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

癌细胞由于其高增殖率而处于缺氧状态，但癌细胞对缺氧诱导的细胞死亡具有抵抗性。缺氧诱导因子（Hypoxia Inducible Factor， HIF）被认为是维持细胞在缺氧状态下稳态的转录因子。我们通过DNA微阵列检测了HIF的下游基因，发现了一种血管扩张肽编码基因产物腺瘤髓质素。本文对北海道大学附属医院22例舌鳞癌患者进行免疫组织化学检查。22例中有11例检测到肾上腺髓质素。对他们进行了临床病理调查。在12例颈部淋巴结转移病例中，肾上腺髓质素阳性8例。10例无淋巴结转移的患者中肾上腺髓质素阳性仅3例。我们重建了两个被认为具有拮抗剂功能的肾上腺髓质素突变表达质粒，AMA214缺失和27-115个氨基酸缺失和116个苏氨酸转化为丝氨酸的突变质粒。AMA224缺失95-115个氨基酸，116个氨基酸发生相同突变。注射AMA214和AMA224可诱导SCID小鼠移植肿瘤消退。cd31阳性肿瘤内皮细胞在这些动物中消失。

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.