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Basic research for Molecular target therapy on Oral Cancer

口腔癌分子靶向治疗基础研究

基本信息

批准号：
14370675
负责人：
SHINTANI Satoru
金额：
$ 9.15万
依托单位：
EHIME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370675/
关键词：
Oral Cancer EGFR p27 Skp2 Cervical Lymph node metastasis Molecular Target Therapy Cell Cycle TAT

项目摘要

We evaluated the expression of p27^<KIP1>, a cell cycle regulator, in Oral squamous cell carcinoma (OSCC). P27^<KIP1> expressein was reduced in OSCC. Inversely, Skp2 and Jab-1 that regulate p27^<KIP1>, was overexpressed (Oncology 65, 2003). Epidermal growth factor receptor (EGFR) are frequently overexpressed in OSCC. EGFR inhibitor suppressed the cell growth of OSCC cell lines with p27^<KIP1> expression and a complete arrest in the G1 phase. So, we investigated whether treatment with ZD1839 (Iressa), a selective EGFR-tyrosine kinase inhibitor, would inhibit the cell proliferation, metastatic spread, and enhance response to radiotherapy in OSCC cells. ZD1839 suppressed the cell growth of OSCC cell lines. Growth arrest was observed in OSCC xenografts when mice were treated with ZD1839. The mechanism for cell growth arrest was accompanied by increased p27^<KIP1> and decreased Skp2 (Oral Oncol.40,2004). ZD1839 also have antimetastatic activity, in OSCC xenograft cervival lymph node metastasis model (Cancer Lett 201,2003). We also observed the additive growth inhibitory effects of ZD 1839 to radiation. The same effects were confirmed in OSCC xerografts( Int J Cancer 107,2003). We also evaluated the possibility of the antitumor activity of flavopiridol, a CDK inhibitor. Flavopiridol inhibit cell growth of OSCC cell line with a G1 and S2/M phase arrest and induced apoprttosis (Oral Oncol 39,2003). From these results, the EGFR inhibitor and/or CDK inhibitor will be a effective molecular target therapy agent against oral cancer.

我们检测了<KIP1>口腔鳞状细胞癌（OSCC）中细胞周期调控因子p27 β的表达。P27 ~+<KIP1>在口腔鳞癌中表达减少。调节p27 α的抑制因子Skp 2和Jab-1<KIP1>过表达（Oncology 65，2003）。表皮生长因子受体（EGFR）在口腔鳞状细胞癌中经常过度表达。EGFR抑制剂可抑制p27 ~+表达的OSCC细胞系的生长<KIP1>，并使细胞完全停滞于G1期。因此，我们研究了用选择性EGFR酪氨酸激酶抑制剂ZD 1839（Iressa）治疗是否会抑制OSCC细胞的细胞增殖、转移扩散并增强对放射治疗的反应。ZD 1839抑制OSCC细胞系的细胞生长。当用ZD 1839处理小鼠时，在OSCC异种移植物中观察到生长停滞。细胞生长停滞的机制伴随着p27 β的增加<KIP1>和Skp 2的减少（Oral Oncol.40，2004）。ZD 1839在OSCC异种移植颈部淋巴结转移模型中也具有抗转移活性（Cancer Lett 201，2003）。我们还观察了ZD 1839对辐射的累加生长抑制作用。在OSCC干移植物中证实了相同的效果（Int J Cancer 107，2003）。我们还评估了CDK抑制剂flavopiridol的抗肿瘤活性的可能性。Flavopiridol通过G1和S2/M期阻滞抑制OSCC细胞系的细胞生长并诱导细胞凋亡（Oral Oncol 39，2003）。从这些结果来看，EGFR抑制剂和/或CDK抑制剂将是一种有效的抗口腔癌的分子靶向治疗剂。