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Oncoleaking: Use of the Pore-Forming Clostridium perfringens Enterotoxin (CPE) for Suicide Gene Therapy

  • Jessica Pahle
  • Jutta Aumann
  • Dennis Kobelt
  • Wolfgang Walther
Part of the Methods in Molecular Biology book series (MIMB, volume 1317)

Abstract

Suicide gene therapy has been shown to be very efficient in tumor eradication. Numerous suicide genes were tested in vitro and in vivo demonstrating their therapeutic potential in clinical trials. Apart from this, still growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard bacterial toxins are an alternative, which add to the broad spectrum of different suicide strategies. In this context, the claudin-targeted bacterial Clostridium perfringens enterotoxin (CPE) is an attractive new type of suicide oncoleaking gene, which as pore-forming protein exerts specific and rapid toxicity towards claudin-3- and -4-overexpressing cancers. In this chapter we describe the generation and use of CPE-expressing vectors for the effective tumor cell killing as novel suicide gene approach particularly for treatment of therapy refractory tumors.

Key words

Clostridium perfringens enterotoxin Pore-forming toxin Bacterial toxin Suicide gene therapy Claudin Epithelial tumor 

References

  1. 1.
    Edelstein ML et al (2007) Gene therapy clinical trials worldwide to 2007-an update. J Gene Med 9:833–842PubMedCrossRefGoogle Scholar
  2. 2.
    Walther W, Schlag PM (2013) Current status of gene therapy for cancer. Curr Opin Oncol 25:659–664PubMedCrossRefGoogle Scholar
  3. 3.
    Lo HW et al (2005) Cancer-specific gene therapy. Adv Genet 54:235–255PubMedGoogle Scholar
  4. 4.
    Michl P, Gress TM (2004) Bacteria and bacterial toxins as therapeutic agents for solid tumors. Curr Cancer Drug Targets 4:689–702PubMedCrossRefGoogle Scholar
  5. 5.
    Martin V et al (2000) Cancer gene therapy by thyroid hormone-mediated expression of toxin genes. Cancer Res 60:3218–3224PubMedGoogle Scholar
  6. 6.
    Lee EJ, Jameson JL (2002) Cell-specific cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells: potential for cytotoxic gene therapy. Hum Gene Ther 13:533–542PubMedCrossRefGoogle Scholar
  7. 7.
    Li Y et al (2002) Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer. Cancer Res 62:2576–2582PubMedGoogle Scholar
  8. 8.
    Zheng JY et al (2003) Regression of prostate cancer xenografts by a lentiviral vector specifically expressing diphtheria toxin A. Cancer Gene Ther 10:764–770PubMedCrossRefGoogle Scholar
  9. 9.
    Candolfi M et al (2010) Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proc Natl Acad Sci U S A 107:20021–20026PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Kreitman RJ (2001) Chimeric fusion proteins – Pseudomonas exotoxin based. Curr Opin Investig Drugs 2:1282–1293PubMedGoogle Scholar
  11. 11.
    Laske DW et al (1997) Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3:1362–1368PubMedCrossRefGoogle Scholar
  12. 12.
    Husain SR, Puri RK (2003) Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside. J Neurooncol 65:37–48PubMedCrossRefGoogle Scholar
  13. 13.
    Ayesh B et al (2003) Inhibition of tumor growth by DT-A expressed under the control of IGF2 P3 and P4 promoter sequences. Mol Ther 7:535–541PubMedCrossRefGoogle Scholar
  14. 14.
    Bhakdi S et al (1996) Staphylococcal α-toxin, streptolysin O, and Escherichia coli hemolysin: prototypes of pore-forming bacterial cytolysins. Arch Microbiol 165:73–79PubMedCrossRefGoogle Scholar
  15. 15.
    Yang WS et al (2006) Suicide cancer gene therapy using pore-forming toxin, streptolysin O. Mol Cancer Ther 5:1610–1619PubMedCrossRefGoogle Scholar
  16. 16.
    Michl P et al (2001) Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology 121:678–684PubMedCrossRefGoogle Scholar
  17. 17.
    Kominsky SL et al (2004) Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol 164:1627–1633PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Johnson EA (1999) Clostridial toxins as therapeutic agents: benefits of nature’s most toxic proteins. Annu Rev Microbiol 53:551–575PubMedCrossRefGoogle Scholar
  19. 19.
    Czeczulin JR et al (1993) Cloning, nucleotide sequencing and expression of the Clostridium perfringens enterotoxin gene in Escherichia coli. Infect Immun 61:3429–3439PubMedCentralPubMedGoogle Scholar
  20. 20.
    McClane BA (2001) The complex interactions between Clostridium perfringens enterotoxin and epithelial tight junctions. Toxicon 39:1781–1791PubMedCrossRefGoogle Scholar
  21. 21.
    Smedley JG 3rd et al (2007) Indentification of a prepore large-complex in the mechanism of action of Clostridium perfringens enterotoxin. Infect Immun 75:2381–2390PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Katahira J et al (1997) Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J Biol Chem 272:26652–26658PubMedCrossRefGoogle Scholar
  23. 23.
    Kokai-Kun JF, McClane BA (1997) Deletion analysis of the Clostridium perfringens enterotoxin. Clin Infect Dis 65:1014–1022Google Scholar
  24. 24.
    Kokai-Kun JF et al (1999) Identification of a Clostridium perfringens enterotoxin region required for large complex formation and cytotoxicity by random mutagenesis. Infect Immun 67:5634–5641PubMedCentralPubMedGoogle Scholar
  25. 25.
    Fujita K et al (2000) Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Lett 476:258–2561PubMedCrossRefGoogle Scholar
  26. 26.
    Morita K et al (1999) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A 96:511–516PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Long H et al (2001) Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium. Cancer Res 61:7878–7881PubMedGoogle Scholar
  28. 28.
    Rangel LB et al (2003) Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 9:2567–2575PubMedGoogle Scholar
  29. 29.
    Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65:9603–9606PubMedCrossRefGoogle Scholar
  30. 30.
    Soini Y (2005) Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumors. Histopathology 46:551–560PubMedCrossRefGoogle Scholar
  31. 31.
    Hewitt KJ et al (2006) The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer 6:186PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Kominsky SL et al (2007) Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer Res 67:7977–7982PubMedCrossRefGoogle Scholar
  33. 33.
    Smedley JG III, McLane BA (2004) Fine mapping of the N-terminal cytotoxicity region of Clostridium perfringens enterotoxin by site-directed mutagenesis. Infect Immun 72:6914–6923PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Santin AD et al (2005) Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens enterotoxin. Cancer Res 65:4334–4342PubMedCrossRefGoogle Scholar
  35. 35.
    Santin AD et al (2007) Overexpression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in uterine carcinomas. Clin Cancer Res 13:3339–3346PubMedCrossRefGoogle Scholar
  36. 36.
    Santin AD et al (2007) Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma. Cancer 109:1312–1322PubMedCrossRefGoogle Scholar
  37. 37.
    Walther W et al (2012) Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3 and -4 overexpressing tumors. Gene Ther 19:494–503PubMedCrossRefGoogle Scholar
  38. 38.
    Dirks WG, Drexler HG (2013) STR DNA typing of human cell lines: detection of intra- and interspecies cross-contamination. Methods Mol Biol 946:27–38PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jessica Pahle
    • 1
    • 2
  • Jutta Aumann
    • 1
    • 2
  • Dennis Kobelt
    • 2
  • Wolfgang Walther
    • 3
  1. 1.Experimental and Clinical Research Center (ECRC)Charité University Medicine BerlinBerlinGermany
  2. 2.Max-Delbrück-Center for Molecular MedicineBerlinGermany
  3. 3.Translational Oncology of Solid Tumors, Experimental and Clinical Research Center (ECRC)Charité University Medicine Berlin and Max-Delbrück-Center for Molecular MedicineBerlinGermany

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