Fu De-Xue, Tanhehco Yvette, Chen Jianmeng, Foss Catherine A, Fox James J, Chong Ja-Mun, Hobbs Robert F, Fukayama Masashi, Sgouros George, Kowalski Jeanne, Pomper Martin G, Ambinder Richard F
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
Nat Med. 2008 Oct;14(10):1118-22. doi: 10.1038/nm.1864. Epub 2008 Sep 7.
We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.
我们研究了使用一种药物制剂调节病毒基因表达，从而将放射治疗靶向肿瘤组织的可能性。在小鼠异种移植模型中，我们之前已证明[(125)I]2'-氟-2'-脱氧-β-D-5-碘尿嘧啶阿拉伯呋喃糖苷([(125)I]FIAU)可靶向工程改造为表达爱泼斯坦-巴尔病毒胸苷激酶(EBV-TK)的肿瘤。在此，我们将这些结果扩展至将治疗性放射性药物[(131)I]FIAU靶向以减缓或停止肿瘤生长或实现肿瘤消退。在组成性表达EBV-TK的肿瘤异种移植中实现了这些结果。对于天然感染EBV的肿瘤细胞系（伯基特淋巴瘤和胃癌），需要通过硼替佐米预处理激活病毒基因表达。在用硼替佐米预处理后，天然感染卡波西肉瘤疱疹病毒的肿瘤的肿瘤生长也可发生显著变化。硼替佐米诱导的酶靶向放射治疗说明了通过药理学调节肿瘤基因表达以实现靶向放射治疗的可能性。
