| Budget Amount *help |
¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 2009: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2008: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2007: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2006: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Research Abstract |
We have been developing nucleoside antimetabolites CNDAC and ECyd as new types of antitumor agents. After incorporation of CNDAC in DNA-strands, strand-breaks were induced. In order to repair the breaks, G2-check point was activated. Therefore, it is important to develop its abrogators for combination therapy. We designed a new Chk1 inhibitor, PGED (IC50=2.8nM), which has combination effects with SN-38. ECyd is a potent inhibitor of RNA polymerase after its conversion to the corresponding 5'-triphosphate. In combination treatment with X-ray irradiation and ECyd, antitumor effects towards colon 26 tumors in vivo were effectively enhanced, due to inhibition of expression of antiapoptotic protein such as survivin. We also found that by increasing the length of the bridging linker, the PU3 (an Hsp90 inhibitor) dimmers became more cytotoxic against human breast cancer cell lines.
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