Department of Genetic Engineering Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
Int J Cancer. 2010 Feb 1;126(3):733-42. doi: 10.1002/ijc.24700.
Safety, efficacy and enhanced transgene expression are the primary concerns while using any vector for gene therapy. One of the widely used vectors in clinical trials is adenovirus which provides a safe way to deliver the therapeutic gene. However, adenovirus has poor transduction efficiency in vivo since most tumor cells express low coxsackie and adenovirus receptors. Similarly transgene expression remains low, possibly because of the chromatization of adenoviral genome upon infection in eukaryotic cells, an effect mediated by histone deacetylases (HDACs). Using a recombinant adenovirus (Ad-HSVtk) carrying the herpes simplex thymidine kinase (HSVtk) and GFP genes we demonstrate that HDAC inhibitor valproic acid can bring about an increase in CAR expression on host cells and thereby enhanced Ad-HSVtk infectivity. It also resulted in an increase in transgene (HSVtk and GFP) expression. This, in turn, resulted in increased cell kill of HNSCC cells, following ganciclovir treatment in vitro as well as in vivo in a xenograft nude mouse model.
在进行基因治疗时，安全性、疗效和增强的转基因表达是主要关注点。在临床试验中广泛使用的载体之一是腺病毒，它为携带治疗基因提供了一种安全的方法。然而，由于大多数肿瘤细胞表达低柯萨奇和腺病毒受体，腺病毒在体内的转导效率很差。同样，转基因表达仍然很低，可能是因为腺病毒基因组在真核细胞感染时发生染色质化，这种效应由组蛋白去乙酰化酶（HDACs）介导。我们使用携带单纯疱疹胸苷激酶（HSVtk）和 GFP 基因的重组腺病毒（Ad-HSVtk）证明，组蛋白去乙酰化酶抑制剂丙戊酸可以增加宿主细胞上 CAR 的表达，从而增强 Ad-HSVtk 的感染力。它还导致转基因（HSVtk 和 GFP）表达增加。这反过来又导致 HNSCC 细胞在体外和裸鼠异种移植模型中的细胞杀伤增加，随后进行更昔洛韦治疗。
