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

负责抗癌药物摄取的新型转运蛋白的研究是提高抗癌药物疗效的新策略

• 批准号: 13470231
• 负责人: SHIIBA Kenichi
• 金额: $ 10.37万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470231/
• 关键词: transporter; organic anion; anticancer drug; drug sensitivity; solid tumor; lymph node; 抗癌剤感受性; 癌細胞

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.

1.(1)实时RT-PCR分析显示，一种新的转运体LST-2在肝癌、胃癌、结直肠癌和乳腺癌细胞系中均有高表达。(2)肿瘤细胞系对多种抗癌药物的敏感性与LST-2.2的表达相关。引入LST-1和LST-2 mRNA对药物摄取和敏感性的影响(1)我们构建了LST-1和LST-2重组腺病毒，分别命名为AdLST-1和AdLST-2，并建立了对照病毒（ad β-gal）。(2)在AdLST-1和AdLST-2感染的乳腺癌细胞株MB231和ZR75-1中，LST-1和LST-2蛋白强烈表达。在AdLST-1或AdLST-2感染的细胞中，甲氨蝶呤（MTX）的体外抗增殖活性显著增加。(3)AdLST-1和AdLST-2还能提高MTX在SCID小鼠皮下肿瘤模型中的抗增殖活性。(4)全身放射自显像显示AdLST-1或AdLST-2.3感染的皮下肿瘤模型MTX摄取增加。激活LST-1和LST-2启动子诱导LST-1和KST-2表达(1)我们确定了影响LST-1和LST-2表达的启动子基序和转录因子。(2)我们发现胆汁酸、CDCA和DCA诱导LST-1和LST-2的转录活性。综上所述，我们发现LST-1和LST-2的表达与癌细胞，尤其是乳腺癌细胞的MTX敏感性有关。这些结果可能为提高MTX的疗效和减少MTX的副作用提供一种新的策略。

项目成果

Adachi H et al.: "Molecular characterization of human and rat organic anion transporter OATP-D"Am J Physiol Renal Physiol. 285・6. 1188-1197 (2003)

Adachi H 等：“人和大鼠有机阴离子转运蛋白 OATP-D 的分子特征”Am J Physiol Renal Physiol 285·6（2003）。

Abe T et al.: "Thyroid hormone transporters : recent advances"Trends Endocrinol Metab. 13・5. 215-220 (2002)

Abe T 等：“甲状腺激素转运蛋白：最新进展”Trends Endocrinol Metab. 215-220 (2002)。

Adachi H et al.: "Molecular characterization of human and rat organic anion transporter OATP-D"Am.J.Physiol.Renal Physiol.. 285. 1188-1197 (2003)

Adachi H 等人：“人和大鼠有机阴离子转运蛋白 OATP-D 的分子特征”Am.J.Physiol.Renal Physiol.. 285. 1188-1197 (2003)

Ito A et al.: "Distribution of organic anion-transporting polypeptide 2 (oatp2) and oatp3 in the rat retina"Investt Ophthalmol Vis Sci. 43・3. 858-863 (2002)

Ito A等人：“大鼠视网膜中有机阴离子转运多肽2（oatp2）和oatp3的分布”Investt Ophasemol Vis Sci 43·3（2002）。

Abe T et al.: "Thyroid hormone transporters : recent advances."Trends Endocrinol Metab. 13. 215-220 (2002)

Abe T 等人：“甲状腺激素转运蛋白：最新进展。”内分泌代谢趋势。