| Co-Investigator(Kenkyū-buntansha) |
SAITO Nozomi Hokkaido University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究院, 助教授 (80349258)
TAKANO Masashi Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (50386611)
SUGIYAMA Toru The University of Tokyo, Department of Life Sciences, Research Associate, 大学院・総合文化研究科, 助手 (40242036)
本澤 忍 帝京大学, 薬学部, 助手 (90311547)
荒井 緑 帝京大学, 薬学部, 助手 (40373261)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
1α,25-Dihydroxyvitamin D_3 (1α,25(OH)_2D_3) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1α,25(OH)_2D_3 can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Norvitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized ^3H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of fifteen C-2-substituted 19-nor-1α,25(OH)_2D_3 analogs including 14-epi analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the fifteen analogs we observed that the substitution with the 2α- or 2β-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than the natural 1α,25(OH)_2D_3. The ^3H-thymidine incorporation data were supported by the cell counting data after cells were treated with
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1α,25(OH)_2D_3, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)_2D_3 or 19-nor-2β-(3-hydroxypropyp-1α,25(OH)_2D_3 for 7days. 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH)_2D_3 and 19-nor-2β-(3-hydroxypropy1)-1α,25(OH)_2D_3 were also shown to be about 10-fold more active than 1α,25(OH)_2D_3 in cell invasion studies using prostate cancer cells.
We also found that one of the 14-epi-19-nor-1α,25(OH)_2D_3 analogs with a 2-substituent showed bone formation effect on the OVX model rats, which was 18% increase in bone density after 0.1 μg/kg treatment a day in one week. This analog has no effect for hypercalcemia with that dose. We have more than eleven million patients of osteoporosis in Japan, today, therefore, it is very important to develop effective anti-osteoporosis drugs.
In conclusion, a substitution at the C-2 position of 19-nor-1α,25(OH)_2D_3 molecule with a 3-hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer. We also found the 14-epi-19-nor-1α,25(OH)_2D_3 analog which has strong bone formation activity without calcemic effect. Less
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