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Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

Despite impressive improvements in neurosurgical techniques, radiation and chemotherapy during the past few years, little progress has been made in the treatment of malignant gliomas. Recently, the efficacy of suicide gene therapy based on replication-competent retroviral (RCR) vectors as delivery vehicles for the therapeutic gene has been described in the treatment of experimental cancer, including gliomas. In this study, we have thus critically evaluated a panel of human and rodent glioma/glioblastoma cell lines (U-87MG, U-118MG, LN-18, LN-229, 8-MG-BA, 42-MG-BA, A-172, T-98G, UVW, C6, 9L, G-26, GL-261, Tu-2449, Tu-9648) with respect to RCR virus vector spread, sensitivity towards the cytosine deaminase (CD)/5-flurocytosine (5-FC)/5-flurouracil (5-FU) suicide system, and orthotopic growth characteristics in mice to identify suitable preclinical animal models for the development of a glioblastoma gene therapy. Rapid virus spread was observed in eight out of nine human cell lines tested in vitro. As expected, only CD-expressing cells became sensitive to 5-FC, due to their ability to convert the prodrug in its toxic form, 5-FU. All LD50 values were within the range of concentrations obtained in human body fluids after conventional antifungal 5-FC administration. In addition, a significant bystander effect was observed in all human glioma cell lines tested. Injection of the RCR vector into pre-established orthotopic mouse tumor xenografts revealed substantial infection and virus spread of tumor tissue from most cell types.

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References

  1. Miller CR, Perry A (2007) Glioblastoma. Morphologic and molecular genetic diversity. Arch Pathol Lab Med 131(3):397–406

    Google Scholar 

  2. Hegi ME, Murat A, Lambiv WL et al (2006) Brain tumors: molecular biology and targeted therapies. Ann Oncol 17(Suppl. 10):x191–x197

    Article  PubMed  Google Scholar 

  3. Mizuno M, Yoshida J, Colosi P et al (1998) Adeno-associated virus vector containing the herpes simplex virus thymidine kinase gene causes complete regression of intracerebrally implanted human gliomas in mice, in conjunction with ganciclovir administration. Jpn J Cancer Res 89(1):76–80

    CAS  PubMed  Google Scholar 

  4. Tymiryasova TM, Chen B, Haghighat P (1999) Vaccinia virus-mediated expression of wild-type p53 suppresses glioma cell growth and induces apoptosis. Int J Oncol 14(5):845–854

    Google Scholar 

  5. Ren H, Boulikas T, Lundstrom K et al (2003) Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki Forest virus vector carrying the human interleukin-12 gene–a phase I/II clinical protocol. J Neurooncol 64(1–2):147–154

    CAS  PubMed  Google Scholar 

  6. Shand N, Weber F, Mariani L et al (1999) A phase 1–2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. Hum Gene Ther 10(14):2325–2335

    Article  CAS  PubMed  Google Scholar 

  7. Rainov NG, Ren H (2003) Clinical trials with retrovirus mediated gene therapy—what we have learned? J Neurooncol 65(3):227–236

    Article  PubMed  Google Scholar 

  8. Smitt PS, Driesse M, Wolbers J et al (2003) Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 7(6):851–858

    Article  CAS  PubMed  Google Scholar 

  9. Conrad C, Miller CR, Ji Y, Gomez-Manzano C et al (2005) ∆24-hyCD adenovirus suppresses glioma growth in vivo by combining oncolysis and chemosensitization. Cancer Gene Ther 12(3):284–294

    Article  CAS  PubMed  Google Scholar 

  10. Wollmann G, Tattersall P, van den Pol AN (2005) Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential. J Virol 79(10):6005–6022

    Article  CAS  PubMed  Google Scholar 

  11. Sonabend AM, Ulasov IV, Han Y et al (2006) Oncolytic adenoviral therapy for glioblastoma multiforme. Neurosurg Focus 20(4):1–10

    Article  Google Scholar 

  12. Ulasov IV, Sonabend AM, Nandi S et al (2009) Combination of adenoviral virotherapy and temozolomide chemotherapy eradicates malignant glioma through autophagic and apoptic cell death in vivo. Br J Cancer 100(7):1154–1164

    Article  CAS  PubMed  Google Scholar 

  13. Solly SK, Trajcevski S, Frisen C et al (2003) Replicative retroviral vectors for cancer gene therapy. Cancer Gene Ther 10(1):30–39

    Article  CAS  PubMed  Google Scholar 

  14. Dalba C, Bellier B, Kasahara N et al (2007) Replication-competent vectors and empty virus-like particles: new retroviral vector designs for cancer gene therapy or vaccines. Mol Ther 15(3):457–466

    Article  CAS  PubMed  Google Scholar 

  15. Tai CK, Kasahara N (2008) Replication-competent retrovirus vectors for cancer gene therapy. Front Biosci 13:3083–3095

    Article  CAS  PubMed  Google Scholar 

  16. Wang WJ, Tai CK, Kasahara N et al (2003) Highly efficient and tumor-restricted gene transfer to malignant gliomas by replication-competent retroviral vectors. Hum Gene Ther 14(2):117–127

    Article  CAS  PubMed  Google Scholar 

  17. Wang WJ, Tai CK, Kershaw AD et al (2006) Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model. Neurosurg Focus 20(4):1–7

    Article  Google Scholar 

  18. Tai CK, Wang WJ, Chen TC et al (2005) Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival benefit in experimental glioma. Mol Ther 12(5):842–851

    Article  CAS  PubMed  Google Scholar 

  19. Mathieu V, De Neve N, Le Mercier M et al (2008) Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia 10(12):1383–1392

    CAS  PubMed  Google Scholar 

  20. Xie Q, Thompson R, Hardy K et al (2008) A highly invasive human glioblastoma pre-clinical model for testing therapeutics. J Transl Med 6:77–85

    Article  PubMed  Google Scholar 

  21. Fomchenko EI, Holland EC (2006) Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res 12(18):5288–5297

    Article  CAS  PubMed  Google Scholar 

  22. Smilowitz HM, Weissenberger J, Weis J et al (2007) Orthotopic transplantation of v-src expressing glioma cell lines into immunocompetent mice: establishment of a new transplantable in vivo model for malignant glioma. J Neurosurg 106(4):652–659

    Article  PubMed  Google Scholar 

  23. Martinez-Murillo R, Martinez A (2007) Standardization of an orthotopic mouse brain tumor model following transplantation of CT-2A astrocytoma cells. Histol Histopathol 22(12):1309–1326

    CAS  PubMed  Google Scholar 

  24. Boyd M, Cunningham SH, Brown MM et al (1999) Noradrenaline transporter gene transfer for radiation cell kill by 131I meta-iodobenzylguanidine. Gene Ther 6(6):1147–1152

    Article  CAS  PubMed  Google Scholar 

  25. Perzelova A, Macikova I, Mraz P et al (1998) Characterization of two new permanent glioma cell lines 8-MG-BA and 42-MG-BA. Neoplasma 45(1):25–29

    CAS  PubMed  Google Scholar 

  26. Zimmerman MH (1955) The nature of gliomas as revealed by animal experimentation. Am J Pathol 31:1–29

    CAS  PubMed  Google Scholar 

  27. Sundarraj N, Schachner M, Pfeiffer SE (1975) Biochemically differentiated mouse glial lines carrying a nervous system specific cell surface antigen (NS-1). Proc Natl Acad Sci USA 72(5):1927–1931

    Article  CAS  PubMed  Google Scholar 

  28. Ausman JI, Shapiro WR, Rall DP (1970) Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30(9):2394–2400

    CAS  PubMed  Google Scholar 

  29. Weissenberger J, Steinbach JP, Malin G et al (1997) Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 14(17):2005–2013

    Article  CAS  PubMed  Google Scholar 

  30. Pohl U, Wick W, Weissenberger J et al (1999) Characterization of Tu-2449, a glioma cell line derived from a spontaneous tumor in GFAP-v-src-transgenic mice: comparison with established murine glioma cell lines. Int J Oncol 15(4):829–834

    CAS  PubMed  Google Scholar 

  31. Schmidek HH, Nielsen SL, Schiller AL et al (1971) Morphological studies of rat brain tumors induced by N-nitrosomethylurea. J Neurosurg 34(3):335–340

    Article  CAS  PubMed  Google Scholar 

  32. Liehl B, Hlavaty J, Moldzio R et al (2007) Simian immunodeficiency virus vector pseudotypes differ in transduction efficiency and target cell specificity in brain. Gene Ther 14(18):1330–1343

    CAS  PubMed  Google Scholar 

  33. Klein D, Indraccolo S, von Rombs K et al (1997) Rapid identification of viable retrovirus-transduced cells using the green fluorescent protein as a marker. Gene Ther 4(8):1256–1260

    Article  CAS  PubMed  Google Scholar 

  34. Hlavaty J, Portsmouth D, Stracke A et al (2004) Effects of sequences of prokaryotic origin on titer and transgene expression in retroviral vectors. Virology 330(1):351–360

    Article  CAS  PubMed  Google Scholar 

  35. Evans LH, Morrison RP, Malik FG et al (1990) A neutralizable epitope common to the envelope glycoproteins of ecotropic, polytropic, xenotropic, and amphotropic murine leukemia viruses. J Virol 64(12):6176–6183

    CAS  PubMed  Google Scholar 

  36. Block ER, Bennett JE (1972) Pharmacological studies with 5-fluorocytosine. Antimicrob Agents Chemother 1(6):476–482

    CAS  PubMed  Google Scholar 

  37. Slingsby JH, Baban D, Sutton J et al (2000) Analysis of 4070A envelope levels in retroviral preparations and effect on target cell transduction efficiency. Hum Gene Ther 11(10):1439–1451

    Article  CAS  PubMed  Google Scholar 

  38. Vermes A, Guchelaar HJ, Dankert J (2000) Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 46(2):171–179

    Article  CAS  PubMed  Google Scholar 

  39. Bolteus AJ, Berens ME, Pilkington GJ (2001) Migration and invasion in brain neoplasms. Curr Neurol Neurosci Rep 1(3):225–232

    Article  CAS  PubMed  Google Scholar 

  40. Claes A, Idema AJ, Wesseling P (2007) Diffuse glioma growth: a guerilla war. Acta Neuropathol 114(5):443–458

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Noriyuki Kasahara, University of California, for plasmids pACE-GFP and pACE-CD, and Dr. Yancey Gillespie, University of Alabama at Birmingham for G-26 and GL-261 cells. We are also grateful to Mrs Doris Rosenfelner for excellent histological assistance and to Mr Reinhart Ertl for performing PERT assay. This project was financed in part by The Austrian Industrial Research Promotion Fund program (FFF grant no. 804960).

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Authors and Affiliations

  1. Institute of Virology, Department of Pathobiology, University of Veterinary Medicine, 1210, Vienna, Austria

    Juraj Hlavaty, Gerrit Jandl, Melissa Liszt, Helga Petznek, Marielle König-Schuster, Jenny Sedlak, Walter H. Günzburg & Matthias Renner

  2. Christian Doppler Laboratory for Therapeutic Vector Development, University of Veterinary Medicine, 1210, Vienna, Austria

    Juraj Hlavaty & Walter H. Günzburg

  3. Institute of Histology & Embryology, Department of Pathobiology, University of Veterinary Medicine, 1210, Vienna, Austria

    Monika Egerbacher

  4. Experimental Neurosurgery, Goethe University Hospital, Neuroscience Center, 60590, Frankfurt, Germany

    Jakob Weissenberger

  5. Austrianova Singapore Pte Ltd, 138668, Singapore, Singapore

    Brian Salmons

  6. Department of Medical Biotechnology, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225, Langen, Germany

    Matthias Renner

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  1. Juraj Hlavaty
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Correspondence to Matthias Renner.

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Hlavaty, J., Jandl, G., Liszt, M. et al. Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma. J Neurooncol 102, 59–69 (2011). https://doi.org/10.1007/s11060-010-0295-5

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  • DOI: https://doi.org/10.1007/s11060-010-0295-5

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