Abstract
We constructed an adeno‐associated virus (AAV) vector containing the human interferon‐β(HuIFN‐β) gene (AAV‐IFN‐β) and investigated its antitumor effect against human glioma cells (U251‐SP) inoculated into the brain of nude mice. Prior to this, we examined human glioma cells transduced with AAV‐IFN‐β using video‐enhanced contrast differential interference contrast (VEC‐DIC) microscopy. Infection of AAV‐IFN‐β induced apoptosis and secondary necrosis in human glioma cells. In in vivo experiments, we confirmed production of HuIFN‐β and induction of heat‐shock protein (HSP) in glioma cells transduced with AAV‐IFN‐β. Growth of the experimental gliomas was completely inhibited by six injections of AAV‐IFN‐β, starting 7 days after transplantation of glioma cells. In addition, the survival of mice treated with AAV‐IFN‐β was remarkably prolonged. These results indicate that AAV‐IFN‐β induces apoptosis of glioma cells and has a strong antitumor effect in this experimental glioma model.
Keywords: AAV, IFN‐β, Glioma, Gene therapy
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REFERENCES
- 1.Miyakoshi , J. , Dobler , K. D. , Allalunis‐Turner , J. , McKean , J. D. S. , Petruk , K. , Allen , P. B. R. , Aronyk , K. N. , Weir , B. , Huyser‐Wierenga , D. , Fulton , D. , Urtasun , R. C. and Day , R. S. , III . Absence of IFNA and IFNB genes from human malignant glioma cell lines and lack of correlation with cellular sensitivity to interferons . Cancer Res. , 50 , 278 – 283 ( 1990. ). [PubMed] [Google Scholar]
- 2.James , C. D. , Carlbom , J. H. E. , Nordenskjold , M. , Cavenee , W. K. and Collins , V. P.Chromosome 9 deletion mapping reveals interferon a and interferon β‐1 gene deletion in human glial tumors . Cancer Res. , 51 , 1684 – 1688 ( 1991. ). [PubMed] [Google Scholar]
- 3.Nagai , M. and Asai , T.Clinical effect of interferon in malignant brain tumors . Neurosurg. Rev. , 7 , 55 – 64 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 4.Yoshida , J. , Kajita , Y. , Wakabayashi , T. and Sugita , K.Long‐term follow‐up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radia‐ tion . Acta Neurochir. (Wien) , 127 , 55 – 59 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 5.Samulski , R. J.Adeno‐associated virus‐based vectors for human gene therapy . In “ Gene Therapy from Laboratory to the Clinic ,” ed. Hui K. M. , pp. 232 – 271 ( 1994. ). World Scientific; , Singapore . [Google Scholar]
- 6.Matsushita , T. , Elliger , S. , Elliger , C. , Podsakoff , G. , Villarreal , L. , Kurtzman , G. J. , Iwaki , Y. and Colosi , P.Adeno‐associated virus vectors can be efficiently produced without helper virus . Gene Ther. , 5 , 938 – 945 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 7.Yamazaki , S. , Kuramoto , K. , Matsuo , E. , Hosoi , K. , Hara , M. and Shimizu , H.Highly sensitive enzyme immunoassay of human interferon‐β1 . J. Immunoassay , 10 , 57 – 73 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 8.Hess , H. H. , Lees , M. B. and Derr , J. E.A linear Lowry‐ Folin assay for both water‐soluble and sodium dodecyl sulfate‐solubilized proteins . Anal. Biochem. , 85 , 295 – 300 ( 1978. ). [DOI] [PubMed] [Google Scholar]
- 9.Enomoto , H. , Yoshida , J. , Kageyama , N. , Ueda , R. , Kato , T. and Ota , K.Anti‐tumor activity of human recombinant TNF against human malignant glioma cell lines and combination effect with HuIFN‐β . Jpn. J. Cancer Chemother. , 13 , 1953 – 1961 ( 1986. ). [PubMed] [Google Scholar]
- 10.Ram , Z. , Culver , K. W. , Oshiro , E. M. , Viola , J. J. , DeVroom , H. L. , Otto , E. , Long , Z. , Chiang , Y. , McGarrity , G. J. , Muul , L. M. , Katz , D. , Blaese , R. M. and Oldfield , E. H.Therapy of malignant brain tumors by intratumoral implantation of retroviral vector‐producing cells . Nat. Med. , 3 , 1354 – 1361 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 11.Trask , T. W. , Aguilar‐Cordova , E. , Goodman , J. C. , Guevara , R. , Wyde , P. , Shine , H. D. and Grossman , R. G.A phase I study of adenoviral vector delivery of the HSV‐tk gene and the intravenous administration of ganciclovir in adults with malignant tumors of the central nervous system . ASGT Suppl.) , 112 ( 1998. ). [Google Scholar]
- 12.Okada , H. , Miyamura , K. , Itoh , T. , Hagiwara , M. , Wakabayashi , T. , Mizuno , M. , Colosi , P. , Kurtzman , G. and Yoshida , J.Gene therapy against an experimental glioma using adeno‐associated virus vectors . Gene Ther. , 3 , 957 – 964 ( 1996. ). [PubMed] [Google Scholar]
- 13.Mizuno , M. , Yoshida , J. , Colosi , P. and Kurtzman , G. J.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 , 76 – 80 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Okamoto , K. , Mizuno , M. , Nakahara , N. , Natsume , A. , Yoshida , J. , Mori , T. , Hori , S. and Kobayashi , H.Process of apoptosis induced by TNF‐α in murine fibroblast Ltk‐cells: continuous observation with video enhanced contrast microscopy . Apoptosis ( 2002. ), in press . [DOI] [PubMed] [Google Scholar]
- 15.Laster , S. M. and Mackenzie , J. M. , Jr.Bleb formation and F‐actin distribution during mitosis and tumor necrosis factor‐induced apoptosis . Microsc. Res. Tech. , 34 , 272 – 280 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 16.Katsen , A. D. , Vollmar , B. , Mestres‐Ventura , P. and Menger , M. D.Cell surface and nuclear changes during TNF‐α‐induced apoptosis in WEHI 164 murine fibrosar‐coma cells . Virchows Arch. , 433 , 75 – 83 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 17.Melcher , A. , Todryk , S. , Handwick , N. , Ford , M. , Jacobson , M. and Vile , R. G.Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression . Nat. Med. , 4 , 581 – 587 ( 1998. ). [DOI] [PubMed] [Google Scholar]