In vivo restoration of RhoB expression leads to ovarian tumor regression
In vivo restoration of RhoB expression leads to ovarian tumor regression
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DOI：
10.1038/cgt.2008.12
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Favre, G.
中科院分区：
文献类型：
--
作者：
Couderc, B.;Pradines, A.;Favre, G.
卵巢癌是一种侵袭性很强的癌症，通常在整个腹腔已经发生转移时才被诊断出来。卵巢腺癌细胞的RhoB GTPase水平检测不到。利用临床前卵巢癌模型，我们旨在评估RhoB cDNA作为肿瘤抑制基因在基因治疗中的潜在应用。体外RhoB修复通过重组腺病毒转导，通过激活内源性凋亡caspase级联，导致内源性RhoB蛋白低表达细胞系（OVCAR-3和IGROV-1）凋亡。我们发现，将10(8)p.f.u.的编码报告基因的腺病毒载体单次注射到卵巢荷瘤小鼠的腹腔内，可以诱导整个腹腔内大量细胞的基因修饰。因此，我们测试了AdRhoB注射治疗卵巢癌小鼠的效果。RhoB的异位表达，通过病毒转导引入裸鼠体内后，对抑制卵巢癌异种移植瘤的肿瘤生长非常有效。设计用于在分子水平上纠正RhoB缺陷的治疗剂可能因此为标准治疗无效的患者提供创新的治疗选择。
Ovarian cancers are very aggressive cancers most often diagnosed when metastasis has already occurred in the entire peritoneal cavity. Ovarian adenocarcinoma cells present an undetectable level of RhoB GTPase. Using preclinical ovarian cancer models, we aimed to evaluate the potential use of RhoB cDNA as a tumor suppressor gene in gene therapy. RhoB restoration in vitro, through recombinant adenovirus transduction, resulted in the apoptosis of endogenous RhoB protein low-expressing cell lines (OVCAR-3 and IGROV-1) through the activation of the intrinsic apoptotic caspase cascade. We showed that a single injection of 10(8) p.f.u. of adenoviral vector encoding a reporter gene into the peritoneal cavity of ovarian tumor bearing mice can induce the gene modification of a large quantity of cells throughout the cavity. We thereby tested the effect of AdRhoB injections to treat ovarian cancer-bearing mice. The ectopic expression of RhoB, following its introduction via viral transduction into nude mice in vivo, was highly effective in suppressing tumor growth of ovarian cancer xenografts. Therapeutic agents designed to correct defects of RhoB at the molecular level may thereby provide innovative treatment options for patients not responding to standard therapies.