| Project/Area Number |
17590137
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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 |
Medical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
OGURA Kenichiro Tokyo University of Pharmacy and Life Science, School of Pharmacy, Associate Professor (10185564)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,810,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | tamoxifen / breast cancer / resistance / UGT / glucuronidation / anti cancer drug / 乳癌 / 抗癌薬 / 耐性化 |
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| Research Abstract |
Tamoxifen (TAM) , a nonsterodial antiestrogen, is one of the most widely used drugs in the world for the treatment and prevention of estrogen receptor (ER) positive breast cancer. The growth of breast cancer cells depending on estrogen is stimulated by binding of estradiol to ERs. Recently, it becomes a serious problem that breast cancer cells tolerated to TAM appears in breast cancer cells by long-term administration of TAM. TAM is activated via cytochrome P450-mediated pathways into 4-hydroxytamoxifen (4-OH-TAM) . Trans-4-OH-TAM has been considered to be an active metabolite of TAM because of higher affinity toward ERs than the parent drug and other side-chain metabolites. Recently, we found that N-glucuronidation of TAM and trans-4-OH-TAM were catalyzed by human liver microsomes and UDP-glucuronosyltransferase (UGT) 1A4. We focused on the relationship between the new metabolic pathway and tolerance to TAM. In the present study, we evaluated whether overexpressing UGT1A4 in breast cancer cells, or promotion of N-glucuronidation of TAM and trans-4-OH-TAM is one factor of TAM resistance. The intracellular and extracellular concentration of TAM and trans-4-OH-TAM in the assembled MCF-7 cells expressing human UGT1A4 were compared with wild-type MCF-7 cells. N-Glucuronidating activities of microsomes from human UGT1A4 expressing MCF-7 cells toward TAM and trans-4-OH-TAM were analyzed by HPLC system using a reverse phase column. The intracellular concentration of TAM and trans-4-OH-TAM in the MCF-7 cells expressing human UGT1A4 as compared with wild-type MCF-7 cells were markedly decreased. Furthermore, TAM and 4-OH-TAM N+-glucuronides were excreted in extracellular fluid in dose- and time-dependent manner. These data suggest that the reduction of TAM and trans-4-OH-TAM concentration in breast cancer cells is due to N-glucuronidation of them by UGT1A4 and may be a factor of the TAM resistance.
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