Blasberg R G, Tjuvajev J G
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021-6007, USA.
Q J Nucl Med. 1999 Jun;43(2):163-9.
Imaging transgene expression with radiopharmaceuticals is feasible and has been demonstrated with a gamma camera and by positron emission tomography (PET) in experimental animals. An important consideration in the development of the imaging paradigm was the selection of an appropriate transgene and radiopharmaceutical. The herpes simplex virus thymidine kinase gene (HSV1-tk) was selected as an example of a "marker gene", and radiolabeled 5-iodo-2'-fluoro-2'deoxy-1-beta-D-arabino-furanosyl-uracil (FIAU) was shown to be a substantially better "marker substrate" for the HSV1-TK enzyme than other nucleoside analogues, including radiolabeled ganciclovir and acyclovir. The magnitude of FIAU accumulation in different HSV1-tk transduced cell lines and in tumors derived from these cell lines, was highly correlated with independent measures of HSV1-tk expression; namely, to the level of HSV1-tk mRNA in the corresponding cell lines and to their level of sensitivity to the antiviral drug, ganciclovir. We have demonstrated for the first time that highly specific non-invasive images of HSV1-tk expression in experimental animal tumors can be obtained using radiolabeled FIAU and a clinical gamma camera or a PET system. Given the level of FIAU accumulation in the transduced tumors, it is likely that a clinically applicable method for imaging HSV1-tk gene expression can be implemented using existing clinical imaging techniques. Our results point towards the potential for a wider application of HSV1-tk as a "marker" gene for "indirect" imaging of other therapeutic transgenes. The use of multi-gene vector constructs, where imaging a "marker gene" can be used to assess the level of "therapeutic gene" expression, will be increasingly developed over the next decade. The ability to image the location (distribution) and the level of transgene expression over time will provide new and useful information for monitoring clinical gene therapy protocols in the future.
利用放射性药物对转基因表达进行成像具有可行性，并且已在实验动物中通过γ相机和正电子发射断层扫描（PET）得到证实。成像模式开发中的一个重要考虑因素是选择合适的转基因和放射性药物。单纯疱疹病毒胸苷激酶基因（HSV1-tk）被选作“标记基因”的一个例子，并且放射性标记的5-碘-2'-氟-2'-脱氧-1-β-D-阿拉伯呋喃糖基尿嘧啶（FIAU）被证明是HSV1-TK酶比其他核苷类似物（包括放射性标记的更昔洛韦和阿昔洛韦）更好的“标记底物”。FIAU在不同的HSV1-tk转导细胞系以及源自这些细胞系的肿瘤中的积累量，与HSV1-tk表达的独立测量值高度相关；也就是说，与相应细胞系中HSV1-tk mRNA的水平以及它们对抗病毒药物更昔洛韦的敏感程度相关。我们首次证明，使用放射性标记的FIAU和临床γ相机或PET系统，可以在实验动物肿瘤中获得HSV1-tk表达的高度特异性无创图像。鉴于转导肿瘤中FIAU的积累水平，很可能可以利用现有的临床成像技术实现一种临床上适用的HSV1-tk基因表达成像方法。我们的结果表明HSV1-tk作为其他治疗性转基因“间接”成像的“标记”基因有更广泛应用的潜力。在未来十年中，将越来越多地开发使用多基因载体构建体，其中对“标记基因”成像可用于评估“治疗基因”的表达水平。随着时间推移对转基因表达的位置（分布）和水平进行成像的能力，将为未来监测临床基因治疗方案提供新的有用信息。
