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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表达和类视黄醇信号通路的失调常见于小细胞肺癌（SCLCs），常伴随肿瘤复发，是导致小细胞肺癌患者预后不良的原因之一。在这项研究中，我们研究了覆盖c-myc mRNA翻译位点的c-myc反义寡聚氧核苷磷酸（OPT）与全反式维甲酸（RA）联合使用是否比单独使用任何一种药物更有效地抑制过表达c-myc并扩增基因的SCLS细胞株NCI-H82的生长，以及这种联合是否可以作为一种实验性治疗工具来治疗sclc。在Northern和Western blot分析中，C-myc反义OPT降低了C-myc的表达，与对照组和义OPTs相比，C-myc反义OPT抑制了40%的细胞生长，凋亡频率提高了10% （P<0.01， P<0.05）。全反式RA也通过下调c-myc表达抑制细胞增殖，抑制率为40%。得到这些结果后，我们验证了c-myc反义OPT联合all-trans-RA可能进一步降低c-myc表达并改善细胞生长控制的假设。该组合通过增强下调c-myc表达而抑制细胞增殖（P<0.01）（与对照混乱或单独使用sense OPT相比，细胞生长抑制率为60%，P<0.01）。总之，c-myc反义DNA联合其他方式下调c-myc可能是未来一种有吸引力的基于基因调控的sclc治疗方法，尽管需要进一步努力使用新的寡脱氧核苷酸类似物，对DNA传递到细胞的特定干预，以及更有效的治疗药物来增强c-myc下调和细胞生长抑制的能力。