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Efficient Inhibition of In Vivo Human Malignant Glioma Growth and Angiogenesis by Interferon-ß Treatment at Early Stage of Tumor Development¹

Departments of Neurosurgery [Y-K. H., D-S. C., Y-J. Y., Y-S. P., J-K. K.] and Pathology [K-M. K.] and Cancer Research Institute [Y-K. H., Y-A. J.], The Catholic University of Korea, 137-040 Seoul, Korea, and Department of Neuro-Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030 [W. K. A. Y.]

Malignant gliomas are highly angiogenic and aggressive tumors. IFN-ß has been used for the treatment of patients with malignant glioma; however, its antitumor mechanism in vivo remains unclear. To understand the in vivo antitumor effect and mechanism of recombinant human IFN-ß (rhIFN-ß) depending on the stages of tumor development or progression, we used orthotopic xenograft brain tumors generated by stereotactic intracerebral implantation of U-87 human glioma cells in nude mice. Mice bearing tumors 7 days (group 1) and 21 days (group 2) postimplant were treated with 2 x 10⁵ IU/day of rhIFN-ß or saline i.p. for 15 days, respectively. Tumor growth was suppressed by 69.6% in group 1 and 10.8% in group 2 compared with tumors of each control group treated with saline. rhIFN-ß-treated group 1 animals showed 38% reduction in vascularization along with a 2.5-fold increase of the apoptotic index and no change in the proliferative index as compared with untreated tumors. The expression level of vascular endothelial cell growth factor and basic fibroblast growth factor was not affected by rhIFN-ß treatment. rhIFN-ß showed inhibitory activity on proliferation of U-87 cells, human umbilical vein endothelial cells, and PAM 212 murine keratinocytes in vitro. Our results indicate that the in vivo antitumor effect of rhIFN-ß on malignant gliomas may be mediated, at least in part, via angiogenesis inhibition rather than antiproliferative activity and that rhIFN-ß may be more effective for the treatment of malignant glioma patients at an early stage with minimal or microscopic tumor burdens rather than at an advanced stage of tumor development.

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