Functional regulation and clinical application of the organic anion transporter LST family.

在过去的十年中，许多转运蛋白已被分离，表征了它们的分布和底物。其中有机阴离子转运体OATP家族，运输胆汁酸、激素以及类二十烷类化合物和各种化合物（BSP、HMG-CoA还原酶抑制剂、血管紧张素转换酶抑制剂等）。到目前为止，申请人在国际上首次分离并报道了15个以上的oatp家族无性系。我们分离出了有机阴离子转运蛋白OATP/LST家族，该家族在多种胃肠道肿瘤中均有表达。然后我们建立了LST-2重组腺病毒，命名为AdLST-2。在使用SCID小鼠的皮下肿瘤模型中估计了MTX与腺病毒联合使用的体内效应。用AdLST-2/MTX治疗的肿瘤比用Adβ-gal/MTX治疗的肿瘤生长更慢。全身放射自显像证实了AdLST-1/MTX和AdLST2/MTX治疗小鼠肿瘤中[^3H]-MTX的掺入。我们的观察结果有力地支持了内流泵的过表达是增强癌症化疗的新途径的可能性。我们还提出了一种利用腺病毒和LST-2荧光素筛选配体的方法。该系统无法筛选各种更适合LST-2转运的化合物。

In the last decade, many transporters have been isolated, characterized their distribution and substrates. Among them, the organic anion transporter OATP family, transport bile acids, hormones as well as eicosanoids and various compounds (BSP, HMG-CoA reductase inhibitor, angiotensin converting enzyme inhibitor, etc.). So far, applicant isolated more than 15 clones of the oatp family firstly in the world and reported. We have isolated the organic anion transporter OATP/LST family which exclusively expressed in various gastrointestinal cancers.Thenm we established LST-2 recombinant adenoviruses, termed AdLST-2. In vivo effects of the combination of MTX with the adenoviruses were estimated in a subcutaneous tumor model using SCID mice. Tumors treated with AdLST-2/MTX grew more slowly than those treated with Adβ-gal/MTX. Whole-body autoradiograph confirmed that incorporation of [^3H]-MTX in tumors of mice treated with AdLST-1/MTX and AdLST2/MTX.Our observations strongly support the possibility that overexpression of influx pumps is a new avenue in the enhancement of cancer chemotherapy. We also raised a ligand-screening method using adenovirus and fluorescent lignd of LST-2. This system unable us to screening various compounds preferable to transported by LST-2.