Skip to main content
SpringerLink
Log in

Selective Suicide Gene Therapy of Colon Cancer Exploiting the Urokinase Plasminogen Activator Receptor Promoter

  • Original Research Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Background

Colon cancer is the third and fourth most prevalent cancer among Iranian men and women, respectively. Suicide gene therapy is one of the alternative therapeutic modalities for cancer. The application of specific promoters for therapeutic genes should decrease the adverse effects of this modality.

Objectives

The combined aims of this study were to design a specific suicide gene therapy construct for colon cancer and study its effect in distinct representatives of transformed and nontransformed cells.

Study Design

The KRAS oncogene signaling pathway is one of the most important signaling pathways activated in colon cancer; therefore, we inserted the urokinase plasminogen activator receptor (uPAR; PLAUR gene) promoter as one of the upregulated promoters by this pathway upstream of a suicide gene (thymidine kinase [TK]) and a reporter gene (β-galactosidase, β-gal [LacZ]). This promoter is a natural combination of different motifs responsive to the RAS signaling pathway, such as the transcription factors AP1 (FOS/JUN), SP1, SP3, and AP2α, and nuclear factor kappa B (NFκB).

Results

The reporter plasmid under the control of the uPAR promoter (PUCUPARLacZ) had the ability to express b-gal in colon cancer cells (human colon adenocarcinoma [SW480] and human colorectal carcinoma [HCT116] cell lines), while it could not express β-gal in nontransformed human umbilical vein endothelial cells (HUVEC) and normal colon cells. After confirming the ability of pUCUPARTK (suicide plasmid) to express TK in SW480 and HCT116 cells by real-time PCR, cytotoxicity assays showed that pUCUPARTK decreased the viability of these cells in the presence of ganciclovir 20 and 40 μg/mL (and higher), respectively. Although M30 CytoDEATH™ antibody could not detect a significant rate of apoptosis induced by ganciclovir in pUCUPARTK-transfected HCT116 cells, the percentage of stained cells was marked in comparison with untreated cells. While this antibody could detect apoptosis in HCT116 cell line transfected with positive control plasmid, it could not detect apoptosis in SW480 cells transfected with the same positive control. This discrepancy could be attributed to the different mechanisms of TK/ganciclovir-induced apoptosis in tumor protein p53 (TP53)-expressing (HCT116) and -deficient (SW480) cells. Annexin-propidium iodide staining could detect apoptosis in treated, pUCUPARTK-transfected SW480 and HCT116 cells.

Conclusion

This study showed that the uPAR promoter can be considered as a suitable candidate for specific suicide gene therapy of colon cancer and probably other cancers in which the RAS signaling pathway is involved in their carcinogenesis process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Sadjadi A, Nouraie M, Mohagheghi MA, et al. Cancer occurrence in Iran in 2002: an international perspective. Asian Pac J Cancer Prev 2005 Jul; 6(3): 359–63

    PubMed  Google Scholar 

  2. Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1996. CA Cancer J Clin 1996 Jan; 46(1): 5–27

    Article  PubMed  CAS  Google Scholar 

  3. Lipinski KS, Djeha AH, Ismail T, et al. High-level, beta-catenin/TCF-dependent transgene expression in secondary colorectal cancer tissue. Mol Ther 2001 Oct; 4(4): 365–71

    Article  PubMed  CAS  Google Scholar 

  4. Zeng ZJ, Li ZB, Luo SQ, et al. Retrovirus-mediated tk gene therapy of implanted human breast cancer in nude mice under the regulation of Tet-On. Cancer Gene Ther 2006 Mar; 13(3): 290–7

    Article  PubMed  CAS  Google Scholar 

  5. Wiewrodt R, Amin K, Kiefer M, et al. Adenovirus-mediated gene transfer of enhanced herpes simplex virus thymidine kinase mutants improves prodrug-mediated tumor cell killing. Cancer Gene Ther 2003 May; 10(5): 353–64

    Article  PubMed  CAS  Google Scholar 

  6. Sterman DH, Recio A, Vachani A, et al. Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 2005 Oct 15; 11(20): 7444–53

    Article  PubMed  CAS  Google Scholar 

  7. Konson A, Ben-Kasus T, Mahajna JA, et al. Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells. Cancer Gene Ther 2004 Dec; 11(12): 830–40

    Article  PubMed  CAS  Google Scholar 

  8. Freeman SM, Abboud CN, Whartenby KA, et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993 Nov 1; 53(21): 5274–83

    PubMed  CAS  Google Scholar 

  9. Freytag SO, Stricker H, Peabody J, et al. Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther 2007 Mar; 15(3): 636–42

    Article  PubMed  CAS  Google Scholar 

  10. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 2000 Nov 20; 11(17): 2389–401

    Article  PubMed  CAS  Google Scholar 

  11. Zabala M, Wang L, Hernandez-Alcoceba R, et al. Optimization of the Tet-on system to regulate interleukin 12 expression in the liver for the treatment of hepatic tumors. Cancer Res 2004 Apr 15; 64(8): 2799–804

    Article  PubMed  CAS  Google Scholar 

  12. Ikegami S, Tadakuma T, Yamakami K, et al. Selective gene therapy for prostate cancer cells using liposomes conjugated with IgM type monoclonal antibody against prostate-specific membrane antigen. Hum Cell 2005 Mar; 18(1): 17–23

    Article  PubMed  Google Scholar 

  13. Nettelbeck DM, Jerome V, Muller R. Gene therapy: designer promoters for tumour targeting. Trends Genet 2000 Apr; 16(4): 174–81

    Article  PubMed  CAS  Google Scholar 

  14. Pang S, Taneja S, Dardashti K, et al. Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer. Hum Gene Ther 1995 Nov; 6(11): 1417–26

    Article  PubMed  CAS  Google Scholar 

  15. Richards CA, Austin EA, Huber BE. Transcriptional regulatory sequences of carcinoembryonic antigen: identification and use with cytosine deaminase for tumor-specific gene therapy. Hum Gene Ther 1995 Jul; 6(7): 881–93

    Article  PubMed  CAS  Google Scholar 

  16. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001 Jul 18; 93(14): 1062–74

    Article  PubMed  CAS  Google Scholar 

  17. Arber N, Shapira I, Ratan J, et al. Activation of c-K-ras mutations in human gastrointestinal tumors. Gastroenterology 2000 Jun; 118(6): 1045–50

    Article  PubMed  CAS  Google Scholar 

  18. Duursma AM, Agami R. Ras interference as cancer therapy. Semin Cancer Biol 2003 Aug; 13(4): 267–73

    Article  PubMed  CAS  Google Scholar 

  19. Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988 May; 195(3): 255–71

    Article  PubMed  CAS  Google Scholar 

  20. Sutter T, Arber N, Moss SF, et al. Frequent K-ras mutations in small bowel adenocarcinomas. Dig Dis Sci 1996 Jan; 41(1): 115–8

    Article  PubMed  CAS  Google Scholar 

  21. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987 May 28; 327(6120): 293–7

    Article  PubMed  CAS  Google Scholar 

  22. Gao HG, Chen JK, Stewart J, et al. Distribution of p53 and K-ras mutations in human lung cancer tissues. Carcinogenesis 1997 Mar; 18(3): 473–8

    Article  PubMed  CAS  Google Scholar 

  23. Beck SE, Jung BH, Del RE, et al. BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK. Cell Signal 2007 Jul; 19(7): 1465–72

    Article  PubMed  CAS  Google Scholar 

  24. Zuber J, Tchernitsa OI, Hinzmann B, et al. A genome-wide survey of RAS transformation targets. Nat Genet 2000 Feb; 24(2): 144–52

    Article  PubMed  CAS  Google Scholar 

  25. Pollock CB, Shirasawa S, Sasazuki T, et al. Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells. Cancer Res 2005 Feb 15; 65(4): 1244–50

    Article  PubMed  CAS  Google Scholar 

  26. Wu M, Huang C, Li X, et al. LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses. J Cell Physiol 2008 Jan; 214(1): 65–74

    Article  PubMed  CAS  Google Scholar 

  27. Mesa Jr C, Mirza M, Mitsutake N, et al. Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Res 2006 Jul 1; 66(13): 6521–9

    Article  PubMed  CAS  Google Scholar 

  28. Backlund MG, Mann JR, Wang D, et al. Ras up-regulation of cyclooxygenase-2. Methods Enzymol 2005; 407: 401–10

    Article  Google Scholar 

  29. Gum R, Juarez J, Allgayer H, et al. Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules. Oncogene 1998 Jul 16; 17(2): 213–25

    Article  PubMed  CAS  Google Scholar 

  30. Campbell SL, Khosravi-Far R, Rossman KL, et al. Increasing complexity of Ras signaling. Oncogene 1998 Sep 17; 17: 1395–413

    Article  PubMed  CAS  Google Scholar 

  31. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989 Sep 1; 49(17): 4682–9

    PubMed  CAS  Google Scholar 

  32. Neibergs HL, Hein DW, Spratt JS. Genetic profiling of colon cancer. J Surg Oncol 2002 Aug; 80(4): 204–13

    Article  PubMed  CAS  Google Scholar 

  33. Andreyev HJ, Ross PJ, Cunningham D, et al. Antisense treatment directed against mutated Ki-ras in human colorectal adenocarcinoma. Gut 2001 Feb; 48(2): 230–7

    Article  PubMed  CAS  Google Scholar 

  34. Dvory-Sobol H, Kazanov D, Arber N. Gene targeting approach to selectively kill colon cancer cells, with hyperactive K-Ras pathway. Biomed Pharma-cother 2005 Oct; 59Suppl. 2: S370–4

    Article  CAS  Google Scholar 

  35. Reddy MA, Langer SJ, Colman MS, et al. An enhancer element responsive to ras and fms signaling pathways is composed of two distinct nuclear factor binding sites. Mol Endocrinol 1992 Jul; 6(7): 1051–60

    Article  PubMed  CAS  Google Scholar 

  36. Rosenberg S. New developments in the urokinase-type plasminogen activator system. Expert Opin Ther Targets 2001 Dec; 5(6): 711–22

    Article  PubMed  CAS  Google Scholar 

  37. Hagiwara H, Sato H, Shirai S, et al. Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells. Life Sci 2006 Apr 4; 78(19): 2249–54

    Article  PubMed  CAS  Google Scholar 

  38. Barinka C, Parry G, Callahan J, et al. Structural basis of interaction between urokinase-type plasminogen activator and its receptor. J Mol Biol 2006 Oct 20; 363(2): 482–95

    Article  PubMed  CAS  Google Scholar 

  39. D’Alessio S, Margheri F, Pucci M, et al. Antisense oligodeoxynucleotides for urokinase-plasminogen activator receptor have anti-invasive and anti-proliferative effects in vitro and inhibit spontaneous metastases of human melanoma in mice. Int J Cancer 2004 May 20; 110(1): 125–33

    Article  PubMed  Google Scholar 

  40. Begum FD, Hogdall CK, Kjaer SK, et al. The prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) levels in stage III ovarian cancer patients. Anticancer Res 2004 May; 24(3b): 1981–5

    PubMed  CAS  Google Scholar 

  41. Bagheri-Yarmand R, Mazumdar A, Sahin AA, et al. LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 2006 Jun 1; 118(11): 2703–10

    Article  PubMed  CAS  Google Scholar 

  42. Akahane T, Ishii M, Ohtani H, et al. Stromal expression of urokinase-type plasminogen activator receptor (uPAR) is associated with invasive growth in primary liver cancer. Liver 1998 Dec; 18(6): 414–9

    PubMed  CAS  Google Scholar 

  43. Cantero D, Friess H, Deflorin J, et al. Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997; 75(3): 388–95

    Article  PubMed  CAS  Google Scholar 

  44. Albo D, Tuszynski GP. Thrombospondin-1 up-regulates tumor cell invasion through the urokinase plasminogen activator receptor in head and neck cancer cells. J Surg Res 2004 Jul; 120(1): 21–6

    Article  PubMed  CAS  Google Scholar 

  45. Ahmed N, Oliva K, Wang Y, et al. Proteomic profiling of proteins associated with urokinase plasminogen activator receptor in a colon cancer cell line using an antisense approach. Proteomics 2003 Mar; 3(3): 288–98

    Article  PubMed  CAS  Google Scholar 

  46. Bauer TW, Fan F, Liu W, et al. Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. Ann Surg 2005 May; 241(5): 748–56

    Article  PubMed  Google Scholar 

  47. Dass K, Ahmad A, Azmi AS, et al. Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 2008 Apr; 34(2): 122–36

    Article  PubMed  CAS  Google Scholar 

  48. Allgayer H, Wang H, Shirasawa S, et al. Targeted disruption of the K-ras oncogene in an invasive colon cancer cell line down-regulates urokinase receptor expression and plasminogen-dependent proteolysis. Br J Cancer 1999 Aug; 80(12): 1884–91

    Article  PubMed  CAS  Google Scholar 

  49. Lengyel E, Stepp E, Gum R, et al. Involvement of a mitogen-activated protein kinase signaling pathway in the regulation of urokinase promoter activity by c-Ha-ras. J Biol Chem 1995 Sep 29; 270(39): 23007–12

    Article  PubMed  CAS  Google Scholar 

  50. Muller SM, Okan E, Jones P. Regulation of urokinase receptor transcription by Ras- and Rho-family GTPases. Biochem Biophys Res Commun 2000 Apr 21; 270(3): 892–8

    Article  PubMed  CAS  Google Scholar 

  51. Schewe DM, Biller T, Maurer G, et al. Combination analysis of activator protein-1 family members, Sp 1 and an activator protein-2alpha-related factor binding to different regions of the urokinase receptor gene in resected colorectal cancers. Clin Cancer Res 2005 Dec 15; 11 (24 Pt 1): 8538–48

    Article  PubMed  CAS  Google Scholar 

  52. Sambrook J, Russell DW. Molecular cloninga laboratory manual. 3rd ed. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press, 2001

    Google Scholar 

  53. Azadmanesh K, Rohvand F, Amini S, et al. Evaluation of stimulatory effects of HTLV-I tax protein on CREB and NFKB related signaling pathways two B-glycosidase based reporter plasmids. Yakhteh Med J 2005; 6(24): 218–25

    Google Scholar 

  54. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2 CT method. Methods 2001; 25(4): 402–8

    Article  PubMed  CAS  Google Scholar 

  55. Bilbao R, Gerolami R, Bralet MP, et al. Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model. Cancer Gene Ther 2000 May; 7(5): 657–62

    Article  PubMed  CAS  Google Scholar 

  56. Hauck W, Stanners CP. Transcriptional regulation of the carcinoembryonic antigen gene. Identification of regulatory elements and multiple nuclear factors. J Biol Chem 1995 Feb 24; 270(8): 3602–10

    Article  PubMed  CAS  Google Scholar 

  57. Dabrowska A, Szary J, Kowalczuk M et al. CEA-negative glioblastoma and melanoma cells are sensitive to cytosine deaminase/5-fluorocytosine therapy directed by the carcinoembryonic antigen promoter. Acta Biochim Pol 2004; 51(3): 723–34

    PubMed  CAS  Google Scholar 

  58. Ueda K, Iwahashi M, Nakamori M, et al. Improvement of carcinoembryonic antigen-specific prodrug gene therapy for experimental colon cancer. Surgery 2003 Mar; 133(3): 309–17

    Article  PubMed  Google Scholar 

  59. Block A, Milasinovic D, Mueller J et al. Amplified Muc1-specific gene expression in colon cancer cells utilizing a binary system in adenoviral vectors. Anticancer Res 2002 Nov–Dec; 22(6A): 3285–92

    PubMed  CAS  Google Scholar 

  60. Yamamoto M, Alemany R, Adachi Y, et al. Characterization of the cyclooxy-genase-2 promoter in an adenoviral vector and its application for the mitigation of toxicity in suicide gene therapy of gastrointestinal cancers. Mol Ther 2001 Mar; 3(3): 385–94

    Article  PubMed  CAS  Google Scholar 

  61. Lehmann K, Janda E, Pierreux CE, et al. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 2000 Oct 15; 14(20): 2610–22

    Article  PubMed  CAS  Google Scholar 

  62. Ahnen DJ, Feigl P, Quan G, et al. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res 1998 Mar 15; 58(6): 1149–58

    PubMed  CAS  Google Scholar 

  63. Shirasawa S, Furuse M, Yokoyama N, et al. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 1993 Apr 2; 260(5104): 85–8

    Article  PubMed  CAS  Google Scholar 

  64. Dumler I, Weis A, Mayboroda OA, et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 1998 Jan 2; 273(1): 315–21

    Article  PubMed  CAS  Google Scholar 

  65. Koshelnick Y, Ehart M, Stockinger H, et al. Mechanisms of signaling through urokinase receptor and the cellular response. Thromb Haemost 1999 Aug; 82(2): 305–11

    PubMed  CAS  Google Scholar 

  66. Tang H, Kerins DM, Hao Q, et al. The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells. J Biol Chem 1998 Jul 17; 273(29): 18268–72

    Article  PubMed  CAS  Google Scholar 

  67. Koch A, Waha A, Hartmann W, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res 2005 Jun 15; 11(12): 4295–304

    Article  PubMed  CAS  Google Scholar 

  68. Wang Y, Dang J, Johnson LK, et al. Structure of the human urokinase receptor gene and its similarity to CD59 and the Ly-6 family. Eur J Biochem 1995 Jan 15; 227(1-2): 116–22

    Article  PubMed  CAS  Google Scholar 

  69. Li CY, Tan L, Zhang GJ, et al. Transcriptional regulation of urokinase receptor in high- (95D) and low-metastatic (95C) human lung cancer cells. Acta Biochim Biophys Sin (Shanghai) 2004 Jun; 36(6): 405–11

    Article  CAS  Google Scholar 

  70. Allgayer H, Wang H, Wang Y, et al. Transactivation of the urokinase-type plasminogen activator receptor gene through a novel promoter motif bound with an activator protein-2alpha-related factor. J Biol Chem 1999 Feb 19; 274(8): 4702–14

    Article  PubMed  CAS  Google Scholar 

  71. Leupold JH, Asangani I, Maurer GD, et al. Src induces urokinase receptor gene expression and invasion/intravasation via activator protein-1/p-c-Jun in colorectal cancer. Mol Cancer Res 2007 May; 5(5): 485–96

    Article  PubMed  CAS  Google Scholar 

  72. Soravia E, Grebe A, De LP, et al. A conserved TATA-less proximal promoter drives basal transcription from the urokinase-type plasminogen activator receptor gene. Blood 1995 Jul 15; 86(2): 624–35

    PubMed  CAS  Google Scholar 

  73. Dang J, Boyd D, Wang H, et al. A region between -141 and -61 bp containing a proximal AP-1 is essential for constitutive expression of urokinase-type plasminogen activator receptor. Eur J Biochem 1999 Aug; 264(1): 92–9

    Article  PubMed  CAS  Google Scholar 

  74. Allgayer H, Wang H, Gallick GE, et al. Transcriptional induction of the urokinase receptor gene by a constitutively active Src: requirement of an upstream motif (—152/—13 5) bound with Sp1. J Biol Chem 1999 Jun 25; 274(26): 18428–37

    Article  PubMed  CAS  Google Scholar 

  75. Wang Y, Dang J, Wang H, et al. Identification of a novel nuclear factor-kappaB sequence involved in expression of urokinase-type plasminogen activator receptor. Eur J Biochem 2000 Jun; 267(11): 3248–54

    Article  PubMed  CAS  Google Scholar 

  76. Hapke S, Gawaz M, Dehne K, et al. beta(3)A-integrin downregulates the urokinase-type plasminogen activator receptor (u-PAR) through a PEA3/ets transcriptional silencing element in the u-PAR promoter. Mol Cell Biol 2001 Mar; 21(6): 2118–32

    Article  PubMed  CAS  Google Scholar 

  77. Schewe DM, Leupold JH, Boyd DD, et al. Tumor-specific transcription factor binding to an activator protein-2/Sp 1 element of the urokinase-type plasminogen activator receptor promoter in a first large series of resected gastrointestinal cancers. Clin Cancer Res 2003 Jun; 9(6): 2267–76

    PubMed  CAS  Google Scholar 

  78. Malerba M, Nikolova D, Cornelis J, et al. Targeting of autonomous parvo-viruses to colon cancer by insertion of Tcf sites in the P4 promoter. Cancer Gene Ther 2006 Mar; 13(3): 273–80

    Article  PubMed  CAS  Google Scholar 

  79. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000 Oct 13; 103(2): 311–20

    Article  PubMed  CAS  Google Scholar 

  80. Uch R, Gerolami R, Faivre J, et al. Hepatoma cell-specific ganciclovir-mediated toxicity of a lentivirally transduced HSV-TkEGFP fusion protein gene placed under the control of rat alpha-fetoprotein gene regulatory sequences. Cancer Gene Ther 2003 Sep; 10(9): 689–95

    Article  PubMed  CAS  Google Scholar 

  81. Thust R, Tomicic M, Klocking R, et al. Comparison of the genotoxic and apoptosis-inducing properties of ganciclovir and penciclovir in Chinese hamster ovary cells transfected with the thymidine kinase gene of herpes simplex virus-1: implications for gene therapeutic approaches. Cancer Gene Ther 2000 Jan; 7(1): 107–17

    Article  PubMed  CAS  Google Scholar 

  82. Caulin C, Salvesen GS, Oshima RG. Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis. J Cell Biol 1997 Sep 22; 138(6): 1379–94

    Article  PubMed  CAS  Google Scholar 

  83. Beltinger C, Fulda S, Kammertoens T, et al. Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci U S A 1999 Jul 20; 96(15): 8699–704

    Article  PubMed  CAS  Google Scholar 

  84. Wei SJ, Chao Y, Shih YL, et al. Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase. Gene Ther 1999 Mar; 6(3): 420–31

    Article  PubMed  CAS  Google Scholar 

  85. Tomicic MT, Thust R, Kaina B. Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. Oncogene 2002 Mar 28; 21(14): 2141–53

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was funded by the Pasteur Institute of Iran. We hereby thank Mrs Maryam Noorayee Kia (Head Nurse of 1st Surgery Ward, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran), Mrs Leyli Ghaffarpour (Head Nurse of 1st Operating Room, Imam Khomeini Hospital), and other nurses in these wards for their kind help in obtaining the normal colon tissue. We also thank Dr Ahmad Kaviani (1st Surgery Ward, Imam Khomeini Hospital) for his kind help in obtaining the colon tissue during an operation.

The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, 69th Pasteur Street, Kargar Avenue, Tehran, 13169-43551, Iran

    Ladan Teimoori-Toolabi &  Sirous Zeinali

  2. Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, Iran

    Kayhan Azadmanesh

  3. Virology Department, Pasteur Institute of Iran, Tehran, Iran

    Kayhan Azadmanesh

  4. National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran

    Amir Amanzadeh

Authors
  1. Ladan Teimoori-Toolabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kayhan Azadmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amir Amanzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sirous Zeinali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sirous Zeinali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teimoori-Toolabi, L., Azadmanesh, K., Amanzadeh, A. et al. Selective Suicide Gene Therapy of Colon Cancer Exploiting the Urokinase Plasminogen Activator Receptor Promoter. BioDrugs 24, 131–146 (2010). https://doi.org/10.2165/11530840-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11530840-000000000-00000

Keywords

Search

Navigation