Eastham J A, Chen S H, Sehgal I, Yang G, Timme T L, Hall S J, Woo S L, Thompson T C
Matsunaga-Conte Prostate Cancer Research Center, Houston, TX, USA.
Hum Gene Ther. 1996 Mar 1;7(4):515-23. doi: 10.1089/hum.1996.7.4-515.
Prostate cancer is the most common internal malignancy in men in the United States. Most cancers are diagnosed when they are locally advanced or metastatic and there is no effective treatment. In this study we evaluated the effectiveness of cytotoxic gene therapy in human PC-3 and DU145 prostate cancer cell lines and in a rodent cell line, RM-1, derived from the mouse prostate reconstitution model system. The cell lines were efficiently transduced in vitro by a replicative-defective recombinant adenovirus (ADV) carrying the herpes simplex virus thymidine kinase gene (HSV-tk). A virus titer-dependent sensitivity to ganciclovir (GCV) was observed. To determine a target therapeutic viral dose in vivo, subcutaneous tumors were generated by injection of RM-1 cells in syngeneic male hosts and injected with escalating doses of HSV-tk virus (5 x 10(7) to 1 x 10(9) pfu). The mice received GCV twice daily for 6 days and were sacrificed when tumor volumes exceeded 2.5 cm3 or when they appeared to be in distress. Because the two highest doses were equally as effective, further controlled studies were performed with the lower dose of 5 x 10(8) pfu with ADV/RSV-tk or a control virus containing the beta-galactosidase gene (ADV/RSV-beta-Gal) and treated with GCV or saline (PBS). The mean tumor volume in the treated animals was 16% that of control animals at 13 days. Histologically, treated tumors demonstrated necrosis and had a significantly higher apoptotic index. Survival data indicated that the treatment animals lived 7 days (21 in total) longer than the control animals, with 1 treatment animal being totally free of tumor. These results demonstrate that HSV-tk + GCV cytotoxic gene therapy can inhibit the growth of mouse and human prostate cancer cells in vitro and interrupt tumor growth of an aggressive mouse prostate cancer cell line in vivo.
前列腺癌是美国男性中最常见的内部恶性肿瘤。大多数癌症在局部进展或转移时才被诊断出来，且没有有效的治疗方法。在本研究中，我们评估了细胞毒性基因疗法对人PC-3和DU145前列腺癌细胞系以及源自小鼠前列腺重建模型系统的啮齿动物细胞系RM-1的有效性。这些细胞系在体外被携带单纯疱疹病毒胸苷激酶基因（HSV-tk）的复制缺陷型重组腺病毒（ADV）有效转导。观察到对更昔洛韦（GCV）的病毒滴度依赖性敏感性。为了确定体内的目标治疗病毒剂量，通过在同基因雄性宿主中注射RM-1细胞产生皮下肿瘤，并注射递增剂量的HSV-tk病毒（5×10⁷至1×10⁹ pfu）。小鼠每天接受两次GCV，共6天，当肿瘤体积超过2.5 cm³或出现痛苦症状时处死。由于两个最高剂量同样有效，因此对较低剂量5×10⁸ pfu的ADV/RSV-tk或含有β-半乳糖苷酶基因的对照病毒（ADV/RSV-β-Gal）进行了进一步的对照研究，并用GCV或生理盐水（PBS）处理。在第13天时，治疗动物的平均肿瘤体积是对照动物的16%。组织学上，治疗后的肿瘤显示出坏死，且凋亡指数显著更高。生存数据表明，治疗动物比对照动物多活了7天（总共21天），有1只治疗动物完全没有肿瘤。这些结果表明，HSV-tk + GCV细胞毒性基因疗法在体外可抑制小鼠和人前列腺癌细胞的生长，并在体内阻断侵袭性小鼠前列腺癌细胞系的肿瘤生长。
