Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But
Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But
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DOI：
10.1158/1078-0432.ccr-04-0349
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发表时间：
2004-07-15
影响因子：
11.5
通讯作者：
Perbellini, A
中科院分区：
文献类型：
--
作者：
Coradini, D;Zorzet, S;Perbellini, A
目的：评价CD44-BUT(一种与丁酸(BUT)残基酯化的透明质酸--RA-BUT)在体外对肝癌细胞株和体内肝转移瘤的靶向性。实验设计：体外研究CD44高表达和低表达的两种人肝癌细胞株(HepB3和HepG2)CD44依赖的细胞毒作用；体内比较不同给药途径对小鼠Lewis肺癌(LL3)或B16-F10黑色素瘤脾内移植瘤肝转移的影响，并比较不同给药途径在器官和组织分布的药代动力学。结果：HepB3和HepG2细胞株中CD44的表达不同(分别为78%和18%)，这导致了CD44依赖的HA-BUT的抑制作用，放射性标记的HA-BUT(TC-99m-RA-BUT)的摄取分析也证明了这一点。药代动力学研究表明，不同的给药途径(静注、静注或皮下注射)给药后的分布速度不同：静脉注射后非常快(几分钟)。治疗，肝和脾大量蓄积；腹腔注射后相对缓慢。或者南加州大学。治疗，药物在注射部位有明显的持久性。S.C.的影响。和IP。用HA-BUT治疗脾内LL3癌或B16-F10黑色素瘤(CD44阳性分别为68%和87%)所致的肝转移，分别有87%和100%的无转移动物(无论采用何种给药途径)，并与对照组相比显著延长寿命。结论：HA-BUT倾向于集中在肝和脾，有望成为治疗肝内肿瘤病变的新药物。
Purpose: The purpose is to evaluate the CD44-mediated cellular targeting of RA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo.Experimental Design: In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration.Results: HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But (Tc-99m-RA-But). Pharmacokinetic studies showed different rates of Tc-99m-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups.Conclusions: HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions.