P-糖蛋白表达对新型吡咯并苯二氮卓二聚体SJG-136体外细胞毒性和体内抗肿瘤活性的影响。
Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136.
作者信息
Guichard S M, Macpherson J S, Thurston D E, Jodrell D I
机构信息
Pharmacology and Drug Development Team, Cancer Research UK Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XR, UK.
出版信息
Eur J Cancer. 2005 Aug;41(12):1811-8. doi: 10.1016/j.ejca.2005.04.026.
SJG-136 is a novel pyrrolobenzodiazepine dimer analogue that acts as a minor-groove interstrand DNA cross-linking agent. The present study investigated the impact of ABCB1 (mdr-1) expression on the activity of SJG-136 using both in vitro and in vivo systems. SJG-136 was highly potent in the colon cancer cell lines HCT-116, HT-29 and SW620 (IC50 0.1-0.3 nM). However, HCT-8 and HCT-15 cells expressing significant levels of mdr-1 were less sensitive (IC50 2.3 and 3.7 nM, respectively) using a SRB assay. The cytotoxicity was increased in HCT-15 and A2780(AD) in presence of 5 microg/ml verapamil. Mdr-1 mRNA expression was determined by qRT-PCR and correlated to SJG-136 IC50s (r2=0.86, P=0.0001). Isogenic 3T3 cells expressing mdr-1 cDNA (3T3 pHamdr-1) were less sensitive to SJG-136 than the parental 3T3 cells (IC50 208 and 6.3 nM, respectively). Finally, SJG-136 (120 microg/kg/d dx5) was highly active against A2780 xenografts (SGD=275) but not A2780(AD) xenografts (SGD=67).
SJG-136是一种新型吡咯并苯二氮卓二聚体类似物，作为一种小沟链间DNA交联剂。本研究使用体外和体内系统研究了ABCB1（多药耐药基因1）表达对SJG-136活性的影响。SJG-136在结肠癌细胞系HCT-116、HT-29和SW620中具有高效力（半数抑制浓度[IC50]为0.1 - 0.3 nM）。然而，使用磺酰罗丹明B（SRB）测定法，表达高水平多药耐药基因1的HCT-8和HCT-15细胞敏感性较低（IC50分别为2.3和3.7 nM）。在存在5微克/毫升维拉帕米的情况下，HCT-15和A2780（AD）细胞的细胞毒性增加。通过定量逆转录聚合酶链反应（qRT-PCR）测定多药耐药基因1的信使核糖核酸（mRNA）表达，并与SJG-136的IC50相关（r2 = 0.86，P = 0.0001）。表达多药耐药基因1互补DNA（cDNA）的同基因3T3细胞（3T3 pHamdr-1）对SJG-136的敏感性低于亲代3T3细胞（IC50分别为208和6.3 nM）。最后，SJG-136（120微克/千克/天，连用5天）对A2780异种移植瘤具有高活性（生长抑制率[SGD] = 275），但对A2780（AD）异种移植瘤无活性（SGD = 67）。
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