Inhibition of lung cancer cell growth by antisense oligonucleotide to tumor growth factor gene

肿瘤生长因子基因反义寡核苷酸抑制肺癌细胞生长

• 批准号: 06671360
• 负责人: CHIMOTO Masayuki
• 金额: $ 1.22万
• 依托单位: Dokkyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671360/
• 关键词: Lung cancer; Growth inhibition; Molecular analysis; Antisense oligonucleotide; 肺炎; 癌遺伝子

Usually the specificity of basis on cell cytotoxity for cancer chemotherapy has been dependent upon the uptake ratio of drugs to difference of originate in cell growth between tumor and normal cells. In advance tumor account of most of tumors, because getting good results by long prognosis of chemotherapy for patients was insufficient, now new drugs and therapy are expected eagerly. Then we made plan for the specific inhibition of tumor cell growth in lung cancer by oligonucleotides, founded on information of cell biology. The target gene we chose were transforming growth factor-alpha (TGF-alpha), which we considered the high expression on lung cancer, frequency of crisis, and having resistance for chemotherapy in adenocarcinoma.We produced phosphorothioate-modified antisense oligonucleotide spanning the 3-end codons of TGF-alpha mRNA.Analysis of TGF-alpha mRNA expression in cancer cell lines by RT-PCR,we observed 7 lines of lung cancer and osteosarcoma line, and especially strong expression of these gene were shown in 3 lung cancer cell lines. Antisense oligonucleotide suppressed the growth of HPC-93EP cells, which expressed TGF-alpha gene strongly, the effect was on dose dependent manner, on other hand the sense oligonucleotide had no effect. TGF-alpha antisense oligonucleo-tide decreased TGF-alpha mRNA and protein expression when analyzed by RT-PCR and flow cytometry.Thus antisense oligonucleotide to growth factor might be promising as a possible therapy for lung cancers.

通常，癌症化疗的细胞毒性基础的特异性取决于药物的摄取比率与肿瘤细胞和正常细胞之间细胞生长起源的差异。肿瘤占肿瘤的绝大部分，由于长期化疗对患者预后的良好效果还不够，现在人们迫切期待新的药物和疗法。然后我们根据细胞生物学信息制定了寡核苷酸特异性抑制肺癌肿瘤细胞生长的方案。我们选择的靶基因是转化生长因子-α (TGF-α)，我们认为该基因在肺癌中高表达，危象频率高，并且对腺癌中的化疗具有抵抗性。我们生产了跨越 TGF-α mRNA 3 端密码子的硫代磷酸修饰的反义寡核苷酸。癌细胞系中 TGF-α mRNA 表达的分析 通过RT-PCR，我们观察了7个肺癌细胞系和骨肉瘤细胞系，其中该基因在3个肺癌细胞系中表现出特别强的表达。反义寡核苷酸对强烈表达TGF-α基因的HPC-93EP细胞的生长有抑制作用，其作用呈剂量依赖性，而正义寡核苷酸则无此作用。通过 RT-PCR 和流式细胞术分析，TGF-α 反义寡核苷酸降低了 TGF-α mRNA 和蛋白表达。因此，生长因子反义寡核苷酸可能有望成为肺癌的可能疗法。