| Project/Area Number |
16591229
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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 |
Radiation science
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
MITSUHASHI Norio Tokyo Women's Medical University, Dept of Medicine, M.D., Ph.D., Professor, 医学部, 教授 (20008585)
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| Co-Investigator(Kenkyū-buntansha) |
MAEBAYASHI Katsuya Tokyo Women's Medical University, Dept of Medicine, M.D., Ph.D., Assistant, 医学部, 助手 (60332350)
NASU Sachiko Tokyo Women's Medical University, Dept of Medicine, M.D., Assistant, 医学部, 助手 (50292602)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | Hypoxic cell / Survival signals / HIF-1α / Radiosensitivity / TKR Inhibitor / HIF1-α / 子宮頸癌 |
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| Research Abstract |
1) Enhancement of Radiosensitivity by Dual Inhibition of HER family with ZD1839 ('Iressa') and Trastuzumab ('Herceptin')
Radiation-induced activation of EGFR and HER2/neu was inhibited with ZD 1839 and/or trastuzumab. Radiation in combination with HER family inhibitors also inhibited the activation of Akt and MEK1/2, the downstream survival signaling of HER family. ZD1839 enhanced radiosensitivity with a DMF (SF3) of 1.45 and trastuzumab with a DMF (SF3) of 1.11. Simultaneous blockade of HER2 family by ZD 1839 and trastuzumab induced synergistic radiosensitizing effect with a DMF (SF3) of 2.29. A dual inhibition of HER family enhanced radiosensitivity synergistically by inhibiting activation of survival signal transduction pathway. Our study suggests that HER family in combination with radiation therapy may be one of the potent candidates for molecular therapeutic targets.
2) Modification of cell growth and radiosensitivity under a hypoxic condition
Reduction of radiosensitivity under the
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hypoxia (5% O_2 and 1% O_2) was investigated by using A549 cell in vitro. The cell growth was significantly inhibited under the condition with 1% O_2 hypoxia but not under the condition with 5% O_2 hypoxia. Plating efficiency under the condition with 1% O_2 hypoxia was the same as that under an oxic condition. Increase in radioresistance was not observed under a hypoxic condition although the sizes of colonies were smaller under the condition with 1% O_2 hypoxia compared with those under an oxic condition.
3) Expression of hypoxic-inducible factor 1α predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma
Of 38 patients, high expression of HIF-1α, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed positive infection with HPV. There was a significant positive correlation between high HIF-1α expression and disease recurrence (p < 0.05). Furthermore, HIF-1α had a significant correlation with the recurrence-free survival rate (p = 0.04). No statistical correlation was noted between high HIF-1α expression and the local control rate (p = 0.17), whereas the HIF-1α status predicted distant metastasis with strong significance (p = 0.03). Conversely, other factors demonstrated no impact on the clinical outcome. The present results suggest that HIF-1α is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix. Less
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