Dash Rupesh, Azab Belal, Shen Xue-Ning, Sokhi Upneet K, Sarkar Siddik, Su Zhao-zhong, Wang Xiang-Yang, Claudio Pier Paolo, Dent Paul, Dmitriev Igor P, Curiel David T, Grant Steven, Sarkar Devanand, Fisher Paul B
Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, 23298, USA.
Discov Med. 2011 Jan;11(56):46-56.
Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer.
前列腺癌是美国男性癌症相关死亡的第二大主要原因。目前，没有单一疗法或联合疗法在降低转移性疾病患者的疾病进展方面显示出疗效。基因治疗是一种治疗晚期前列腺癌的潜在可行方法。腺病毒（Ad）是最常用的基因递送方式，但使用这种载体的进展受到包括条件性复制腺病毒（CRAds）在内的病毒安全性和实用性问题的阻碍，特别是对于静脉内递送，以及非病毒转染技术的低效率。使用腺病毒进行有效基因治疗的主要挑战是常规5型腺病毒血清型（Ad5）的感染性有限，以及无法将治疗剂直接特异性递送至患病组织而不被困在肝脏或被免疫系统清除。使用Ad5的缺点主要归因于癌细胞表面柯萨奇腺病毒受体（CAR）的减少，这可以通过产生嗜性修饰的腺病毒来缓解，从而允许肿瘤细胞进行不依赖CAR的感染。现在可以通过使用一种新型靶向递送方法来克服全身基因递送的局限性，例如使用超声（US）造影剂（微泡）递送有效的治疗试剂、腺病毒或重组蛋白，并结合超声靶向微泡破坏（UTMD），在免疫健全的转基因小鼠模型中开发一种位点特异性疗法。这些提高基因治疗疗效的独特策略为从实验室转化到临床开发有效的前列腺癌基因治疗提供了一条直接途径。
