Hanna N N, Mauceri H J, Wayne J D, Hallahan D E, Kufe D W, Weichselbaum R R
Department of Surgery, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA.
Cancer Res. 1997 Oct 1;57(19):4205-9.
Gene therapy combined with radiation therapy to enhance selectively radiation cytotoxicity in malignant cells represents a new approach for cancer treatment. We investigated the efficacy of adenoviral (Ad5)-directed cytosine deaminase/5-fluorocytosine (CD/5-FC) enzyme/prodrug gene therapy to enhance selectively the tumoricidal action of ionizing radiation in human cancer xenografts derived from a human squamous carcinoma cell line (SQ-20B). Tumor xenografts grown in hindlimbs of nude mice were transfected with an adenoviral vector (Ad.CMV.CD) containing the cytosine deaminase (CD) gene under the control of a cytomegalovirus (CMV) promoter. Mice were injected i.p. with 800 mg/kg of 5-FC for 12 days, and tumors were treated with fractionated radiation at a dose of 5 Gy/day to a total dose of 50 Gy. In larger tumors with a mean volume of 1069 mm3, marked tumor regression to 11% of the original tumor volume was observed at day 21 (P = 0.01). The volumetric regression of smaller tumors with a mean volume of 199 mm3, which received the same combined treatment protocol, was significant at day 12 (P = 0.014). However, unlike large tumors, regression of the smaller tumors continued until day 36 (P = 0.01), with 43% cured at day 26. No cures or significant volumetric reduction in size was observed in tumors treated with radiation alone; Ad.CMV.CD with or without radiation; or with Ad.CMV.CD and 5-FC. These results suggest that the CD/5-FC gene therapy approach is an effective radiosensitizing strategy and may lead to substantial improvement in local tumor control that would translate into improved cure rates and better survival.
基因治疗联合放射治疗以增强恶性细胞对辐射的选择性细胞毒性是一种癌症治疗的新方法。我们研究了腺病毒（Ad5）介导的胞嘧啶脱氨酶/5-氟胞嘧啶（CD/5-FC）酶/前药基因治疗在源自人鳞状癌细胞系（SQ-20B）的人癌异种移植模型中选择性增强电离辐射杀瘤作用的疗效。将生长于裸鼠后肢的肿瘤异种移植瘤用含有在巨细胞病毒（CMV）启动子控制下的胞嘧啶脱氨酶（CD）基因的腺病毒载体（Ad.CMV.CD）进行转染。小鼠腹腔注射800 mg/kg的5-FC，持续12天，肿瘤接受分割放疗，剂量为5 Gy/天，总剂量为50 Gy。在平均体积为1069 mm3的较大肿瘤中，在第21天观察到肿瘤显著消退至原始肿瘤体积的11%（P = 0.01）。接受相同联合治疗方案的平均体积为199 mm3的较小肿瘤，在第12天体积消退显著（P = 0.014）。然而，与大肿瘤不同，较小肿瘤的消退一直持续到第36天（P = 0.01），在第26天有43%的肿瘤被治愈。单独接受放疗的肿瘤；接受Ad.CMV.CD单独或联合放疗的肿瘤；或接受Ad.CMV.CD和5-FC治疗的肿瘤均未观察到治愈或显著的体积缩小。这些结果表明，CD/5-FC基因治疗方法是一种有效的放射增敏策略，可能会显著改善局部肿瘤控制，从而提高治愈率和生存率。
