Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

CRAdRGDflt-IL24 virotherapy in combination with chemotherapy of experimental glioma

Cancer Gene Therapy volume 16, pages 794–805 (2009)Cite this article

Abstract

Malignant forms of glioma, the most common primary brain tumors, remain poorly responsive to multimodality therapeutic interventions, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are important distinctive features that contribute to the malignant phenotype of glioma. We have developed the vascular endothelial growth factor receptor 1 (VEGFR-1/flt-1) conditional replicating adenoviral vector (CRAdRGDflt-IL24) encoding the interleukin-24 (IL-24) gene. We investigated whether a combination of CRAdRGDflt-IL24-mediated oncolytic virotherapy and chemotherapy using temozolomide (TMZ) produces increased cytotoxicity against human glioma cells in comparison with these agents alone. Combination of CRAdRGDflt-IL24 and TMZ significantly enhanced cytotoxicity in vitro, inhibited D54MG tumor growth and prolonged survival of mice harboring intracranial human glioma xenografts in comparison with CRAdRGDflt-IL24 or TMZ alone. These data indicate that combined treatment with CRAdRGDflt-IL24-mediated oncolytic virotherapy and TMZ chemotherapy provides a promising approach for glioma therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Barzon L, Boscaro M, Palu G . Endocrine aspects of cancer gene therapy. Endocr Rev 2004; 25: 1–44.

    Article  CAS  Google Scholar 

  2. Pulkkanen KJ, Yla-Herttuala S . Gene therapy for malignant glioma: current clinical status. Mol Ther 2005; 12: 585–598.

    Article  CAS  Google Scholar 

  3. Giese A, Bjerkvig R, Berens ME, Westphal M . Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 2003; 21: 1624–1636.

    Article  CAS  Google Scholar 

  4. Lopes MB . Angiogenesis in brain tumors. Microsc Res Tech 2003; 60: 225–230.

    Article  CAS  Google Scholar 

  5. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H et al. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990; 5: 519–524.

    CAS  PubMed  Google Scholar 

  6. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT . The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989–991.

    Article  CAS  Google Scholar 

  7. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187: 1579–1586.

    Article  CAS  Google Scholar 

  8. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993; 72: 835–846.

    Article  CAS  Google Scholar 

  9. Omura T, Miyazawa K, Ostman A, Heldin CH . Identification of a 190-kDa vascular endothelial growth factor 165 cell surface binding protein on a human glioma cell line. J Biol Chem 1997; 272: 23317–23322.

    Article  CAS  Google Scholar 

  10. Chan AS, Leung SY, Wong MP, Yuen ST, Cheung N, Fan YW et al. Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol 1998; 22: 816–826.

    Article  CAS  Google Scholar 

  11. Gesundheit B, Klement G, Senger C, Kerbel R, Kieran M, Baruchel S et al. Differences in vasculature between pilocytic and anaplastic astrocytomas of childhood. Med Pediatr Oncol 2003; 41: 516–526.

    Article  Google Scholar 

  12. Steiner HH, Karcher S, Mueller MM, Nalbantis E, Kunze S, Herold-Mende C . Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels. J Neurooncol 2004; 66: 129–138.

    Article  Google Scholar 

  13. Johnstone RW, Ruefli AA, Lowe SW . Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108: 153–164.

    Article  CAS  Google Scholar 

  14. Fulda S, Debatin KM . Targeting apoptosis pathways in cancer therapy. Curr Cancer Drug Targets 2004; 4: 569–576.

    Article  CAS  Google Scholar 

  15. Koizumi N, Mizuguchi H, Hosono T, Ishii-Watabe A, Uchida E, Utoguchi N et al. Efficient gene transfer by fiber-mutant adenoviral vectors containing RGD peptide. Biochim Biophys Acta 2001; 1568: 13–20.

    Article  CAS  Google Scholar 

  16. Zheng S, Ulasov IV, Han Y, Tyler MA, Zhu ZB, Lesniak MS . Fiber-knob modifications enhance adenoviral tropism and gene transfer in malignant glioma. J Gene Med 2007; 9: 151–160.

    Article  CAS  Google Scholar 

  17. Nicklin SA, Reynolds PN, Brosnan MJ, White SJ, Curiel DT, Dominiczak AF et al. Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium. Hypertension 2001; 38: 65–70.

    Article  CAS  Google Scholar 

  18. Nicklin SA, Dishart KL, Buening H, Reynolds PN, Hallek M, Nemerow GR et al. Transductional and transcriptional targeting of cancer cells using genetically engineered viral vectors. Cancer Lett 2003; 201: 165–173.

    Article  CAS  Google Scholar 

  19. Work LM, Ritchie N, Nicklin SA, Reynolds PN, Baker AH . Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control. Gene Therapy 2004; 11: 1296–1300.

    Article  CAS  Google Scholar 

  20. Fisher PB, Gopalkrishnan RV, Chada S, Ramesh R, Grimm EA, Rosenfeld MR et al. mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic. Cancer Biol Ther 2003; 2: S23–S37.

    Article  CAS  Google Scholar 

  21. Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Lebedeva IV, Dent P et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev 2003; 14: 35–51.

    Article  CAS  Google Scholar 

  22. Su ZZ, Lebedeva IV, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C et al. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 2003; 22: 1164–1180.

    Article  CAS  Google Scholar 

  23. Miller CR, Buchsbaum DJ, Reynolds PN, Douglas JT, Gillespie GY, Mayo MS et al. Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer. Cancer Res 1998; 58: 5738–5748.

    CAS  PubMed  Google Scholar 

  24. Schnell O, Krebs B, Wagner E, Romagna A, Beer AJ, Grau SJ et al. Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 2008; 18: 378–386.

    Article  CAS  Google Scholar 

  25. Plate KH, Breier G, Millauer B, Ullrich A, Risau W . Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 1993; 53: 5822–5827.

    CAS  PubMed  Google Scholar 

  26. Plate KH, Breier G, Weich HA, Mennel HD, Risau W . Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 1994; 59: 520–529.

    Article  CAS  Google Scholar 

  27. Carroll RS, Zhang J, Bello L, Melnick MB, Maruyama T, Mc LBP . KDR activation in astrocytic neoplasms. Cancer 1999; 86: 1335–1341.

    Article  CAS  Google Scholar 

  28. Yao Y, Kubota T, Sato K, Kitai R, Takeuchi H, Arishima H . Prognostic value of vascular endothelial growth factor and its receptors Flt-1 and Flk-1 in astrocytic tumours. Acta Neurochir (Wien) 2001; 143: 159–166.

    Article  CAS  Google Scholar 

  29. Yacoub A, Mitchell C, Brannon J, Rosenberg E, Qiao L, McKinstry R et al. MDA-7 (interleukin-24) inhibits the proliferation of renal carcinoma cells and interacts with free radicals to promote cell death and loss of reproductive capacity. Mol Cancer Ther 2003; 2: 623–632.

    CAS  PubMed  Google Scholar 

  30. Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K et al. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003; 63: 5105–5113.

    CAS  PubMed  Google Scholar 

  31. Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE . Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004; 9: 818–828.

    Article  CAS  Google Scholar 

  32. Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S . Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 2004; 9: 510–518.

    Article  CAS  Google Scholar 

  33. Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M et al. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 2008; 14: 2900–2908.

    Article  CAS  Google Scholar 

  34. Stewart LA . Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002; 359: 1011–1018.

    Article  CAS  Google Scholar 

  35. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002; 20: 1375–1382.

    Article  CAS  Google Scholar 

  36. Jendrossek V, Belka C, Bamberg M . Novel chemotherapeutic agents for the treatment of glioblastoma multiforme. Expert Opin Investig Drugs 2003; 12: 1899–1924.

    Article  CAS  Google Scholar 

  37. Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007; 26: 186–197.

    Article  CAS  Google Scholar 

  38. Kanzawa T, Bedwell J, Kondo Y, Kondo S, Germano IM . Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 2003; 99: 1047–1052.

    Article  CAS  Google Scholar 

  39. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G . Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741–752.

    Article  CAS  Google Scholar 

  40. Alonso MM, Gomez-Manzano C, Bekele BN, Yung WK, Fueyo J . Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res 2007; 67: 11499–11504.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Sally B Lagan for assistance in preparing the paper. Supported in part by NCI SPORE in Brain Cancer Grant P50 CA97247.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    L N Kaliberova, V Krendelchtchikova, D J Buchsbaum & S A Kaliberov

  2. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    D K Harmon, J M Markert & G Y Gillespie

  3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    C R Stockard & W E Grizzle

  4. Department of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA

    A S Petersen

Authors
  1. L N Kaliberova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Krendelchtchikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D K Harmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C R Stockard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A S Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J M Markert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Y Gillespie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W E Grizzle
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D J Buchsbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S A Kaliberov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S A Kaliberov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaliberova, L., Krendelchtchikova, V., Harmon, D. et al. CRAdRGDflt-IL24 virotherapy in combination with chemotherapy of experimental glioma. Cancer Gene Ther 16, 794–805 (2009). https://doi.org/10.1038/cgt.2009.23

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2009.23

Keywords

This article is cited by

Search

Advanced search

Quick links