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An exploitation of gene targeting therapy against hypoxic condition of oral carcinoma.

针对口腔癌缺氧状态的基因靶向治疗的开发。

基本信息

批准号：
17592061
负责人：
ONO Mitsunobu
金额：
$ 2.05万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17592061/
关键词：
Oral carcinoma Adrenomedullin Gene targeting therapy

项目摘要

Cancer cells are exposed to hypoxic state because of their high proliferation rate: however, cancer cells are resistant to hypoxia-induced cell death. Hypoxia Inducible Factor (HIF) was identified as the transcription factor which maintains the homeostasis of the cell in hypoxic state. We examined the downstream genes of HIF by DNA micro array and we found that adenomemedullin, a blood vessel expansive peptide encoding gene product.Twenty-two cases of tongue squamous cell carcinoma who consulted the Hokkaido University Hospital were examined by immunohistochmistry. Adrenomedullin was detected in 11 of 22 cases examined. They were investigated clinico-pathologically. mong the 12 cases of cervical lymph node metastasis cases, 8 cases were positive for aderenomedullin. In contrast, only 3 cases were positive for adrenomedullin in 10 cases without lymph node metastasis.We reconstruct two mutant expression plasmids of adrenomedullin that are thought to function as antagonist, AMA214 is deletion and mutant plasmid with 27-115 amino acid deletion and 116 threonine into serine..AMA224 has deletion of 95-115 amino acid and the same mutation in 116 amino acid. AMA214 and AMA224 injection induced the regression of transplanted tumors in SCID mouse. CD31-positive tumor endothelial cells were disappeared in these animals.

癌细胞因其高增殖率而暴露于缺氧状态：然而，癌细胞对缺氧诱导的细胞死亡具有抵抗力。缺氧诱导因子（HIF）被认为是在缺氧状态下维持细胞稳态的转录因子。我们通过DNA微阵列检测了HIF的下游基因，发现了血管扩张肽编码基因产物腺髓质素。对北海道大学医院就诊的22例舌鳞状细胞癌进行了免疫组织化学检查。 22 例检查中，11 例检测到肾上腺髓质素。对他们进行临床病理学研究。 12例颈部淋巴结转移病例中，8例腺髓质素阳性。相比之下，10例无淋巴结转移的病例中，只有3例肾上腺髓质素呈阳性。我们重建了两种被认为具有拮抗剂功能的肾上腺髓质素突变表达质粒，AMA214是缺失的，突变质粒有27-115个氨基酸缺失，116个苏氨酸变成了丝氨酸。AMA224有95-115个氨基酸缺失和相同的突变。含116个氨基酸。 AMA214和AMA224注射诱导SCID小鼠移植肿瘤的消退。 CD31 阳性肿瘤内皮细胞在这些动物中消失。