2002 Fiscal Year Final Research Report Summary
A study on overcoming drug resistance by antisense Bcl-2 for breast cancer
| Project/Area Number |
13671236
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
TOGE Tetsuya Research Institute for Radiation Biology and Medicine Professor, 原爆放射線医科学研究所, 教授 (40034657)
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| Co-Investigator(Kenkyū-buntansha) |
OSAKI Akihiko University Medical Hospital Research Associate, 医学部附属病院, 助手 (90291484)
KIM Ryungsa Research Institute for Radiation Biology and Medicine Associate Professor, 原爆放射線医科学研究所, 助教授 (80274132)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Bcl-2 / Antisense / Breast cancer / Solid tumor / Anticancer drug / Apoptosis |
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| Research Abstract |
We examined preclinical study for enhancement of drug sensitivity using antisense (AS) Bcl-2 phosphorothioated oligonucleotides (ODNs) in solid tumors including breast, gastric and thyroid cancer. The results are the followings :
1. Downregulation of Bcl-2 protein was observed in approximately 60% by treatment with 1.0 μM AS Bcl-2 in a dose-dependent manner compared to control cells. This concentration was appropriate for maximal inhibition of Bcl-2 in terms of the cytotoxic effect of ODNs.
2. Enhancement of drug sensitivity in combination with AS Bcl-2 was observed in mitomycin (MMC), paclitaxel (TXL) for breast cancer, cisplatin (CDDP) for gastric cancer, and adriamycin (ADM), CDDP, taxanes for thyroid cancer. The increased drug sensitivity was associated with induction of apoptotic cell death, which was activated by Bax, cytochrome c, caspase-3, and caspase-8 in the death receptor-dependent and -independent pathway.
3. In vivo experiment with nude mice xenograft, similar enhancement of therapeutic effects to MMC, TXL, and TXT were observed with intraperitoneal administration of 5 mg/kg AS Bcl-2 for 6 consecutive days. Downreguiation of Bcl-2 was observed at day 4 after the treatment with AS Bcl-2 and it was continued for day 14.
4. These results suggest that the targeting therapy with AS Bcl-2 is a useful method for enhancement of drug sensitivity in vitro and in vivo in the modulation of apoptotic pathway for solid tumors.
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