The Second Affiliated Hospital of Guangzhou Medical University, Changgang Dong Lu, No 250, Guangzhou 510260, China.
Med Oncol. 2012 Sep;29(3):1938-47. doi: 10.1007/s12032-011-0091-x. Epub 2011 Oct 20.
Novel treatment strategies such as gene therapy are warranted in view of the failure of current treatment approaches to cure a high percentage of patients with advanced bladder cancers. The emergence of cancer gene therapy potentially offers a number of exciting treatments. The majority of approaches involve strategies to suppress the function of activated oncogenes to restore the expression of functional tumour suppressor genes or to initiate tumour self-destruction. One gene therapy approach against tumours that holds great promise is suicide gene therapy. Herpes simplex virus thymidine kinase (HSV-TK) phosphorylates ganciclovir (GCV), which in turn interacts with cellular DNA polymerase and interferes with DNA synthesis to cause death of rapidly dividing cells. The development of an effective delivery system is absolutely critical to the usefulness and safety of gene therapy. At present, the adeno-associated virus (AAV) vector has the most promising potential in view of its non-pathogenicity, wide tropisms and long-term transgene expression in vivo. Gene therapy studies using different serotypes of recombinant AAV (rAAV) as delivery vehicles have proved rAAVs to be an effective modality of cancer gene therapy. In the present study, we investigated the suppression effect of AAV-mediated HSV-TK/GCV system on the bladder cancer cells and in mice xenograft models of bladder cancer. Our data demonstrate that rAAV-HSV-TK system controlled tumour cell growth and achieves strong antitumour efficacy in vivo. These findings provide a foundation for the development of potential targeted clinical therapies for bladder cancer in humans.
鉴于目前的治疗方法未能治愈很大一部分晚期膀胱癌患者，因此需要新的治疗策略，如基因治疗。癌症基因治疗的出现为许多令人兴奋的治疗方法提供了可能。大多数方法涉及抑制激活癌基因的功能以恢复功能性肿瘤抑制基因的表达或启动肿瘤自我毁灭的策略。一种有很大前途的针对肿瘤的基因治疗方法是自杀基因治疗。单纯疱疹病毒胸苷激酶（HSV-TK）磷酸化更昔洛韦（GCV），进而与细胞 DNA 聚合酶相互作用并干扰 DNA 合成，导致快速分裂细胞死亡。有效的递送系统的开发对于基因治疗的有效性和安全性至关重要。目前，腺相关病毒（AAV）载体因其无致病性、广泛的嗜性和体内长期转基因表达而具有最有前途的潜力。使用不同血清型重组 AAV（rAAV）作为递送载体的基因治疗研究已证明 rAAV 是癌症基因治疗的有效方式。在本研究中，我们研究了 AAV 介导的 HSV-TK/GCV 系统对膀胱癌细胞和膀胱癌小鼠异种移植模型的抑制作用。我们的数据表明，rAAV-HSV-TK 系统可控制肿瘤细胞生长并在体内实现强大的抗肿瘤疗效。这些发现为开发针对人类膀胱癌的潜在靶向临床治疗方法奠定了基础。
