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Publications (3)19.14 Total impact

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    ABSTRACT: Tumor growth is partially dependent on angiogenesis, a process that relies on angiogenic factors. Tumorigenicity of cancer cells is thought to be associated with the production of various angiogenic factors that stimulate or inhibit the rate of endothelial cell migration and proliferation. However, the relative importance of specific individual factors originally studied in cancer cell lines has yet to be determined in vivo. In this study, we examined seven human glioma cell lines for dynamic changes of two major angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), and for doubling time and tumorigenicity in nude mice. Various correlation studies demonstrated that in these glioma cell lines, VEGF expression correlated well with RBC density in tumor sections (r2 = 0.804) and with average tumor weight (r2 = 0.987). In contrast, bFGF expression in the observed glioma cell lines did not correlate with tumorigenicity (r2 = 0.001) or with VEGF expression (r2 = 0.255). Furthermore, there was no correlation between doubling time and tumorigenicity in these cell lines (r2 = 0.160). Taken together, these results suggest that VEGF plays a major role in glioma formation and that down-regulation of VEGF, rather than bFGF, would be a more effective choice for glioma gene therapy.
    Clinical Cancer Research 07/2000; 6(6):2562-72. · 7.84 Impact Factor
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    ABSTRACT: MMAC/PTEN, a tumor suppressor gene located on chromosome 10q, has recently been shown to act as a phosphatidylinositol 3,4,5-triphosphate phosphatase and to modulate cell growth and apoptosis. Somatic mutations of MMAC/PTEN have been reported in a number of human cancers, especially in glioblastoma multiforme (GBM), although the number of identified mutations (approximately 10-35%) is significantly lower than the frequency of LOH affecting the MMAC/PTEN locus in the specimens (approximately 75-95%). To further investigate the possible alterations that may affect MMAC/PTEN, we examined the expression of the gene by reverse transcription-PCR in a series of gliomas. A significant difference (P < 0.001) was observed between the expression of MMAC/PTEN in GBMs versus lower grades of gliomas, thus mimicking the difference in allelic deletion associated with the locus in these tumors. Furthermore, Kaplan-Meier survival plots, adjusted for age and tumor grade, showed a significantly better prognosis for patients whose tumors expressed high levels of MMAC/PTEN. Additionally, immunostaining of GBMs revealed little or no MMAC/PTEN expression in about two-thirds of the tumors, whereas the other approximately one-third of tumors had significantly higher levels of expression. However, in about two-thirds of the high-expressing specimens, a heterogeneous pattern of expression was observed, indicating that certain cells within the tumor failed to express MMAC/PTEN. The combination of these results suggest that, in addition to molecular alterations affecting the gene, altered expression of MMAC/PTEN may play a significant role in the progression of GBM and patient outcome.
    Cancer Research 04/1999; 59(8):1820-4. · 8.65 Impact Factor
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    ABSTRACT: Glioblastoma multiforme is one of the most highly vascularized solid neoplasms, therefore treatments that target neovascularization process would be of great clinical importance. Studies of glioblastoma angiogenesis have revealed that expression of the vascular endothelial growth factor (VEGF) is up-regulated in these tumors. Previous reports have shown that down-regulation of VEGF correlates with modification in the glioma growth. To examine this phenomenon further, in this study we constructed two hammerhead ribozymes (RZI and RZII) to target the 5' common region of VEGF mRNA. Both ribozymes exhibited site-specific cleavage to a 318-nucleotide VEGF transcript and showed a high digestion efficiency in vitro (65-95%). After the transfection of glioma cells with two expression vectors carrying the ribozyme sequence, Northern blot analyses detected high levels of ribozyme expression. Treatment of the glioma cells with the ribozymes resulted in a reduction in VEGF mRNA in six of eight clones. Furthermore, the anti-VEGF effect was confirmed at protein level. Thus, enzyme-linked immunoabsorbent analyses (ELISA) showed a >70% reduction in the VEGF165 expression level. These results indicate that hammerhead ribozymes may be useful in down-regulating VEGF expression and suggest that anti-VEGF strategies may be used to potentiate other gene therapies targeting tumor suppressor genes.
    International Journal of Oncology 06/1998; 12(6):1391-6. · 2.66 Impact Factor