title: Analysis of promoters and expression-targeted gene therapy optimization based on doubling time and transfectability.
abstract: Genes under the control of the cyclooxygenase-2 (Cox-2), human epidermal growth factor receptor 2 (Her-2), and survivin promoters were constructed and delivered to murine and human carcinoma cells. It was found that (P)Cox-2-driven reporter expression was strong and correlated well with endogenous Cox-2 levels, while (P)Her-2 and (P)survivin yielded poor results, consistent with the three distinct expression mechanisms used by cancer cells to overexpress the endogenous versions of the selected genes. The (P)Cox-2 was then used to drive the expression of caspase genes both in vitro and in vivo to bring about targeted apoptosis of carcinoma cells successfully. The results led to the following conclusions. 1) When selecting a promoter/enhancer for expression-targeted gene delivery, it is not enough to perform a microarray on some tumor tissue and select the control element associated with the greatest amount of gene up-regulation vs. normal controls. The mechanism of expression for the particular gene should be taken into account to prevent lengthy and costly research trials. 2) When overexpression is due to activator binding, a predictive model based on endogenous gene expression levels, overall cell transfectability, and cell doubling rates can be used to predict expression-targeted gene delivery outcomes with significant accuracy.
authors: Department of Comparative Medicine, Tulane University, New Orleans, LA 70118, USA. godbey@tulane.edu
authors: Georgina L
authors: GL
authors: Dobek
authors: Xiujuan
authors: X
authors: Zhang
authors: Daniel A
authors: DA
authors: Balazs
authors: W T
authors: WT
authors: Godbey
references: Cancer Lett. 2001 Oct 30;172(2):177-85
references: 11566494
references: Cancer Res. 1999 Nov 15;59(22):5647-50
references: 10582676
references: Pharmacol Rep. 2010 Mar-Apr;62(2):233-44
references: 20508278
references: Oncogene. 2003 Nov 24;22(53):8581-9
references: 14634620
references: Oncogene. 2004 Feb 26;23(8):1631-5
references: 14985703
references: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6179-85
references: 17062695
references: Am J Pathol. 1998 Jan;152(1):43-9
references: 9422522
references: J Clin Invest. 1995 Dec;96(6):2980-9
references: 8675670
references: J Biol Chem. 1998 May 1;273(18):11177-82
references: 9556606
references: Mol Biotechnol. 2009 Mar;41(3):236-46
references: 19067254
references: N Engl J Med. 1999 Aug 5;341(6):452-3
references: 10438269
references: J Cell Mol Med. 2003 Jul-Sep;7(3):207-22
references: 14594546
references: Clin Cancer Res. 2000 Jan;6(1):127-34
references: 10656440
references: Clin Cancer Res. 2001 Mar;7(3):558-61
references: 11297248
references: Cancer Treat Rev. 2009 Nov;35(7):553-62
references: 19559538
references: Cancer Lett. 1992 Jan 10;61(2):95-103
references: 1346099
references: Nat Genet. 2000 Sep;26(1):64-6
references: 10973250
references: Br J Cancer. 2000 Feb;82(3):666-74
references: 10682681
references: J Invest Dermatol. 1999 Dec;113(6):1076-81
references: 10594755
references: Trends Genet. 2000 Apr;16(4):174-81
references: 10729833
references: Endocr Relat Cancer. 2001 Jun;8(2):97-114
references: 11397667
references: J Urol. 2001 May;165(5):1468-72
references: 11342898
references: J Biol Chem. 1992 Mar 5;267(7):4338-44
references: 1339449
references: Blood. 2010 Sep 23;116(12):2192-3
references: 20864587
references: Oncol Res. 1997;9(6-7):313-25
references: 9406237
references: Cancer Gene Ther. 2010 Aug;17(8):559-70
references: 20448672
references: Breast Cancer Res. 2001;3(6):395-8
references: 11737892
references: Cancer Res. 1995 Jun 15;55(12):2556-9
references: 7780968
references: Int J Cancer. 2001 Mar 20;95(2):92-5
references: 11241318
references: Pathology. 2001 Nov;33(4):469-74
references: 11827414
references: Clin Cancer Res. 2000 Apr;6(4):1229-38
references: 10778945
references: Biochim Biophys Acta. 2006 Aug;1766(1):104-19
references: 16859832
references: Cancer. 2007 Mar 15;109(6):1106-13
references: 17311310
references: Cancer Lett. 2001 Aug 28;169(2):155-64
references: 11431104
references: Proc Natl Acad Sci U S A. 1996 May 14;93(10):4816-20
references: 8643486
references: Cancer Res. 1997 Apr 1;57(7):1276-80
references: 9102213
references: Biochem Biophys Res Commun. 2010 Mar 19;393(4):592-7
references: 20152814
references: Cancer Immunol Immunother. 2009 Nov;58(11):1801-7
references: 19294381
references: Pharmacol Rev. 2004 Sep;56(3):387-437
references: 15317910
references: World J Urol. 2008 Feb;26(1):59-65
references: 17962949
references: J Vis Exp. 2011 Feb 06;(48):
references: 21339722
references: BJU Int. 2010 Dec;106(11):1812-6
references: 20201832
references: Clin Breast Cancer. 2010;10 Suppl 1:E38-46
references: 20587406
references: J Clin Oncol. 1999 Jul;17(7):2180-9
references: 10561274
references: Oncogene. 2009 May 14;28(19):2046-50
references: 19363521
references: Curr Pharm Des. 2003;9(27):2229-51
references: 14529404
references: Exp Hematol. 2007 May;35(5):712-23
references: 17577921
references: Proc Natl Acad Sci U S A. 1987 Jul;84(13):4374-8
references: 2885835
references: Cancer Res. 1993 Oct 15;53(20):4960-70
references: 8104689
references: Nat Rev Cancer. 2003 Jan;3(1):46-54
references: 12509766
references: Nucleic Acids Res. 2001 May 1;29(9):e45
references: 11328886
references: Cancer Res. 1998 Nov 15;58(22):5071-4
references: 9823313
references: N Engl J Med. 1990 Aug 30;323(9):570-8
references: 2381442
references: Urology. 2009 Jul;74(1):222-8
references: 19285711
references: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1000-5
references: 15657147
references: Gene Ther. 2003 Aug;10(17):1519-27
references: 12900768
references: Nat Med. 1997 Aug;3(8):917-21
references: 9256286
references: Cancer Gene Ther. 2008 Aug;15(8):543-52
references: 18323852