2003 Fiscal Year Final Research Report Summary
A study of novel transporters resposible for Uptake of the anticancer drugs a new strategy to increase the efficacy of anticancer drugs
| Project/Area Number |
13470231
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | TOHOKU UNIVERSITY |
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Principal Investigator |
SHIIBA Kenichi TOHOKU UNIVERSITY, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (90196345)
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| Co-Investigator(Kenkyū-buntansha) |
MIZOI Takayuki TOHOKU UNIVERSITY, Hospital, Research Associate, 医学部附属病院, 助手 (90271949)
ABE Takaaki TOHOKU UNIVERSITY, Hospital, Lecture, 医学部附属病院, 講師 (80292209)
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| Project Period (FY) |
2001 – 2003
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| Keywords | transporter / organic anion / anticancer drug / drug sensitivity / solid tumor / lymph node |
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| Research Abstract |
1.Analysis of the expression of the transporters in human cancer lines
(1)Analysis by real time RT-PCR showed high expression of a new transporter, LST-2 in liver, gastric, colorectal, ad breast cancer cell lines.
(2)The sensitivity of the cancer cell lines to several anticancer drug was correlated with the expression of LST-2.
2.Changes of the drug uptake and sensitivity by introduction of LST-1 and LST-2 mRNA
(1)We created LST-1 and LST-2 recombinant adenoviruses, termed AdLST-1 ad AdLST-2, and a control virus (Adβ-gal).
(2)LST-1 and LST-2 proteins were strongly expressed in the breast cancer cell lines, MB231 and ZR75-1, infected with AdLST-1 and AdLST-2. In vitro antiproliferative activity of methotrexate (MTX) was significantly increased in the cells infected with either AdLST-1 or AdLST-2.
(3)AdLST-1 and AdLST-2 also increased the antiproliferative activity of MTX in a subcutaneous tumor model using SCID mouse.
(4) A whole body autoradiography demonstrated that the uptake of MTX was increased in the subcutaneous tumor model infected with AdLST-1 or AdLST-2.
3.Induction of LST-1 and KST-2 expression by activation of LST-1 and LST-2 promoters
(1)We identified the promoter motifs and transcription factors that affect LST-1 and LST-2 expression.
(2)We found that the LST-1 and LST-2 transcription activities were induced by bile acids, CDCA and DCA.
Taken together, The expression of LST-1 and LST-2 was found to associated with the MTX sensitivity of cancer cells, especially breast cancer cells. These results might provide a new strategy that increases the efficacy of MTX and decreases the side effects of MTX.
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