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Journal of Molecular Medicine

, 89:1113 | Cite as

Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect

  • Ellen Preuß
  • Alexander Muik
  • Kristoffer Weber
  • Jürgen Otte
  • Dorothee von Laer
  • Boris FehseEmail author
Original Article

Abstract

Suicide gene therapy is a promising concept in oncology. We have recently introduced a novel suicide gene, TK.007, which was shown to excel established herpes simplex virus thymidine kinase (HSVtk) variants when used for donor-lymphocyte modification in adoptive immunotherapy models. Here, the potential of TK.007 in killing cancer cells was studied. Initially, we transduced tumour cell lines derived from different neoplasias (glioblastoma, melanoma, lung cancer, colon cancer) with lentiviral LeGO vectors encoding TK.007 or the splice-corrected (sc)HSVtk together with an eGFP/Neo-marker. Based on direct in vitro comparison, we found that TK.007 facilitates more efficient tumour cell killing at significantly lower ganciclovir doses in all tumour cell lines tested. Also, using different readout systems, we found a significantly stronger bystander effect of TK.007 as compared to scHSVtk. Importantly, in vitro data were confirmed in vivo using a subcutaneous G62 glioblastoma model in NOD/SCID mice. In mice transplanted with scHSVtk-positive tumours, treatment with low (10 mg/kg) or standard (50 mg/kg) ganciclovir doses resulted only in short-term growth inhibition or transient tumour remission, respectively. In striking contrast, in the TK.007 group, all animals achieved continuous complete remission after both standard and low-dose ganciclovir. Finally, a substantial bystander effect for TK.007 was also confirmed with the G62 model in vivo, where significantly prolonged survival for mice bearing tumours containing only 10% or 50% TK.007-expressing cells was observed. In summary, our data indicate strongly improved anti-tumour activity of TK.007 as compared to conventional HSVtk. We therefore suppose that TK.007 is an excellent candidate for cancer suicide gene therapy.

Keywords

Suicide gene HSVtk Cancer gene therapy Bystander effect 

Notes

Acknowledgements

The authors wish to thank Daniela Brücher for expert technical assistance and Dr. Sebastian Newrzela for helpful support. We are indebted to Dr. Boris Brill and Ute Burkhardt for assistance with animal experiments. dsRed-positive G62 cells were kindly provided by Yvonne Heidemarie Fischer (Georg-Speyer-Haus Frankfurt am Main, Germany). This work was partially supported by the DFG (FE568/11-1) and the Frankfurter Stiftung für krebskranke Kinder.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ellen Preuß
    • 1
    • 2
  • Alexander Muik
    • 3
    • 4
  • Kristoffer Weber
    • 1
  • Jürgen Otte
    • 2
  • Dorothee von Laer
    • 4
  • Boris Fehse
    • 1
    Email author
  1. 1.Research Department Cell and Gene Therapy, Clinic for Stem Cell TransplantationUniversity Medical Centre Hamburg-EppendorfHamburgGermany
  2. 2.Frankfurter Stiftung für krebskranke KinderFrankfurt am MainGermany
  3. 3.Georg Speyer HausFrankfurt am MainGermany
  4. 4.Virology SectionMedical University InnsbruckInnsbruckAustria

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