Basic study on chemoresistance and thermoresistance of head and neck cancer

头颈癌化疗耐药和耐热的基础研究

• 批准号: 07457397
• 负责人: SAITO Hitoshi
• 金额: $ 3.84万
• 依托单位: Fukui Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457397/
• 关键词: Head and neck cancer; Anticancer drug sensitivity; Chemoresistance; Hyperthermia; Apoptosis; P-glycoprotein; MRP; Glutathione; アンチセンス; CDDP; 頭頸部癌; ATP法; LAK細胞

1995 : The chemosensitivity test by ATP method was applied to 139 cases of head and neck cancer. The evaluated rate was 95%, and the chemosensitive rate was in the order of 5-FU (27%) >CDDP=CBDCA>MTX>PEP (23%). This results indicate that the rest of about 25% show the natural resistance. The expression of P-glycoprotein as one of the cause of chemoresistance appeared in about 60% of them, and showed significant correlation with ADM-resistance. When the content of glutathione (GSH) in squamous cell carcinoma increased, the sensitivity to CDDP decreased. It was proved that the LAK activity increased with hyperthermic condition.1996 : The relationship between the intracellular GSH content and CDDP sensitivity was investigated. The result showed that the decreased level of GSH induced necrotic cell death, while the increased GSH induced apoptosis. The 4 main resistant factors, drug influx, efflux, DNA-Pt adducts and DNA repair, were investigated concerning CDDP sensitivity using several ca … More ncer cell lines. The result showed the heterogeneity among the cell lines. The cases stained with apoptosis-inducing genes, Fas (+) and Bcl-2 (-), showed good chemosensitivity. The cancer cell lines having G-CSF receptors increased the cell invasion by rG-CSF stimulation. This fact should be bore in mind for clinical use.1997 : The expression of multidrug resistance-associated protein (MRP) in 115 cases of head and neck carcinomas was investigated by immunohistochemistry, and 30% of them showed positive staining without any clinical correlation and anticancer drug resistance. The synergistic effects of H-7, a protein kinase inhibitor (PKC), on CDDP cytotoxicity to KB cells, a human pharyngeal carcinoma cell line, was investigated. The treatment with H-7 markedly decreased PKC activity and significantly sensitized the cells to CDDP.The treatment of KB cells with H-7 induced a dose-dependent depletion of intracellular GSH levels. A low hyperthermia at 40ﾟC increased accumulation of platinum of CDDP into cancer cells. As a result, CDDP sensitivity was hyperthermically chemopotentiated in CDDP-resistant variants even at low hyperthermia. A combination with CDDP and bcl-2 antisense therapy increased CDDP sensitivity, and thus a possibility of gene chemotherapy was introduced. The expression of bax, a gene inducing apoptosis, was immunohistchemically examined. The positive expression was significantly more observed in the early stage I and II than the late stage. Less

1995年：采用三磷酸腺苷(ATP)法对139例头颈癌患者进行药敏试验。评价率为95%，化疗敏感率依次为5-FU(27%)&GT；CDDP=CBDCA&GT；MTX&GT；PEP(23%)。这一结果表明，其余约25%的人表现出自然抗性。P-糖蛋白表达作为化疗耐药的原因之一，约占60%，并与ADM耐药密切相关。随着鳞癌组织中谷胱甘肽(GSH)含量的增加，对CDDP的敏感性降低。证明LAK活性随温度升高而升高。1996：研究了细胞内GSH含量与CDDP敏感性的关系。结果表明，GSH水平降低可导致坏死性细胞死亡，而GSH水平升高可诱导细胞凋亡。用几个CA-…研究了药物流入、外排、dna-铂加合物和dna修复4个主要耐药因素对顺铂的敏感性。更多的核型细胞系。结果表明，各细胞系之间存在异质性。凋亡诱导基因Fas(+)和Bcl2(-)染色的病例显示良好的化疗敏感性。具有G-CSF受体的癌细胞株通过rg-CSF刺激增加了细胞的侵袭力。1997年：应用免疫组织化学方法检测了115例头颈癌组织中多药耐药相关蛋白(MRP)的表达，其中30%阳性表达，与临床无相关性，且无抗癌药物耐药性。研究了蛋白激酶抑制剂(PKC)H-7对顺铂(CDDP)对人咽癌细胞株KB的协同杀伤作用。H-7明显降低细胞内PKC活性，并使细胞对CDDP敏感。H-7诱导KB细胞内GSH水平呈剂量依赖性降低。40ﾟC低温可增加顺铂在癌细胞内的铂蓄积。其结果是，即使在低热疗条件下，耐顺铂的变异体对CDDP的敏感性也会在高温下增强。联合顺铂和bcl2反义治疗可增加顺铂的敏感性，从而为基因化疗提供了可能。免疫组织化学方法检测诱导细胞凋亡基因Bax的表达。早期I期和II期阳性表达明显多于晚期。较少

项目成果

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Sugimoto, C：“癌细胞的凋亡。”

Noda,I.: "Enhancement of Sensitivity to CDDP in human pharyngeal carcinoma cells by H-7,a protein kinase inhibitor : Possib;e involvement of dellular glutathione" Oncology Reports. 4. 579-582 (1997)

Noda,I.：“蛋白激酶抑制剂 H-7 增强人咽癌细胞对 CDDP 的敏感性：可能与谷胱甘肽有关”肿瘤学报告。

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Ohtsubo, T.：“顺铂或 254-S 热疗对人牙龈癌细胞系 Ca-9-22 的体外影响”J Exp Clin Cancer Res 15・1 (1996)。

Ohtsubo, T.: "In vitro effect of hyperthermia with cisplatin or 254-S on human gingival carcinoma cell line Ca-9-22" J Exp Clin Cancer Res. 15. 37-42 (1996)

Ohtsubo, T.：“顺铂或 254-S 热疗对人牙龈癌细胞系 Ca-9-22 的体外影响”J Exp Clin Cancer Res。