Study for the Development of Therapy Based on the Regulation of the myc Gene Expression in Lung Cancer

基于myc基因表达调控的肺癌治疗药物开发研究

基本信息

批准号：
09557053
负责人：
AKITA Hirotoshi
金额：
$ 7.3万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557053/
关键词：
Lung Cancer myc Antisense Retionoic Acid myc遺伝子

项目摘要

The disregulation of both c-myc expression and retinoid signaling pathways commonly occurs in small cell lung cancers (SCLCs), frequently accompanying tumor relapse, and contributing to the poor prognosis of patients with SCLCs. In this study, we investated whether c-myc antisense oligodeoxynucleoside phosphorothioate (OPT) covering the translational site of c-myc mRNA used in combination with all-trans-retinoic acid (RA) would be more effective than either agent alone in inhibiting the growth of an SCLS cell line, NCI-H82, overexpressing c-myc with amplification of the gene, and whether this combination could be an experimental therapeutic tool against SCLCs. C-myc Antisense OPT decreased c-myc expression in Northern and Western blot analyses, thus including 40% cell growth inhibition and 10% higher frequency of apoptosis compared with control scrambled and sense OPTs (P<0.01, and P<0.05, respectively). All-trans RA also inhibited cell proliferation at the rate of 40% by down-regulating c-myc expression. Having obtained these results, we tested the hypothesis that c-myc antisense OPT in combination with all-trans-RA may further reduce c-myc expression and lead to improved cell growth control. This combination showed an inhibition of cell proliferation than either agent given alone (P<0.01) (60% inhibition of cell growth compared with treatment of control scrambled or sense OPT alone, p<0.01) through enhanced down-regulation of c-myc expression. In conclusion, c-myc antisense DNA in combination with other modalities for c-myc down-regulation may represent an attractive gene regulation-based therapy of SCLCs in the future, although further efforts using new oligodeoxynucleotide analogues, specific interventions for DNA delivery into cells, and more potent therapeutic agents are required to increase the potentiation of c-myc down-regulation and cell growth inhibition.

C-MYC表达和类视黄素信号通路的脱离通常发生在小细胞肺癌（SCLC）中，经常伴随肿瘤复发，并导致SCLC患者的预后不良。在这项研究中，我们投资了C-MYC反义寡脱氧核苷磷酸酯（OPT）是否涵盖了与全反性运动酸（RA）结合使用的C-MYC mRNA的转化位点，而不是单独使用cls cell and Cell and anci-H82，是否可以抑制ANCI-H82的CYCRESS，该公司是否会更有效地单独使用任何一种代理针对SCLC的实验治疗工具。 C-MYC反义选择降低了北部印迹分析的C-MYC表达，因此与对照组合和感官选择相比，包括40％的细胞生长抑制和凋亡频率高10％（P <0.01和P <0.01和P <0.05）。通过下调C-MYC表达，全反型RA还以40％的速度抑制细胞增殖。获得了这些结果后，我们检验了以下假设：C-MYC反义选择与All-Trans-RA结合使用可以进一步降低C-MYC的表达并导致改善细胞生长控制。这种组合显示出比单独给出的任何一种药物（p <0.01）的抑制作用（与对照组的治疗相比，细胞生长的抑制作用为60％或单独使用，p <0.01），通过增强C-MYC表达的下调。总之，C-MYC反义DNA与其他用于C-MYC下调的模式结合使用可能代表一种有吸引力的基因调节的SCLC治疗，尽管进一步的努力使用新的寡头核苷酸类似物，对细胞的特定寡头核苷酸类似物，对细胞的特定干预措施以及更有效的治疗方法的培养物以及更大的细胞较大的细胞均需要。