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Robust infectivity and replication of Delta-24 adenovirus induce cell death in human medulloblastoma

Cancer Gene Therapy volume 11, pages 713–720 (2004)Cite this article

Abstract

The diverse advanced treatment modalities currently available to children with medulloblastoma, including surgery and radiotherapy, are associated with deleterious side effects and often with an unfavorable prognosis. A mutant adenovirus, Delta-24, which has a 24-base pair deletion in the Rb-binding region of the E1A gene, demonstrates selective replication and oncolysis in various malignant phenotypes. Here we report the ability of Delta-24 to kill medulloblastoma cells. Flow cytometric analyses of cell receptors demonstrated expression of the coxsackie adenovirus receptor and RGD-related integrins in the assessed medulloblastoma cell lines. Infectivity assays using a replication-deficient adenovirus to transduce the green fluorescence protein gene showed that the Delta-24 adenovirus infects 99% of Daoy and 46% of D283 Med medulloblastoma cells at a multiplicity of infection (MOI) of 50. Within 4 days after infecting medulloblastoma cells with Delta-24, a noticeable cytopathic effect was produced. Delta-24 induced a total cytopathic effect in Daoy and D283 Med medulloblastoma cells after 6 and 8 days of infection, respectively. In the infected population of cells, cell death correlated with the accumulation of cells in the S phase. At 5 days post-infection with 2.5 MOIs of Delta-24 adenovirus, the percentage of Daoy medulloblastoma cells in the S phase increased to 71.9±5.5%, compared with control values of 20.5±1.4%. The release of viral progeny was quantified as being increased by two orders of magnitude, indicating efficient replication of Delta-24 in medulloblastoma cells. This is the first report of the ability of oncolytic adenoviruses to infect and kill medulloblastoma cells, the findings of which suggest the potential efficacy of Delta-24 as a therapy for human medulloblastoma tumors.

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References

  1. Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ . What's new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol. 2003;7:53–66.

    Article  Google Scholar 

  2. Packer RJ, Rood BR, MacDonald TJ . Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg. 2003;39:60–67.

    Article  Google Scholar 

  3. Mazzola CA, Pollack IF . Medulloblastoma. Curr Treat Options Neurol. 2003;5:189–198.

    Article  Google Scholar 

  4. Xu W, Janss A, Moshang T . Adult height and adult sitting height in childhood medulloblastoma survivors. J Clin Endocrinol Metab. 2003;10:4677–4681.

    Article  Google Scholar 

  5. Chiocca EA . Oncolytic viruses. Nat Rev Cancer. 2002;2:938–950.

    Article  Google Scholar 

  6. Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996;274:373–376.

    Article  CAS  Google Scholar 

  7. Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene. 2000;19:2–12.

    Article  CAS  Google Scholar 

  8. Fueyo J, Alemany R, Gomez-Manzano C, et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst. 2003;95:652–660.

    Article  CAS  Google Scholar 

  9. Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med. 2000;10:1134–1139.

    Article  Google Scholar 

  10. Yang WQ, Senger D, Muzik H, et al. Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma. Cancer Res. 2003;12:3162–3172.

    Google Scholar 

  11. Gomez-Manzano C, Fueyo J, Kyritsis AP, et al. Adenovirus-mediated transfer of the p53 gene produces rapid and generalized death of human glioma cells via apoptosis. Cancer Res. 1996;4:694–699.

    Google Scholar 

  12. Fueyo J, Gomez-Manzano C, Yung WK, et al. Overexpression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo. Nat Med. 1998;6:685–690.

    Article  Google Scholar 

  13. Alemany R, Dai Y, Lou YC, et al. Complementation of helper dependent adenoviral vectors: size effects and titer fluctuations. J Virol Methods. 1997;68:147–157.

    Article  CAS  Google Scholar 

  14. Alemany R, Ruan S, Kataoka M, et al. Growth inhibitory effect of anti-K-ras adenovirus on lung cancer cells. Cancer Gene Ther. 1996;5:296–301.

    Google Scholar 

  15. Jones N, Shenk T . Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell. 1979;3:683–689.

    Article  Google Scholar 

  16. Skog J, Mei YF, Wadell G . Human adenovirus serotypes 4p and 11p are efficiently expressed in cell lines of neural tumour origin. J Gen Virol. 2002;83:1299–1309.

    Article  CAS  Google Scholar 

  17. Kenney AM, Cole MD, Rowitch DH . Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development. 2003;130:15–28.

    Article  CAS  Google Scholar 

  18. Berman DM, Karhadkar SS, Hallahan AR . Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002;5586:1559–1561.

    Article  Google Scholar 

  19. Oliver TG, Grasfeder LL, Carroll AL . Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA. 2003;12:7331–7336.

    Article  Google Scholar 

  20. Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW . c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia. 2003;3:198–204.

    Article  Google Scholar 

  21. Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A . Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 2000;8:994–1004.

    Google Scholar 

  22. Lamfers ML, Grill J, Dirven CM, et al. Potential of the conditionally replicative adenovirus Delta-24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. Cancer Res. 2002;62:5736–5742.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Joann Aaron for editorial assistance (Department of Neuro-Oncology, MD Anderson Cancer Center). This work was supported by grants from the Pediatric Brain Tumor Foundation of the United States, the National Institutes of Health R01CA90879, and the Anthony Bullock Foundation.

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Authors and Affiliations

  1. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Robert Stolarek, Candelaria Gomez-Manzano, Hong Jiang, Gary Suttle, Michael G Lemoine & Juan Fueyo

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  1. Robert Stolarek
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  2. Candelaria Gomez-Manzano
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  3. Hong Jiang
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  4. Gary Suttle
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  5. Michael G Lemoine
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  6. Juan Fueyo
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Correspondence to Juan Fueyo.

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Stolarek, R., Gomez-Manzano, C., Jiang, H. et al. Robust infectivity and replication of Delta-24 adenovirus induce cell death in human medulloblastoma. Cancer Gene Ther 11, 713–720 (2004). https://doi.org/10.1038/sj.cgt.7700731

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