A study of novel transporters resposible for Uptake of the anticancer drugs a new strategy to increase the efficacy of anticancer drugs

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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.