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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表达和维甲酸信号通路的失调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，我们调查是否c-myc反义寡脱氧核苷硫代磷酸（OPT）覆盖的c-myc mRNA的翻译位点与全反式维甲酸（RA）联合使用将更有效地抑制SCLS细胞系，NCI-H82，过度表达c-myc基因扩增的生长，以及这种组合是否可能是一个实验性的治疗工具，对SCLC。在北方和Western印迹分析中，C-myc反义OPT降低c-myc表达，因此与对照乱序和正义OPT相比，包括40%的细胞生长抑制和10%的细胞凋亡率（分别为P<0.01和P<0.05）。全反式维甲酸还通过下调c-myc表达抑制细胞增殖，抑制率为40%。在获得这些结果后，我们检验了c-myc反义OPT与全反式RA组合可能进一步降低c-myc表达并导致改善细胞生长控制的假设。该组合通过增强c-myc表达的下调而显示出比单独给予的任一种试剂对细胞增殖的抑制（P<0.01）（与单独的对照乱序或正义OPT处理相比，细胞生长抑制60%，p<0.01）。总之，c-myc反义DNA与其他方式的c-myc下调可能是一个有吸引力的基因调控为基础的治疗SCLC在未来，虽然进一步的努力，使用新的寡脱氧核苷酸类似物，特定的干预DNA递送到细胞，更有效的治疗药物，需要增加c-myc下调和细胞生长抑制的增强。