| Project/Area Number |
09557053
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
AKITA Hirotoshi Lecturer, First Department of Medicine, Hokkaido University Medical Hospital, 医学部・附属病院, 講師 (70222528)
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| Co-Investigator(Kenkyū-buntansha) |
MURAKAMI Akira Professor, Department of Polymer Science and Engineering, Kyoto Institute of Technology, 繊維学部, 教授 (60210001)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥11,400,000 (Direct Cost: ¥11,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1997: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | Lung Cancer / myc / Antisense / Retionoic Acid / myc遺伝子 |
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| Research Abstract |
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.
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