Mitrofanova Elena, Unfer Robert, Vahanian Nick, Daniels Wayne, Roberson Erica, Seregina Tatiana, Seth Prem, Link Charles
Iowa Cancer Research Foundation, Des Moines, Iowa, USA.
Clin Cancer Res. 2004 Oct 15;10(20):6969-76. doi: 10.1158/1078-0432.CCR-04-0687.
Design and development of new approaches for targeted radiotherapy of cancer and improvement of therapeutic index by more local radiation therapy are very important issues. Adenovirus-mediated delivery of the sodium iodide symporter (NIS) gene to cancer cells is a powerful technique to concentrate lethal radiation in tumor cells and eradicate tumors with increased therapeutic index. A replication-defective adenoviral vector expressing the rat NIS gene (Ad-rNIS) was used for in vitro gene delivery and into human prostate cancer xenografts to study antitumor effect. Robust function of the rat symporter was detected in DU145, T47D, and HCT-15 human cancer cell lines transduced with Ad-rNIS. All three cancer cell lines successfully transferred functionally active rat symporter to the plasma membrane, resulting in very high levels of iodine-125 accumulation. Three-dimensional multicellular tumor spheroids derived from DU145 human prostate cancer cells were transduced with Ad-rNIS and incubated with (131)I for 24 hours. After treatment, spheroids rapidly decreased in size and disappeared within 10 days. In vivo data revealed an inhibition of tumor growth in athymic nude mice after intratumoral Ad-rNIS injection followed by (131)I administration. Eighty-eight percent of experimental mice survived >30 days, whereas control groups had only 18% survival >30 days. This is the first report that demonstrates the rat NIS gene can effectively induce growth arrest of human tumor xenografts after in vivo adenoviral gene delivery and (131)I administration. The data confirm our hypothesis that the rat NIS gene is an attractive suicide gene candidate for cancer treatment.
设计和开发癌症靶向放射治疗的新方法以及通过更局部的放射治疗提高治疗指数是非常重要的问题。腺病毒介导的碘化钠同向转运体（NIS）基因递送至癌细胞是一种强大的技术，可将致死性辐射集中在肿瘤细胞中，并以提高的治疗指数根除肿瘤。一种表达大鼠NIS基因的复制缺陷型腺病毒载体（Ad-rNIS）用于体外基因递送并导入人前列腺癌异种移植物中以研究抗肿瘤作用。在用Ad-rNIS转导的DU145、T47D和HCT-15人癌细胞系中检测到大鼠同向转运体的强大功能。所有这三种癌细胞系均成功地将功能活跃的大鼠同向转运体转移至质膜，导致非常高水平的碘-125积累。用Ad-rNIS转导源自DU145人前列腺癌细胞的三维多细胞肿瘤球体，并与（131）I孵育24小时。处理后，球体大小迅速减小并在10天内消失。体内数据显示，在瘤内注射Ad-rNIS后再给予（131）I，无胸腺裸鼠的肿瘤生长受到抑制。88%的实验小鼠存活超过30天，而对照组存活超过30天的仅为18%。这是第一份证明大鼠NIS基因在体内腺病毒基因递送和（131）I给药后可有效诱导人肿瘤异种移植物生长停滞的报告。这些数据证实了我们的假设，即大鼠NIS基因是一种有吸引力的癌症治疗自杀基因候选物。
