cancer pp 1237-1268 | Cite as

Gene Therapy for Pancreatic Cancer

  • Han Hsi Wong
  • Nicholas R. Lemoine
Reference work entry


Pancreatic cancer has high morbidity and mortality and remains one of the most difficult cancers to treat. Clearly there is a strong need for the development of novel therapeutic approaches. Since the first clinical trial in 1990, gene therapy has improved and expanded tremendously, largely due to the advancement in molecular technology. It involves the introduction of exogenous nucleic acids to express, restore, or inhibit a gene of interest to reverse or destroy the malignant phenotype of cancer cells. Recent understanding of the genetics and pathogenesis of pancreatic cancer has generated a large number of studies targeting these abnormalities, albeit with variable levels of success.

In this chapter, gene delivery systems (viral and nonviral), molecular targets, and gene therapy approaches in the context of pancreatic cancer treatment are discussed. These include the RNA-directed strategies, dominant-negative mutants, gene restoration, gene-directed prodrug activation therapy, oncolytic viruses, and immunotherapy. In each section the genetic and molecular aberrations of pancreatic cancer are introduced, followed by results from laboratory studies and subsequent clinical trials, where available.


Vascular Endothelial Growth Factor Pancreatic Cancer Hepatocyte Growth Factor Pancreatic Cancer Cell Adenoviral Vector 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Wong HH, Lemoine NR: Biological approaches to therapy of pancreatic cancer. Pancreatology 2008; 8:431–461.Google Scholar
  2. 2.
    Kasuya H, Mizuno M, Yoshida J, Nishiyama Y, Nomoto S, Nakao A: Combined effects of adeno-associated virus vector and a herpes simplex virus mutant as neoplastic therapy. J Surg Oncol 2000;74:214–218.CrossRefPubMedGoogle Scholar
  3. 3.
    Saraga G, Mafficini A, Ghaneh P, Sorio C, Costello E: Both HIV- and EIAV-based lentiviral vectors mediate gene delivery to pancreatic cancer cells and human pancreatic primary patient xenografts. Cancer Gene Ther 2007;14:781–790.CrossRefPubMedGoogle Scholar
  4. 4.
    Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM: Development of a self-inactivating lentivirus vector. J Virol 1998;72:8150–8157.PubMedGoogle Scholar
  5. 5.
    Liau SS, Ashley SW, Whang EE: Lentivirus-mediated RNA interference of HMGA1 promotes chemosensitivity to gemcitabine in pancreatic adenocarcinoma. J Gastrointest Surg 2006;10:1254–1262; discussion 1263.CrossRefPubMedGoogle Scholar
  6. 6.
    Schmid RM, Weidenbach H, Yamagushi H, Luhrs H, Liptay S, Adler G: Direct gene transfer into the rat pancreas using DNA-liposomes. Eur J Clin Invest 1998;28:220–226.CrossRefPubMedGoogle Scholar
  7. 7.
    Aoki K, Yoshida T, Matsumoto N, Ide H, Hosokawa K, Sugimura T, Terada M: Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene. Hum Gene Ther 1997;8:1105–1113.CrossRefPubMedGoogle Scholar
  8. 8.
    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.PubMedGoogle Scholar
  9. 9.
    Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004;96:1593–1603.CrossRefPubMedGoogle Scholar
  10. 10.
    Kallifatidis G, Beckermann BM, Groth A, Schubert M, Apel A, Khamidjanov A, Ryschich E, Wenger T, Wagner W, Diehlmann A, Saffrich R, Krause U, Eckstein V, Mattern J, Chai M, Schutz G, Ho AD, Gebhard MM, Buchler MW, Friess H, Buchler P, Herr I: Improved lentiviral transduction of human mesenchymal stem cells for therapeutic intervention in pancreatic cancer. Cancer Gene Ther 2008;15:231–240.CrossRefPubMedGoogle Scholar
  11. 11.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960–1966.CrossRefPubMedGoogle Scholar
  12. 12.
    Kijima H, Yamazaki H, Nakamura M, Scanlon KJ, Osamura RY, Ueyama Y: Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer. Int J Oncol 2004;24:559–564.PubMedGoogle Scholar
  13. 13.
    Tsuchida T, Kijima H, Hori S, Oshika Y, Tokunaga T, Kawai K, Yamazaki H, Ueyama Y, Scanlon KJ, Tamaoki N, Nakamura M: Adenovirus-mediated anti-K-ras ribozyme induces apoptosis and growth suppression of human pancreatic carcinoma. Cancer Gene Ther 2000;7:373–383.CrossRefPubMedGoogle Scholar
  14. 14.
    Yoshida T, Ohnami S, Aoki K: Development of gene therapy to target pancreatic cancer. Cancer Sci 2004;95:283–289.CrossRefPubMedGoogle Scholar
  15. 15.
    Alberts SR, Schroeder M, Erlichman C, Steen PD, Foster NR, Moore DF, Jr., Rowland KM, Jr., Nair S, Tschetter LK, Fitch TR: Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J Clin Oncol 2004;22:4944–4950.CrossRefPubMedGoogle Scholar
  16. 16.
    Brummelkamp TR, Bernards R, Agami R: Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002;2:243–247.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang YA, Nemunaitis J, Samuel SK, Chen P, Shen Y, Tong AW: Antitumor activity of an oncolytic adenovirus-delivered oncogene small interfering RNA. Cancer Res 2006;66:9736–9743.CrossRefPubMedGoogle Scholar
  18. 18.
    Takeuchi M, Shichinohe T, Senmaru N, Miyamoto M, Fujita H, Takimoto M, Kondo S, Katoh H, Kuzumaki N: The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice. Gene Ther 2000;7:518–526.CrossRefPubMedGoogle Scholar
  19. 19.
    Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR: Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996;93:3636–3641.CrossRefPubMedGoogle Scholar
  20. 20.
    Stoll V, Calleja V, Vassaux G, Downward J, Lemoine NR: Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut 2005;54:109–116.CrossRefPubMedGoogle Scholar
  21. 21.
    Smith JP, Stanley WB, Verderame MF, Zagon IS: The functional significance of the cholecystokinin-C (CCK-C) receptor in human pancreatic cancer. Pancreas 2004;29:271–277.CrossRefPubMedGoogle Scholar
  22. 22.
    Adachi Y, Yamamoto H, Imsumran A, Wang Y, Li R, Min Y, Arimura Y, Lee C, Shinomura Y, Carbone DP, Imai K: Molecular targeting of IGF-I receptor for human pancreatic cancer. J Clin Oncol (Meeting Abstracts) 2007;25:14051.Google Scholar
  23. 23.
    Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE: Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 2004;135:555–562.CrossRefPubMedGoogle Scholar
  24. 24.
    Duda DG, Sunamura M, Lefter LP, Furukawa T, Yokoyama T, Yatsuoka T, Abe T, Inoue H, Motoi F, Egawa S, Matsuno S, Horii A: Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells. Oncogene 2003;22:6857–6864.CrossRefPubMedGoogle Scholar
  25. 25.
    Stauder G, Bischof A, Egger T, Hafner M, Herrmuth H, Jachimczak P, Kielmanowicz M, Schlingensiepen R, Schlingensiepen KH: TGF-β2 suppression by the antisense oligonucleotide AP 12009 as treatment for pancreatic cancer: preclinical efficacy data. J Clin Oncol (Meeting Abstracts) 2004;22:4106.Google Scholar
  26. 26.
    Hilbig A, Seufferlein T, Schmid RM, Luger T, Oettle H, Schneider G, Schmaus S, Wuerth G, Heinrichs H, Schlingensiepen KH: Preliminary results of a phase I/II study in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma, using systemic i.v. administration of AP 12009. J Clin Oncol (Meeting Abstracts) 2008;26:4621.Google Scholar
  27. 27.
    Chang DZ: Synthetic miRNAs targeting the GLI-1 transcription factor inhibit division and induce apoptosis in pancreatic tumor cells. AACR Meeting Abstracts 2006;2006:639b.Google Scholar
  28. 28.
    Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH: Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006;5:483–493.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang Z, Banerjee S, Li Y, Rahman KM, Zhang Y, Sarkar FH: Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 2006;66:2778–2784.CrossRefPubMedGoogle Scholar
  30. 30.
    Dang T, Vo k, Washington K, Berlin J: The role of Notch3 signaling pathway in pancreatic cancer. J Clin Oncol (Meeting Abstracts) 2007;25:21049.Google Scholar
  31. 31.
    Tsutsumida H, Swanson BJ, Singh PK, Caffrey TC, Kitajima S, Goto M, Yonezawa S, Hollingsworth MA: RNA interference suppression of MUC1 reduces the growth rate and metastatic phenotype of human pancreatic cancer cells. Clin Cancer Res 2006;12:2976–2987.CrossRefPubMedGoogle Scholar
  32. 32.
    Basu GD, Tinder TL, Bradley JM, Gendler SJ, Petris GD, Mukherjee P: Role of MUC1 in pancreatic cancer. AACR Meeting Abstracts 2006;2006:1198b.Google Scholar
  33. 33.
    Kusumoto M, Ogawa T, Mizumoto K, Ueno H, Niiyama H, Sato N, Nakamura M, Tanaka M: Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells. Clin Cancer Res 1999;5:2140–2147.PubMedGoogle Scholar
  34. 34.
    Teng LS, Fahey TJ, 3rd: Can inhibition of telomerase increase pancreatic cancer cell's susceptibility to chemotherapeutic reagents? Hepatobiliary Pancreat Dis Int 2002;1:155–160.PubMedGoogle Scholar
  35. 35.
    Wang YF, Guo KJ, Huang BT, Liu Y, Tang XY, Zhang JJ, Xia Q: Inhibitory effects of antisense phosphorothioate oligodeoxynucleotides on pancreatic cancer cell Bxpc-3 telomerase activity and cell growth in vitro. World J Gastroenterol 2006;12:4004–4008.PubMedGoogle Scholar
  36. 36.
    Bouvet M, Bold RJ, Lee J, Evans DB, Abbruzzese JL, Chiao PJ, McConkey DJ, Chandra J, Chada S, Fang B, Roth JA: Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol 1998;5:681–688.CrossRefPubMedGoogle Scholar
  37. 37.
    Hwang RF, Gordon EM, Anderson WF, Parekh D: Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 1998;124:143–150; discussion 150–141.PubMedGoogle Scholar
  38. 38.
    Cascallo M, Calbo J, Gelpi JL, Mazo A: Modulation of drug cytotoxicity by reintroduction of wild-type p53 gene (Ad5CMV-p53) in human pancreatic cancer. Cancer Gene Ther 2000;7:545–556.CrossRefPubMedGoogle Scholar
  39. 39.
    Yin S, Goodrich DW: Combination gene therapy with p53 and Thoc1/p84 is more effective than either single agent in an animal model of human pancreatic adenocarcinoma. Int J Oncol 2006;28:781–785.PubMedGoogle Scholar
  40. 40.
    Kobayashi S, Shirasawa H, Sashiyama H, Kawahira H, Kaneko K, Asano T, Ochiai T: P16INK4a expression adenovirus vector to suppress pancreas cancer cell proliferation. Clin Cancer Res 1999;5:4182–4185.PubMedGoogle Scholar
  41. 41.
    Joshi US, Dergham ST, Chen YQ, Dugan MC, Crissman JD, Vaitkevicius VK, Sarkar FH: Inhibition of pancreatic tumor cell growth in culture by p21WAF1 recombinant adenovirus. Pancreas 1998;16:107–113.CrossRefPubMedGoogle Scholar
  42. 42.
    Rodicker F, Putzer BM: p73 is effective in p53-null pancreatic cancer cells resistant to wild-type TP53 gene replacement. Cancer Res 2003;63:2737–2741.PubMedGoogle Scholar
  43. 43.
    Schweinfest CW, Graber MW, Chapman JM, Papas TS, Baron PL, Watson DK: CaSm: an Sm-like protein that contributes to the transformed state in cancer cells. Cancer Res 1997;57:2961–2965.PubMedGoogle Scholar
  44. 44.
    Kelley JR, Fraser MM, Hubbard JM, Watson DK, Cole DJ: CaSm antisense gene therapy: a novel approach for the treatment of pancreatic cancer. Anticancer Res 2003;23:2007–2013.PubMedGoogle Scholar
  45. 45.
    Guan HT, Xue XH, Dai ZJ, Wang XJ, Li A, Qin ZY: Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity. World J Gastroenterol 2006;12:2901–2907.PubMedGoogle Scholar
  46. 46.
    Tsuji N, Asanuma K, Kobayashi D, Yagihashi A, Watanabe N: Introduction of a survivin gene-specific small inhibitory RNA inhibits growth of pancreatic cancer cells. Anticancer Res 2005;25:3967–3972.PubMedGoogle Scholar
  47. 47.
    Carrasco RA, Stamm NB, Rizza ME, Spencer C, Kim Y, Marcusson EG, Trask OJ, Syed S, Sandusky G, Patel BK: Antisense inhibition of survivin expression as a cancer therapeutic. AACR Meeting Abstracts 2004;2004:1239a.Google Scholar
  48. 48.
    Tokunaga T, Abe Y, Tsuchida T, Hatanaka H, Oshika Y, Tomisawa M, Yoshimura M, Ohnishi Y, Kijima H, Yamazaki H, Ueyama Y, Nakamura M: Ribozyme mediated cleavage of cell-associated isoform of vascular endothelial growth factor inhibits liver metastasis of a pancreatic cancer cell line. Int J Oncol 2002;21:1027–1032.PubMedGoogle Scholar
  49. 49.
    Tseng JF, Farnebo FA, Kisker O, Becker CM, Kuo CJ, Folkman J, Mulligan RC: Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice. Surgery 2002;132:857–865.CrossRefPubMedGoogle Scholar
  50. 50.
    Buchler P, Reber HA, Ullrich A, Shiroiki M, Roth M, Buchler MW, Lavey RS, Friess H, Hines OJ: Pancreatic cancer growth is inhibited by blockade of VEGF-RII. Surgery 2003;134:772–782.CrossRefPubMedGoogle Scholar
  51. 51.
    Hotz HG, Hines OJ, Masood R, Hotz B, Foitzik T, Buhr HJ, Gill PS, Reber HA: VEGF antisense therapy inhibits tumor growth and improves survival in experimental pancreatic cancer. Surgery 2005;137:192–199.CrossRefPubMedGoogle Scholar
  52. 52.
    Saimura M, Nagai E, Mizumoto K, Maehara N, Minamishima YA, Katano M, Matsumoto K, Nakamura T, Tanaka M: Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clin Cancer Res 2002;8:3243–3249.PubMedGoogle Scholar
  53. 53.
    Maehara N, Nagai E, Mizumoto K, Sato N, Matsumoto K, Nakamura T, Narumi K, Nukiwa T, Tanaka M: Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer. Clin Exp Metastasis 2002;19:417–426.CrossRefPubMedGoogle Scholar
  54. 54.
    Murakami M, Nagai E, Mizumoto K, Saimura M, Ohuchida K, Inadome N, Matsumoto K, Nakamura T, Maemondo M, Nukiwa T, Tanaka M: Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice. Int J Cancer 2005;117:160–165.CrossRefPubMedGoogle Scholar
  55. 55.
    Saimura M, Nagai E, Mizumoto K, Maehara N, Okino H, Katano M, Matsumoto K, Nakamura T, Narumi K, Nukiwa T, Tanaka M: Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice. Cancer Gene Ther 2002;9:799–806.CrossRefPubMedGoogle Scholar
  56. 56.
    Ogura Y, Mizumoto K, Nagai E, Murakami M, Inadome N, Saimura M, Matsumoto K, Nakamura T, Maemondo M, Nukiwa T, Tanaka M: Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival. Cancer Gene Ther 2006;13:520–529.CrossRefPubMedGoogle Scholar
  57. 57.
    Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD: Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 2007;120:1046–1054.CrossRefPubMedGoogle Scholar
  58. 58.
    Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L, Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC, Iovanna JL, Carrier A, Pebusque MJ, Dusetti NJ: Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA 2007;104:16170–16175.CrossRefPubMedGoogle Scholar
  59. 59.
    Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA: Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006;9:435–443.CrossRefPubMedGoogle Scholar
  60. 60.
    Rosenfeld ME, Vickers SM, Raben D, Wang M, Sampson L, Feng M, Jaffee E, Curiel DT: Pancreatic carcinoma cell killing via adenoviral mediated delivery of the herpes simplex virus thymidine kinase gene. Ann Surg 1997;225:609–618; discussion 618–620.CrossRefPubMedGoogle Scholar
  61. 61.
    Fogar P, Greco E, Basso D, Habeler W, Navaglia F, Zambon CF, Tormen D, Gallo N, Cecchetto A, Plebani M, Pedrazzoli S: Suicide gene therapy with HSV-TK in pancreatic cancer has no effect in vivo in a mouse model. Eur J Surg Oncol 2003;29:721–730.CrossRefPubMedGoogle Scholar
  62. 62.
    Carrio M, Romagosa A, Mercade E, Mazo A, Nadal M, Gomez-Foix AM, Fillat C: Enhanced pancreatic tumor regression by a combination of adenovirus and retrovirus-mediated delivery of the herpes simplex virus thymidine kinase gene. Gene Ther 1999;6:547–553.CrossRefPubMedGoogle Scholar
  63. 63.
    Harris JD, Gutierrez AA, Hurst HC, Sikora K, Lemoine NR: Gene therapy for cancer using tumour-specific prodrug activation. Gene Ther 1994;1:170–175.PubMedGoogle Scholar
  64. 64.
    Evoy D, Hirschowitz EA, Naama HA, Li XK, Crystal RG, Daly JM, Lieberman MD: In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer. J Surg Res 1997;69:226–231.CrossRefPubMedGoogle Scholar
  65. 65.
    Fogar P, Navaglia F, Basso D, Greco E, Zambon CF, Fadi E, Falda A, Stranges A, Vannozzi F, Danesi R, Pedrazzoli S, Plebani M: Suicide gene therapy with the yeast fusion gene cytosine deaminase/uracil phosphoribosyltransferase is not enough for pancreatic cancer. Pancreas 2007;35:224–231.CrossRefPubMedGoogle Scholar
  66. 66.
    Sunamura M, Oonuma M, Motoi F, Abe H, Saitoh Y, Hoshida T, Ottomo S, Horii A, Matsuno S: Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus. Hum Cell 2002;15:138–150.CrossRefPubMedGoogle Scholar
  67. 67.
    Green NK, Youngs DJ, Neoptolemos JP, Friedlos F, Knox RJ, Springer CJ, Anlezark GM, Michael NP, Melton RG, Ford MJ, Young LS, Kerr DJ, Searle PF: Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther 1997;4:229–238.PubMedGoogle Scholar
  68. 68.
    McNeish IA, Green NK, Gilligan MG, Ford MJ, Mautner V, Young LS, Kerr DJ, Searle PF: Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954. Gene Ther 1998;5:1061–1069.CrossRefPubMedGoogle Scholar
  69. 69.
    Weedon SJ, Green NK, McNeish IA, Gilligan MG, Mautner V, Wrighton CJ, Mountain A, Young LS, Kerr DJ, Searle PF: Sensitisation of human carcinoma cells to the prodrug CB1954 by adenovirus vector-mediated expression of E. coli nitroreductase. Int J Cancer 2000;86:848–854.CrossRefPubMedGoogle Scholar
  70. 70.
    Mulvihill S, Warren R, Venook A, Adler A, Randlev B, Heise C, Kirn D: Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Ther 2001;8:308–315.CrossRefPubMedGoogle Scholar
  71. 71.
    Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM, Kirn DH, Freeman SM: A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003;9:555–561.PubMedGoogle Scholar
  72. 72.
    O'Shea CC, Johnson L, Bagus B, Choi S, Nicholas C, Shen A, Boyle L, Pandey K, Soria C, Kunich J, Shen Y, Habets G, Ginzinger D, McCormick F: Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004;6:611–623.CrossRefPubMedGoogle Scholar
  73. 73.
    Zheng X, Rao XM, Gomez-Gutierrez JG, Hao H, McMasters KM, Zhou HS: Adenovirus E1B55K region is required to enhance cyclin E expression for efficient viral DNA replication. J Virol 2008;82:3415–3427.CrossRefPubMedGoogle Scholar
  74. 74.
    McAuliffe PF, Jarnagin WR, Johnson P, Delman KA, Federoff H, Fong Y: Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses. J Gastrointest Surg 2000;4:580–588.CrossRefPubMedGoogle Scholar
  75. 75.
    Kasuya H, Nishiyama Y, Nomoto S, Hosono J, Takeda S, Nakao A: Intraperitoneal delivery of hrR3 and ganciclovir prolongs survival in mice with disseminated pancreatic cancer. J Surg Oncol 1999;72:136–141.CrossRefPubMedGoogle Scholar
  76. 76.
    Watanabe I, Kasuya H, Nomura N, Shikano T, Shirota T, Kanazumi N, Takeda S, Nomoto S, Sugimoto H, Nakao A: Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer. Cancer Chemother Pharmacol 2008;61:875–882.CrossRefPubMedGoogle Scholar
  77. 77.
    Kasuya H, Nishiyama Y, Nomoto S, Goshima F, Takeda S, Watanabe I, Nomura N, Shikano T, Fujii T, Kanazumi N, Nakao A: Suitability of a US3-inactivated HSV mutant (L1BR1) as an oncolytic virus for pancreatic cancer therapy. Cancer Gene Ther 2007;14:533–542.CrossRefPubMedGoogle Scholar
  78. 78.
    Fu X, Tao L, Li M, Fisher WE, Zhang X: Effective treatment of pancreatic cancer xenografts with a conditionally replicating virus derived from type 2 herpes simplex virus. Clin Cancer Res 2006;12:3152–3157.CrossRefPubMedGoogle Scholar
  79. 79.
    Kami K, Doi R, Miyatake S, Imamura M: Viral therapy for human pancreatic cancer cells in vitro by a conditionally replication-competent herpes simplex virus 1 vector using survivin promoter. AACR Meeting Abstracts 2004;2004:1062e–1063e.Google Scholar
  80. 80.
    Etoh T, Himeno Y, Matsumoto T, Aramaki M, Kawano K, Nishizono A, Kitano S: Oncolytic viral therapy for human pancreatic cancer cells by reovirus. Clin Cancer Res 2003;9:1218–1223.PubMedGoogle Scholar
  81. 81.
    Posner M, Chang KJ, Rosemurgy A, Stephenson J, Khan M, Reid T, Fisher WE, Waxman I, Von Hoff D, Hecht R, Jr.: Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC). J Clin Oncol (Meeting Abstracts) 2007;25:4518.Google Scholar
  82. 82.
    Kimura M, Tagawa M, Yoshida Y, Takenouchi T, Takenaga K, Azuma K, Yamaguchi T, Saisho H, Sakiyama S: Impaired in vivo tumor growth of human pancreatic carcinoma cells retrovirally transduced with GM-CSF gene. Anticancer Res 1998;18:165–170.PubMedGoogle Scholar
  83. 83.
    Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ: Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001;19:145–156.PubMedGoogle Scholar
  84. 84.
    Laheru D, Yeo C, Biedrzycki B, Solt S, Lutz E, Onners B, Tartakovsky I, Herman J, Hruban R, Piantadosi S, Jaffee E: A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas. J Clin Oncol (Meeting Abstracts) 2007;25:3010.Google Scholar
  85. 85.
    Clary BM, Coveney EC, Philip R, Blazer DG, 3rd, Morse M, Gilboa E, Lyerly HK: Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells. Cancer Gene Ther 1997;4:97–104.PubMedGoogle Scholar
  86. 86.
    Kimura M, Tagawa M, Takenaga K, Kondo F, Yamaguchi T, Saisho H, Nakagawara A, Sakiyama S: Loss of tumorigenicity of human pancreatic carcinoma cells engineered to produce interleukin-2 or interleukin-4 in nude mice: a potentiality for cancer gene therapy. Cancer Lett 1998;128:47–53.CrossRefPubMedGoogle Scholar
  87. 87.
    Motoi F, Sunamura M, Ding L, Duda DG, Yoshida Y, Zhang W, Matsuno S, Hamada H: Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus. Hum Gene Ther 2000;11:223–235.CrossRefPubMedGoogle Scholar
  88. 88.
    Sangro B, Mazzolini G, Ruiz J, Herraiz M, Quiroga J, Herrero I, Benito A, Larrache J, Pueyo J, Subtil JC, Olague C, Sola J, Sadaba B, Lacasa C, Melero I, Qian C, Prieto J: Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 2004;22:1389–1397.CrossRefPubMedGoogle Scholar
  89. 89.
    Marshall JL, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwu L, Park S, Panicali D, Schlom J: Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol 2005;23:720–731.CrossRefPubMedGoogle Scholar
  90. 90.
    Marshall JL, Hawkins MJ, Tsang KY, Richmond E, Pedicano JE, Zhu MZ, Schlom J: Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 1999;17:332–337.PubMedGoogle Scholar
  91. 91.
    Therion reports results of phase 3 PANVAC-VF trial and announces plans for company sale. In Nordqvist C (ed): Medical News Today. 2006.Google Scholar
  92. 92.
    Morse MA, Nair SK, Boczkowski D, Tyler D, Hurwitz HI, Proia A, Clay TM, Schlom J, Gilboa E, Lyerly HK: The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer. Int J Gastrointest Cancer 2002;32:1–6.CrossRefPubMedGoogle Scholar
  93. 93.
    Gaffney MC, Goedegebuure P, Kashiwagi H, Hornick JR, Thaker RI, Eberlein T, Hawkins WG: DNA vaccination targeting mesothelin combined with anti-GITR antibody induces rejection of pancreatic adenocarcinoma. AACR Meeting Abstracts 2006;2006:329a.Google Scholar
  94. 94.
    Zhu K, Qin H, Cha SC, Neelapu SS, Overwijk W, Lizee GA, Abbruzzese JL, Hwu P, Radvanyi L, Kwak LW, Chang DZ: Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models. Vaccine 2007;25:7955–7961.CrossRefPubMedGoogle Scholar
  95. 95.
    Pecher G, Haring A, Kaiser L, Thiel E: Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunol Immunother 2002;51:669–673.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Han Hsi Wong
    • 1
  • Nicholas R. Lemoine
    • 2
  1. 1.Queen MaryUniversity of LondonLondonUK
  2. 2.University of LondonLondonUK

Personalised recommendations