2005 Fiscal Year Final Research Report Summary
Basic research for the combination with anti-angiogenic therapy and heavy charged particle therapy against malignant gliomas
| Project/Area Number |
15591522
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Kobe University |
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Principal Investigator |
EHARA Kazumasa Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (20151996)
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| Co-Investigator(Kenkyū-buntansha) |
KOHMURA Eiji Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (30225388)
KAWAMURA Atsufumi Kobe University, Graduate School of Medicine, Visiting Medical Scientist, 大学院・医学系研究科, 医学研究員 (00346256)
SUGIMURA Kazurou Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00136384)
HAYASHI Yoshitake Kobe University, School of Medicine, Professor, 医学部, 教授 (50189669)
SASAYAMA Takashi Kobe University, Hospital, Clinical Research Fellow, 医学部附属病院, 臨床研究員 (10379399)
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| Project Period (FY) |
2003 – 2005
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| Keywords | brain tumor / radiotherapy / angiogenesis / gene therapy |
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| Research Abstract |
C6 rat glioma cells were transfected with VEGF164. Spheroids cells were implanted orthotopically into 60 rat brains. Expression of VEGF and fetal liver kinase-1 (VEGF receptor 2) was assessed immunohistochemically. Animals with gliomas received orally administered VEGF inhibitor PTK787/ZK222584. Growth and vascularization were evaluated by magnetic resonance imaging and immunohistochemistry. Early and delayed application of PTK787/ZK222584 in glioma-bearing animals resulted in a reduction of tumor size (71% and 36%) as measured by magnetic resonance imaging volumetry. Vessel density was significantly reduced (42.3% and 25.7%), and areas of intratumoral necrosis were enlarged (by 1.7-fold after early treatment).
Additionally, proliferation was decreased by 89% and 72%. There was no growth-inhibiting effect of PTK787/ZK222584 on cells observed. PTK787/ZK222584 significantly halted VEGF-mediated glioma growth by inhibition of neovascularization and proliferation, providing a promising new
… More
tool in malignant glioma therapy.
Rapamycin is a highly specific inhibitor of the mammalian target of rapamycin (mTOR) and has been reported to induce cell cycle arrest and to inhibit VEGF signaling in a broad range of human tumor cell lines. Here, we investigated the effect of rapamycin on cell and tumor growth and in combination with nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In established human malignant glioma cells, we confirmed that rapamycin enhanced the apoptosis-inducing effects of ACNU, although treatment with rapamycin alone could not induce apoptosis. Our studies showed that rapamycin inhibited the expressions of p21 protein and mRNA after ACNU treatment in U251MG cells. Moreover, combined treatment of rapamycin and ACNU demonstrated more increase in the Bax/Bcl-xL ratio than ACNU treatment alone. Next, treatment of established intracerebral U251MG xenografts with the rapamycin in vivo resulted in statistically prolonged median survival (p<0.05) compared with control rats. Finally, treatment of established intracerebral U251MG xenografts with the combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (p<0.05). These results suggested that combination therapy with mTOR inhibitors and ACNU might be a useful strategy for human malignant gliomas. Less
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