AAD01 reduces tumor hypoxia by increasing tissue perfusion in high grade malignant gliomas

• Main Authors: Shao-En Chang, 張韶恩
• Other Authors: Henrich Cheng
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/04381384016067650565

碩士 === 國立陽明大學 === 腦科學研究所 === 98 === Background: Intra-tumoral hypoxia is associated with malignant progression, tumor invasion and resistance to radiotherapy and chemotherapy of cancers. Anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) / VEGF receptor (V EGFR) have shown therapeutic effect for malignant tumors. However, they also increase intra-tumoral hypoxia. Anti-angiogenic drug 01 (AAD01), on the other hand, targets endothelial cells directly. Tetramethylpyrazine (TMP) decreased the expression of VEGF and reduced angiogenesis. This study would test these two drugs to decrease tumor hypoxia in malignant gliomas in rat. Hypothesis: It is hypothesized that by limiting the rapid proliferation of endothelial cells, AAD01 increase tissue perfusion in gliomas, which in turn result in the decrease of intra-tumoral hypoxia. This study has also evaluated if TMP has similar effect. Materials and Methods: Suspended 1x107 C6 glioma cells were implanted intracerebrally of the adult female Sprague-Dawley rats. The treatment group received AAD01 (10 µg / every 3 days) or TMP (2.4 mg/day, for 7 days) beginning for the 5th day. At day 13, animals were sacrificed. Tumor hypoxia and angiogenic factors were analyzed by immunohistochemistry and quantified by Western blot. Multiple groups were analyzed by one-way analysis of variance (ANOVA). P-value of less than 0.05 was considered significant. Results: In the AAD01 treated group, tumor size was decreased (60.42%). These rats also showed less body weight loss. The expression of hypoxic inducible factor-1 α (HIF-1α) and VEGF both decreased significantly in the treatment group than in control group. The sprouting vessel, which is evaluated by staining of VEGFR2 was inhibited in the AAD01 group. The density of total vessels was decreased. The contrast, the density of perfused vessels was increased. The peri-tumor infiltration was less prominent in the AAD01 group. On the hand, the expression of HIF-1α and VEGF in the TMP group was decreased but less effect than AAD01 group. The density of perfused vessels was not significant statistically different from control. Conclusion: AAD01 reduced tumor hypoxia by increasing tissue perfusion. Otherwise, it can reduce peri-tumor infiltration.