Marples B, Greco O, Joiner M C, Scott S D
Department of Radiation Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, MI 48201-2013, USA.
Curr Pharm Des. 2003;9(26):2105-12. doi: 10.2174/1381612033454090.
The aim of cancer gene therapy is to selectively kill malignant cells at the tumor site, by exploiting traits specific to cancer cells and/or solid tumors. Strategies that take advantage of biological features common to different tumor types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia, the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumor volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene (e.g., herpes simplex virus thymidine kinase) to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug (e.g., ganciclovir). The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumor targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance.
癌症基因治疗的目的是通过利用癌细胞和/或实体瘤特有的特征，在肿瘤部位选择性地杀死恶性细胞。利用不同肿瘤类型共有的生物学特征的策略尤其具有前景，因为它们具有广泛的临床适用性。很多注意力都集中在补充主要治疗方式放疗的基因方法，或利用大多数实体癌最普遍存在的特征——缺氧的基因方法上。本综述的目的是强调专门为靶向肿瘤体积而开发的两种有前景的基因治疗方法，它们可以很容易地与放疗联合使用。第一种方法使用辐射响应基因启动子来控制自杀基因（例如单纯疱疹病毒胸苷激酶）仅在受辐射组织中的选择性表达，在存在前体药物（例如更昔洛韦）的情况下导致靶向细胞杀伤。第二种方法利用氧依赖性启动子在对传统放疗有抗性的缺氧细胞中产生选择性治疗基因表达和前体药物激活。通过在由单一和双重刺激激活的嵌合启动子中组合辐射和缺氧响应元件，可以进一步优化肿瘤靶向。本综述中描述的体外和体内研究表明，基因治疗和放疗方案的联合在癌症治疗中具有应用潜力，特别是在目前由于内在或缺氧介导的放射抗性而难治的病例中。
