|Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
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.