Pancreatic cancer: Gene therapy approaches and gene delivery systems

Expert Opinion on Biological Therapy

Volumn 10, Issue 1, 2010, Pages 73-88

  Xu, Jin ^a   Jin, Chen ^a   Hao, Sijie ^a   Luo, Guopei ^a   Fu, Deliang ^a  

^a FUDAN UNIVERSITY   (China)

Author keywords

Gene delivery system; Gene therapy approach; Pancreatic cancer

Indexed keywords

ADENOVIRUS VECTOR; CYTOSINE DEAMINASE; FLUCYTOSINE; GANCICLOVIR; LIPOSOME; MICRORNA; NAKED DNA; NANOPARTICLE; PARVOVIRUS VECTOR; POLYMER; PROTEIN P16; PROTEIN P53; RETROVIRUS VECTOR; THYMIDINE KINASE; VASCULOTROPIN; VIRUS VECTOR;

ACTIVE IMMUNIZATION; ANTIANGIOGENIC GENE THERAPY; CARCINOGENICITY; GENE DELIVERY SYSTEM; GENE THERAPY; GENETIC TRANSFECTION; HERPES SIMPLEX VIRUS; HUMAN; IMMUNOGENICITY; INFLAMMATION; NONHUMAN; ONCOGENE K RAS; ONCOLYTIC VIROTHERAPY; PANCREAS CANCER; PASSIVE IMMUNIZATION; REOVIRUS; REVIEW; SUICIDE GENE THERAPY; TUMOR SUPPRESSOR GENE; UPREGULATION;

GENE THERAPY; GENE TRANSFER TECHNIQUES; GENETIC VECTORS; HUMANS; PANCREATIC NEOPLASMS;

EID: 72449196211     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712590903321454     Document Type: Review

References (205)

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96
2. Mancuso A, Calabrò F, Sternberg CN. Current therapies and advances in the treatment of pancreatic cancer. Crit Rev Oncol Hematol 2006;58(3):231-241
3. Garcea G, Dennison AR, Pattenden CJ, et al. Survival following curative resection for pancreatic ductal adenocarcinoma. A systematic review of the literature JOP 2008;9(2):99-132
4. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009;27(13):2269-2277
5. Klautke G, Brunner TB. Radiotherapy in pancreatic cancer. Strahlenther Onkol 2008;184(11):557-564
6. Zuckerman DS, Ryan DP. Adjuvant therapy for pancreatic cancer: a review. Cancer 2008;112(2):243-249
7. Freelove R, Walling AD. Pancreatic cancer: diagnosis and management. Am Fam Physician 2006;73(3):485-492
8. Costa ET, Forti FL, Matos TG, et al. Fibroblast growth factor 2 restrains Ras-driven proliferation of malignant cells by triggering RhoA-mediated senescence. Cancer Res 2008;68(15):6215-6223
9. Fischbach MA, Settleman J. Regulation of the nucleotide state of oncogenic ras proteins by nucleoside diphosphate kinase. Methods Enzymol 2006;407:33-45
10. Dreissigacker U, Mueller MS, Unger M, et al. Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38. Cell Signal 2006;18(8):1156-1168
11. Shields JM, Pruitt K, McFall A, et al. Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol 2000;10(4): 147-154
12. Fryzek JP, Garabrant DH, Schenk M, et al. The association between selected risk factors for pancreatic cancer and the expression of p53 and K-ras codon 12 mutations. Int J Gastrointest Cancer 2006;37(4):139-145
13. Talar-Wojnarowska R, Gasiorowska A, Smolarz B, et al. Clinical significance of K-ras and c-erbB-2 mutations in pancreatic adenocarcinoma and chronic pancreatitis. Int J Gastrointest Cancer 2005;35(1):33-41
14. Wei S, Liang Z, Gao J, et al. Patterns of K-ras codon 12 and 13 mutations found in pancreatic adenocarcinoma of 30 Chinese patients by microdissection, PCR and direct sequencing. J Gastroenterol Hepatol 2005;20(1):67-72
15. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2(12):897-909
16. Koliopanos A, Avgerinos C, Paraskeva C, et al. Molecular aspects of carcinogenesis in pancreatic cancer. Hepatobiliary Pancreat Dis Int 2008;7(4):345-356
17. Minamoto T. Detection and characterization of oncogene mutations in preneoplastic and early neoplastic lesions. Methods Mol Biol 2005;291:263-278
18. Shichinohe T, Senmaru N, Furuuchi K, et al. Suppression of pancreatic cancer by the dominant negative ras mutant, N116Y. J Surg Res 1996;66(2):125-130
19. Takeuchi M, Shichinohe T, Senmaru N, et al. 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(6):518-526
20. Aoki K, Yoshida T, Matsumoto N, et al. Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation. Mol Carcinog 1997;20(2):251-258
21. Miura Y, Ohnami S, Yoshida K, et al. Intraperitoneal injection of adenovirus expressing antisense K-ras RNA suppresses peritoneal dissemination of hamster syngeneic pancreatic cancer without systemic toxicity. Cancer Lett 2005;218(1):53-62
22. Kijima H, Scanlon KJ. Ribozyme as an approach for growth suppression of human pancreatic cancer. Mol Biotechnol 2000;14(1):59-72
23. Tsuchida T, Kijima H, Hori S, et al. Adenovirus-mediated anti-K-ras ribozyme induces apoptosis and growth suppression of human pancreatic carcinoma. Cancer Gene Ther 2000;7(3):373-383
24. Kijima H, Yamazaki H, Nakamura M, et al. Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer. Int J Oncol 2004;24(3):559-564
25. Chen LM, Le HY, Qin RY, 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(6):831-838
26. Wang W, Wang CY, Dong JH, et al. Identification of effective siRNA against K-ras in human pancreatic cancer cell line MiaPaCa-2 by siRNA expression cassette. World J Gastroenterol 2005;11(13):2026-2031 (Pubitemid 40521006)
27. He W, Parker R. Functions of Lsm proteins in mRNA degradation and splicing. Curr Opin Cell Biol 2000;12(3):346-350
28. Schweinfest CW, Graber MW, Chapman JM, et al. CaSm: an Sm-like protein that contributes to the transformed state in cancer cells. Cancer Res 1997;57(14):2961-2965
29. Kelley JR, Brown JM, Frasier MM, et al. The cancer-associated Sm-like oncogene: a novel target for the gene therapy of pancreatic cancer. Surgery 2000;128(2):353-360
30. Santamariña M, Hernández G, Zalvide J. CDK redundancy guarantees cell cycle progression in Rb-negative tumor cells independently of their p16 status. Cell Cycle 2008;7(13):1962-1972
31. Cánepa ET, Scassa ME, Ceruti JM, et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 2007;59(7):419-426
32. Ashizawa S, Nishizawa H, Yamada M, et al. Collective inhibition of pRB family proteins by phosphorylation in cells with p16INK4a loss or cyclin E overexpression. J Biol Chem 2001;276(14):11362-11370
33. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997;57(11):2140-2143
34. Attri J, Srinivasan R, Majumdar S, et al. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma. BMC Gastroenterol 2005;5:22. Published online 28 June 2005, doi:10.1186/ 1471-230X-5-2235.
35. Sato N, Ueki T, Fukushima N, et al. Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 2002;123(1):365-372
36. Hruban RH, Goggins M, Kern SE. Molecular genetics and related developments in pancreatic cancer. Curr Opin Gastroenterol 1999;15(5):404-409 (Pubitemid 29390428)
37. Calbó J, Marotta M, Cascalló M, et al. Adenovirus-mediated wt-p16 reintroduction induces cell cycle arrest or apoptosis in pancreatic cancer. Cancer Gene Ther 2001;8(10):740-750
38. Kobayashi S, Shirasawa H, Sashiyama H, et al. P16INK4a expression adenovirus vector to suppress pancreas cancer cell proliferation. Clin Cancer Res 1999;5(12):4182-4185
39. Kastanos E, Hjiantoniou E, Phylactou LA. Restoration of protein synthesis in pancreatic cancer cells by trans-splicing ribozymes. Biochem Biophys Res Commun 2004;322(3):930-934
40. Tarapore P, Horn HF, Tokuyama Y, et al. Direct regulation of the centrosome duplication cycle by the p53-p21Waf1/ Cip1 pathway. Oncogene 2001;20(25):3173-3184
41. Xie G, Habbersett RC, Jia Y, et al. Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints. Oncogene 1998;16(6):721-736
42. Senovilla L, Vitale I, Galluzzi L, et al. p53 represses the polyploidization of primary mammary epithelial cells by activating apoptosis. Cell Cycle 2009;8(9):1380-1385
43. Taii A, Hamada S, Kataoka K, et al. Correlations between p53 gene mutations and histologic characteristics of pancreatic ductal carcinoma. Pancreas 2009;38(2):e60-7
44. Bardeesy N, Aguirre AJ, Chu GC, et al. Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA 2006;103(15):5947-5952
45. Hruban RH, Goggins M, Kern SE. Molecular genetics and related developments in pancreatic cancer. Curr Opin Gastroenterol 1999;15(5):404-409 (Pubitemid 29390428)
46. Cascalló M, Mercadé E, Capellà G, et al. Genetic background determines the response to adenovirus-mediated wild-type p53 expression in pancreatic tumor cells. Cancer Gene Ther 1999;6(5):428-436
47. Bouvet M, Bold RJ, Lee J, et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol 1998;5(8):681-688
48. Hwang RF, Gordon EM, Anderson WF, et al. Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 1998;124(2):143-150
49. Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005;16(9):1016-1027
50. Habbe N, Koorstra JB, Mendell JT, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 2009;8(4):340-346
51. Greither T, Grochola L, Udelnow A, et al. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumours is associated with poorer survival. Int J Cancer 2009; published online: 23 Jun 2009, doi: 10.1002/ijc.24687
52. Dillhoff M, Liu J, Frankel W, et al. MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg 2008;12(12):2171-2176
53. Lanuti M, Gao GP, Force SD, et al. Evaluation of an E1E4-deleted adenovirus expressing the herpes simplex thymidine kinase suicide gene in cancer gene therapy. Hum Gene Ther 1999;10(3):463-475
54. Portsmouth D, Hlavaty J, Renner M. Suicide genes for cancer therapy. Mol Aspects Med 2007;28(1):4-41
55. Wang J, Lu XX, Chen DZ, et al. Herpes simplex virus thymidine kinase and ganciclovir suicide gene therapy for human pancreatic cancer. World J Gastroenterol 2004;10(3):400-403
56. Mäkinen K, Loimas S, Wahlfors J, et al. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer. J Gene Med 2000;2(5):361-367
57. Block A, Chen SH, Kosai K, et al. Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors. Pancreas 1997;15(1):25-34
58. Fogar P, Greco E, Basso D, et al. Suicide gene therapy with HSV-TK in pancreatic cancer has no effect in vivo in a mouse model. Eur J Surg Oncol 2003;29(9):721-730
59. Greco E, Fogar P, Basso D, et al. Retrovirus-mediated herpes simplex virus thymidine kinase gene transfer in pancreatic cancer cell lines: an incomplete antitumor effect. Pancreas 2002;25(2):e21-9
60. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000;46(2):171-179
61. Li ZS, Pan X, Xu GM, et al. Killing effects of cytosine deaminase gene mediated by adenovirus vector on human pancreatic cancer cell lines in vitro. Hepatobiliary Pancreat Dis Int 2003;2(1):147-151
62. Evoy D, Hirschowitz EA, Naama HA, et al. In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer. J Surg Res 1997;69(1):226-231
63. Fogar P, Navaglia F, Basso D, et al. Suicide gene therapy with the yeast fusion gene cytosine deaminase/uracil phosphoribosyltransferase is not enough for pancreatic cancer. Pancreas 2007;35(3):224-231
64. McNeish IA, Green NK, Gilligan MG, et al. Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954. Gene Ther 1998;5(8):1061-1069
65. Karle P, Müller P, Renz R, et al. Intratumoral injection of encapsulated cells producing an oxazaphosphorine activating cytochrome P450 for targeted chemotherapy. Adv Exp Med Biol 1998;451:97-106 (Pubitemid 28543332)
66. Yoshida Y, Tomizawa M, Bahar R, et al. A promoter region of midkine gene can activate transcription of an exogenous suicide gene in human pancreatic cancer. Anticancer Res 2002;22(1A):117-120
67. Hiyama E, Kodama T, Shinbara K, et al. Telomerase activity is detected inpancreatic cancer but not in benign tumors. Cancer Res 1997;57(2):326-331
68. Zhou JH, Tang B, Liu XL, et al. hTERT-targeted E. coli purine nucleoside phosphorylase gene/6-methylpurine deoxyribose therapy for pancreatic cancer. Chin Med J (Engl) 2007;120(15):1348-1352
69. Wang XP, Yazawa K, Yang J, et al. Specific gene expression and therapy for pancreatic cancer using the cytosine deaminase gene directed by the rat insulin promoter. J Gastrointest Surg 2004;8(1):98-108
70. Deharvengt S, Wack S, Aprahamian M, et al. Transcriptional tumor-selective promoter targeting of E. coli purine nucleoside phosphorylase for pancreatic cancer suicide gene therapy. J Gene Med 2005;7(5):672-680
71. Hamdollah Zadeh MA, Glass CA, Magnussen A, et al. VEGF-mediated elevated intracellular calcium and angiogenesis in human microvascular endothelial cells in vitro are inhibited by dominant negative TRPC6. Microcirculation 2008;15(7):605-614
72. Seo Y, Baba H, Fukuda T, et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000;88(10):2239-2245
73. Tokunaga T, Abe Y, Tsuchida T, et al. 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(5):1027-1032
74. Büchler P, Reber HA, Ullrich A, et al. Pancreatic cancer growth is inhibited by blockade of VEGF-RII. Surgery 2003;134(5):772-782
75. Hoshida T, Sunamura M, Duda DG, et al. Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor. Pancreas 2002;25(2):111-121
76. Tseng JF, Farnebo FA, Kisker O, et al. 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(5):857-865
77. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15(3):220-231
78. Kuba K, Matsumoto K, Date K, et al. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 2000;60(23):6737-6743
79. Murakami M, Nagai E, Mizumoto K, et al. 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(1):160-165
80. Saimura M, Nagai E, Mizumoto K, et al. 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(10):799-806
81. Zhang X, Xu J, Lawler J, et al. Adeno-associated virus-mediated antiangiogenic gene therapy with thrombospondin-1 type 1 repeats and endostatin. Clin Cancer Res 2007;13(13):3968-3976
82. Everts B, van der Poel HG. Replication-selective oncolytic viruses in the treatment of cancer. Cancer Gene Ther 2005;12(2):141-161
83. Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274(5286):373-376
84. Mulvihill SWarren R, Venook A, et al. 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(4):308-315
85. Hecht JR, Bedford R, Abbruzzese JL, et al. 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(2):555-561
86. Nemunaitis J, Ganly I, Khuri F, et al. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a Phase II trial. Cancer Res 2000;60(22):6359-6366
87. Vasey PA, Shulman LN, Campos S, et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 2002;20(6):1562-1569
88. Harada JN, Berk AJ. p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication. J Virol 1999;73(7):5333-5344
89. O'Shea CC, Johnson L, Bagus B, et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004;6(6):611-623
90. Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000;19(1):2-12
91. Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 2000;6(10):1134-1139
92. Sunamura M, Hamada H, Motoi F, et al. Oncolytic virotherapy as a novel strategy for pancreatic cancer. Pancreas 2004;28(3):326-329
93. Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther 2002;9(12):967-978
94. Lee JH, Federoff HJ, Schoeniger LO. G207, modified herpes simplex virus type 1, kills human pancreatic cancer cells in vitro. J Gastrointest Surg 1999;3(2):127-131
95. McAuliffe PF, Jarnagin WR, Johnson P, et al. Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses. J Gastrointest Surg 2000;4(6):580-588
96. Kemeny N, Brown K, Covey A, et al. Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther 2006;17(12):1214-1224
97. Aghi MK, Chiocca EA. Phase Ib trial of oncolytic herpes virus G207 shows safety of multiple injections and documents viral replication. Mol Ther 2009;17(1):8-9
98. Etoh T, Himeno Y, Matsumoto T, et al. Oncolytic viral therapy for human pancreatic cancer cells by reovirus. Clin Cancer Res 2003;9(3):1218-2399.
99. Hirano S, Etoh T, Okunaga R, et al. Reovirus inhibits the peritoneal dissemination of pancreatic cancer cells in an immunocompetent animal model. Oncol Rep 2009;21(6):1381-1384
100. Himeno Y, Etoh T, Matsumoto T, et al. Efficacy of oncolytic reovirus against liver metastasis from pancreatic cancer in immunocompetent models. Int J Oncol 2005;27(4):901-906
101. Hekele A, Dall P, Moritz D, et al. Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44v6-specific scFv:z-chimera. Int J Cancer 1996;68(2):232-238
102. Schmidt J, Ryschich E, Sievers E, et al. Telomerase-specific T-cells kill pancreatic tumor cells in vitro and in vivo. Cancer 2006;106(4):759-764
103. Nagaraj S, Neumann J, Winzen B, et al. Pancreas carcinoma antigen fused to invariant chain elicits T-cell response and tumor growth inhibition. Pancreas 2008;37(3):321-327
104. Schnurr M, Galambos P, Scholz C, et al. Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. Cancer Res 2001;61(17):6445-6450
105. Tang ZH, Qiu WH, Wu GS, et al. The immunotherapeutic effect of dendritic cells vaccine modified with interleukin-18 gene and tumor cell lysate on mice with pancreatic carcinoma. World J Gastroenterol 2002;8(5):908-912
106. Pecher G, Häring A, Kaiser L, et al. Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a Phase I/II clinical trial. Cancer Immunol Immunother 2002;51(11-12):669-673
107. Lepisto AJ, Moser AJ, Zeh H, et al. A Phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther 2008;6(B):955-964
108. Clary BM, Coveney EC, Philip R, et al. Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells. Cancer Gene Ther 1997;4(2):97-104
109. Pützer BM, Rödicker F, Hitt MM, et al. Improved treatment of pancreatic cancer by IL-12 and B7.1 costimulation: antitumor efficacy and immunoregulation in a nonimmunogenic tumor model. Mol Ther 2002;5(4):405-412
110. Sangro B, Mazzolini G, Ruiz J, et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 2004;22(8):1389-1397
111. Jaffee EM, Abrams R, Cameron J, et al. A Phase I clinical trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene for the treatment of pancreatic adenocarcinoma. Hum Gene Ther 1998;9(13):1951-1971
112. Shi XH, Liang ZY, Ren XY, et al. Combined silencing of K-ras and Akt2 oncogenes achieves synergistic effects in inhibiting pancreatic cancer cell growth in vitro and in vivo. Cancer Gene Ther 2009;16(3):227-236
113. Ghaneh P, Greenhalf W, Humphreys M, et al. Adenovirus-mediated transfer of p53 and p16INK4a results in pancreatic cancer regression in vitro and in vivo. Gene Ther 2001;8(3):199-208
114. Hatanaka K, Suzuki K, Miura Y, et al. Interferon-alpha and antisense K-ras RNA combination gene therapy against pancreatic cancer. J Gene Med 2004;6(10):1139-1148
115. Kelley JR, Fraser MM, Schweinfest CW, et al. CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer. Surgery 2001;130(2):280-288
116. Ogura Y, Mizumoto K, Nagai E, et al. 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(5):520-529
117. Freytag SO, Barton KN, Brown SL, et al. Replication-competent adenovirus-mediated suicide gene therapy with radiation in a preclinical model of pancreatic cancer. Mol Ther 2007;15(9):1600-1606
118. Miseki T, Kawakami H, Natsuizaka M, et al. Suppression of tumor growth by intra-muscular transfer of naked DNA encoding adrenomedullin antagonist. Cancer Gene Ther 2007;14(1):39-44
119. Deharvengt S, Rejiba S, Wack S, et al. Efficient electrogene therapy for pancreatic adenocarcinoma treatment using the bacterial purine nucleoside phosphorylase suicide gene with fludarabine. Int J Oncol 2007;30(6):1397-1406
120. Shayakhmetov DM, Li ZY, Gaggar A, et al. Genome size and structure determine efficiency of postinternalization steps and gene transfer of capsid-modified adenovirus vectors in a cell-type-specific manner. J Virol 2004;78(18):10009-10022
121. Schindler C, Fooks A, Stephenson J, et al. Replication-incompetent adenoviruses as vectors for protective immunization against measles virus infection. Behring Inst Mitt 1994;(95):109-115
122. Smith-Arica JR, Thomson AJ, Ansell R, et al. Infection efficiency of human and mouse embryonic stem cells using adenoviral and adeno-associated viral vectors. Cloning Stem Cells 2003;5(1):51-62
123. Farinha-Arcieri LE, Porchia BM, Carromeu C, et al. Expression and purification of a recombinant adenovirus fiber knob in a baculovirus system. Intervirology 2008;51(3):189-195
124. Bergelson JM, Cunningham JA, Droguett G, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997;275(5304):1320-1323
125. Majhen D, Nemet J, Richardson J, et al. Differential role of alphavbeta3 and alphavbeta5 integrins in internalization and transduction efficacies of wild type and RGD4C fiber-modified adenoviruses. Virus Res 2009;139(1):64-73
126. Soudais C, Boutin S, Hong SS, et al. Canine adenovirus type 2 attachment and internalization: coxsackievirus-adenovirus receptor, alternative receptors, and an RGD-independent pathway. J Virol 2000;74(22):10639-10649
127. Goldman M, Su Q, Wilson JM. Gradient of RGD-dependent entry of adenoviral vector in nasal and intrapulmonary epithelia: implications for gene therapy of cystic fibrosis. Gene Ther 1996;3(9):811-818
128. Palmer DJ, Ng P. Methods for the production of first generation adenoviral vectors. Methods Mol Biol 2008;433:55-78
129. Gagnoux-Palacios L, Hervouet C, Spirito F, et al. Assessment of optimal transduction of primary human skin keratinocytes by viral vectors. J Gene Med 2005;7(9):1178-86130.
130. Hacker DL, Bertschinger M, Baldi L, et al. Reduction of adenovirus E1A mRNA by RNAi results in enhanced recombinant protein expression in transiently transfected HEK293 cells. Gene 2004;341:227-234
131. Young LS, Searle PF, Onion D, et al. Viral gene therapy strategies: from basic science to clinical application. J Pathol 2006;208(2):299-318
132. Kamen A, Henry O. Development and optimization of an adenovirus production process. J Gene Med 2004;6(Suppl 1):S184-92
133. Crystal RG, Harvey BG, Wisnivesky JP, et al. Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum Gene Ther 2002;13(1):65-100
134. Pearson AS, Koch PE, Atkinson N, et al. Factors limiting adenovirus-mediated gene transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999;5(12):4208-4213
135. Kim M, Zinn KR, Barnett BG, et al. The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumour cells. Eur J Cancer 2002;38(14):1917-1926
136. Wesseling JG, Bosma PJ, Krasnykh V, et al. Improved gene transfer efficiency to primary and established human pancreatic carcinoma target cells via epidermal growth factor receptor and integrin-targeted adenoviral vectors. Gene Ther 2001;8(13):969-976
137. Toyoda E, Doi R, Kami K, et al. Adenovirus vectors with chimeric type 5 and 35 fiber proteins exhibit enhanced transfection of human pancreatic cancer cells. Int J Oncol 2008;33(6):1141-1147
138. Nony P, Tessier J, Chadeuf G, et al. Novel cis-acting replication element in the adeno-associated virus type 2 genome is involved in amplification of integrated rep-cap sequences. J Virol 2001;75(20):9991-9994
139. Van Vliet K, Mohiuddin Y, McClung S, et al. Adeno-associated virus capsid serotype identification: Analytical methods development and application. J Virol Methods 2009;159(2):167-177
140. Nicklin SA, Buening H, Dishart KL, et al. Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Mol Ther 2001;4(3):174-181
141. Belur LR, Kaemmerer WF, McIvor RS, et al. Adeno-associated virus type 2 vectors: transduction and long-term expression in cerebellar Purkinje cells in vivo is mediated by the fibroblast growth factor receptor 1: bFGFR-1 mediates AAV2 transduction of Purkinje cells. Arch Virol 2008;153(11):2107-2110
142. Asokan A, Hamra JB, Govindasamy L, et al. Adeno-associated virus type 2 contains an integrin alpha5beta1 binding domain essential for viral cell entry. J Virol 2006;80(18):8961-8969
143. Buller RM, Janik JE, Sebring ED, et al. Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. J Virol 1981;40(1):241-247
144. Mishra L, Rose JA. Adeno-associated virus DNA replication is induced by genes that are essential for HSV-1 DNA synthesis. Virology 1990;179(2):632-639
145. Leonard JN, Ferstl P, Delgado A, et al. Enhanced preparation of adeno-associated viral vectors by using high hydrostatic pressure to selectively inactivate helper adenovirus. Biotechnol Bioeng 2007;97(5):1170-1179
146. Ding W, Zhang L, Yan Z, et al. Intracellular trafficking of adeno-associated viral vectors. Gene Ther 2005;12(11):873-880
147. Cheng H, Wolfe SH, Valencia V, et al. Efficient and persistent transduction of exocrine and endocrine pancreas by adeno-associated virus type 8. J Biomed Sci 2007;14(5):585-594
148. Wang AY, Peng PD, Ehrhardt A, et al. Comparison of adenoviral and adeno-associated viral vectors for pancreatic gene delivery in vivo. Hum Gene Ther 2004;15(4):405-413
149. Gavrilescu LC, Van Etten RA: Production of replication-defective retrovirus by transient transfection of 293T cells. J Vis Exp 2007;(10):550
150. Swanson CM, Malim MH. Retrovirus RNA trafficking: from chromatin to invasive genomes. Traffic 2006;7(11):1440-1450
151. Nair V. Retrovirus-induced oncogenesis and safety of retroviral vectors. Curr Opin Mol Ther 2008;10(5):431-438
152. Du Y, Spence SE, Jenkins NA, et al. Cooperating cancer-gene identification through oncogenic-retrovirus-induced insertional mutagenesis. Blood 2005;106(7):2498-2505
153. Chinnasamy N, Shaffer J, Chinnasamy D. Production of multicistronic HIV-1 based lentiviral vectors. Methods Mol Biol 2009;515:137-150
154. Howard BD, Boenicke L, Schniewind B, et al. Transduction of human pancreatic tumor cells with vesicular stomatitis virus G-pseudotyped retroviral vectors containing a herpes simplex virus thymidine kinase mutant gene enhances bystander effects and sensitivity to ganciclovir. Cancer Gene Ther 2000;7(6):927-938
155. Saraga G, Mafficini A, Ghaneh P, et al. 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(9):781-790
156. Lewis BC, Klimstra DS, Varmus HE. The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer. Genes Dev 2003;17(24):3127-3138
157. Mayr U, von Werder A, Seidler B, et al. RCAS-mediated retroviral gene delivery: a versatile tool for the study of gene function in a mouse model of pancreatic cancer. Hum Gene Ther 2008;19(9):896-906
158. Seidler B, Schmidt A, Mayr U, et al. A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors. Proc Natl Acad Sci USA 2008;105(29):10137-10142
159. Hirsch-Lerner D, Zhang M, Eliyahu H, et al. Effect of "helper lipid" on lipoplex electrostatics. Biochim Biophys Acta 2005;1714(2):71-84
160. Kearns MD, Donkor AM, Savva M. Structure-transfection activity studies of novel cationic cholesterol-based amphiphiles. Mol Pharm 2008;5(1):128-139
161. Barteau B, Chèvre R, Letrou-Bonneval E, et al. Physicochemical parameters of non-viral vectors that govern transfection efficiency. Curr Gene Ther 2008;8(5):313-323
162. Ahmad A, Evans HM, Ewert K, et al. New multivalent cationic lipids reveal bell curve for transfection efficiency versus membranecharge density: lipid-DNA complexes for gene delivery. J Gene Med 2005;7(6):739-748
163. Kodama K, Katayama Y, Shoji Y, et al. The features and shortcomings for gene delivery of current non-viral carriers. Curr Med Chem 2006;13(18):2155-2161
164. Zintchenko A, Philipp A, Dehshahri A, et al. Simple modifications of branched PEI lead to highly efficient siRNA carriers with low toxicity. Bioconjug Chem 2008;19(7):1448-1455
165. Akinc A, Thomas M, Klibanov AM, et al. Exploring polyethylenimine- mediated DNA transfection and the proton sponge hypothesis. J Gene Med 2005;7(5):657-663
166. Sonawane ND, Szoka FC, Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem 2003;278(45):44826-44831
167. Aoki K, Furuhata S, Hatanaka K, et al. Polyethylenimine-mediated gene transfer into pancreatic tumor dissemination in the murine peritoneal cavity. Gene Ther 2001;8(7):508-514
168. Sharma VK, Thomas M, Klibanov AM. Mechanistic studies on aggregation of polyethylenimine-DNA complexes and its prevention. Biotechnol Bioeng 2005;90(5):614-620
169. Malek A, Merkel O, Fink L, et al. In vivo pharmacokinetics, tissue distribution and underlying mechanisms of various PEI (-PEG)/siRNA complexes. Toxicol Appl Pharmacol 2009;236(1):97-108
170. Veiseh O, Kievit FM, Gunn JW, et al. A ligand-mediated nanovector for targeted gene delivery and transfection in cancer cells. Biomaterials 2009;30(4):649-657
171. van der Aa MA, Koning GA, d'Oliveira C, et al. An NLS peptide covalently linked to linear DNA does not enhance transfection efficiency of cationic polymer based gene delivery systems. J Gene Med 2005;7(2):208-217
172. Moffatt S, Wiehle S, Cristiano RJ. A multifunctional PEI-based cationic polyplex for enhanced systemic p53-mediated gene therapy. Gene Ther 2006;13(21):1512-1523
173. Chang LW, Lue JT. Magnetic properties of multi-walled carbon nanotubes. J Nanosci Nanotechnol 2009;9(3):1956-1963
174. Jin SH, Kang IH, Kim YS, et al. Thermal and electrical properties of nanocomposites based on acrylic copolymers and multiwalled carbon nanotube. J
175. Zhang L, Tu X, Welsher K, et al. Optical characterizations and electronic devices of nearly pure (10,5) single-walled carbon nanotubes. J Am Chem Soc 2009;131(7):2454-2455
176. Tan Y, Resasco DE. Dispersion of single-walled carbon nanotubes of narrow diameter distribution. J Phys Chem B 2005;109(30):14454-14460
177. Fu K, Sun YP. Dispersion and solubilization of carbon nanotubes. J Nanosci Nanotechnol 2003;3(5):351-364
178. Dyke CA, Tour JM. Overcoming the insolubility of carbon nanotubes through high degrees of sidewall functionalization. Chemistry 2004;10(4):812-817
179. Klumpp C, Kostarelos K, Prato M, et al. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics. Biochim Biophys Acta 2006;1758(3):404-412
180. Singh R, Pantarotto D, McCarthy D, et al. Binding and condensation of plasmid DNA onto functionalized carbon nanotubes: toward the construction of nanotube-based gene delivery vectors. J Am Chem Soc 2005;127(12):4388-4396
181. Miyawaki J, Yudasaka M, Azami T, et al. Toxicity of single-walled carbon nanohorns. ACS Nano 2008;2(2):213-226
182. Bellucci S, Chiaretti M, Cucina A, et al. Multiwalled carbon nanotube buckypaper: toxicology and biological effects in vitro and in vivo. Nanomed 2009;4(5):531-540
183. Simeonova PP. Update on carbon nanotube toxicity. Nanomed 2009;4(4):373-375
184. Dumortier H, Lacotte S, Pastorin G, et al. Functionalized carbon nanotubes are non-cytotoxic and preserve the functionality of primary immune cells. Nano Lett 2006;6(7):1522-1528
185. Klumpp C, Kostarelos K, Prato M, et al. Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics. Biochim Biophys Acta 2006;1758(3):404-412
186. Singh R, Pantarotto D, Lacerda L, et al. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci USA 2006;103(9):3357-3362
187. Singh R, Pantarotto D, McCarthy D, et al. Binding and condensation of plasmid DNA onto functionalized carbon nanotubes: toward the construction of nanotube-based gene delivery vectors. J Am Chem Soc 2005;127(12):4388-4396
188. Podesta JE, Al-Jamal KT, Herrero MA, et al. Antitumor activity and prolonged survival by carbon-nanotube-mediated therapeutic siRNA silencing in a human lung xenograft model. Small 2009;5(10):1176-1185
189. Yang F, Fu de L, Long J, et al. Magnetic lymphatic targeting drug delivery system using carbon nanotubes. Med. Hypotheses 2008;70(4):765-767
190. Yang F, Hu J, Yang D, et al. Pilot study of targeting magnetic carbon nanotubes to lymph nodes. Nanomed 2009;4(3):317-330
191. Wang Z, Zhang Y, Li Y, et al. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006;5(3):483-493
192. Kornmann M, Arber N, Korc M. Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum. J Clin Invest 1998;101(2):344-352
193. Guan HT, Xue XH, Dai ZJ, et al. Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity. World J Gastroenterol 2006;12(18):2901-2907
194. Fahy BN, Schlieman MG, Virudachalam S, et al. Inhibition of AKT abrogates chemotherapy-induced NF-kB survival mechanisms: implications for therapy in pancreatic cancer. J Am Coll Surg 2004;198(4):591-599
195. Peng B, Fleming JB, Breslin T, et al. Suppression of tumorigenesis and induction of p15ink4b by Smad4/DPC4 in human pancreatic cancer cells. Clin Cancer Res 2002;8(11):3628-3638
196. Rödicker F, Pützer BM. p73 is effective in p53-null pancreatic cancer cells resistant to wild-type TP53 gene replacement. Cancer Res 2003;63(11):2737-2741
197. Li Y, Qian H, Li X, et al. Adenoviral-mediated gene transfer ofGadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell. J Gene Med 2009;11(1):3-13
198. Pirocanac EC, Nassirpour R, Yang M, et al. Bax-induction gene therapy of pancreatic cancer. J Surg Res 2002;106(2):346-351
199. Pan XT, Zhu QY, Li DC, et al. Effect of recombinant adenovirus vector mediated human interleukin-24 gene transfection on pancreatic carcinoma growth. Chin Med. J (Engl) 2008;121(20):2031-2036
200. Park JK, Lee EJ, Esau C, et al. Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma. Pancreas 2009: published online 2 September 2009, doi: 10.1097/ MPA.0b013e3181ba82e1
201. Moriyama T, Ohuchida K, Mizumoto K, et al. MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol Cancer Ther 2009: published online 12 May 2009, doi: 10.1158/1535-7163. MCT-08-0592
202. Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009;4(8):e6816. Published online 28 August 2009, doi:10.1371/journal. pone.0006816
203. Li Y, VandenBoom TG, Kong D, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 2009;69(16):6704-6712
204. Torrisani J, Bournet B, du Rieu MC, et al. let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gene Ther 2009;20(8):831-844
205. Lee KH, Lotterman C, Karikari C, et al. Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 2009;9(3):293-301