Tetzlaff Michael T, Teh Bin S, Timme Terry L, Fujita Tetsuo, Satoh Takefumi, Tabata Ken-Ichi, Mai Wei-Yuan, Vlachaki Maria T, Amato Robert J, Kadmon Dov, Miles Brian J, Ayala Gustavo, Wheeler Thomas M, Aguilar-Cordova Estuardo, Thompson Timothy C, Butler E Brian
Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, ST 2100, Houston, Texas 77030, USA.
Technol Cancer Res Treat. 2006 Feb;5(1):23-36. doi: 10.1177/153303460600500104.
The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.
放射治疗（三维适形放疗、调强放疗）的进展使得高剂量辐射能够在尽可能降低相关毒性的情况下进行。然而，尽管增加了剂量，癌症仍会持续存在（放疗后局部复发），以及远处转移的出现表明存在微转移，尤其是在高风险疾病的情况下，这凸显了继续改进治疗策略以尽可能确切地控制局部和微转移疾病的必要性。这促使人们想到，通过将放疗与原位基因治疗相结合，可能提高放疗的治疗指数。这些联合治疗的目标是在最大程度上增加对癌细胞生长的选择性压力，同时将治疗相关毒性降至最低。利用不同基因治疗策略的主要努力已与放疗联合应用。我们回顾了我们自己以及其他已发表的利用这种联合放射基因治疗方法的临床试验，包括其相关的临床前体外和体内模型。将原位基因治疗用作放疗的辅助手段，在体外显著降低了细胞活力，在体内抑制了肿瘤生长。在I/II期临床研究中，未发现单模式治疗中通常观察到的毒性有明显恶化。这种联合方法增强了局部和全身的T细胞活化，提示存在抗肿瘤免疫。早期临床结果，包括生化和活检数据，都非常有前景。这些结果表明，在局部前列腺癌的治疗中，将原位基因治疗与放疗相结合可提高治疗效果。联合方法通过放射基因治疗诱导的细胞毒性和抗肿瘤免疫，在局部区域和全身最大程度地实现了肿瘤控制。
