Tjuvajev J G, Finn R, Watanabe K, Joshi R, Oku T, Kennedy J, Beattie B, Koutcher J, Larson S, Blasberg R G
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York New York 10021, USA.
Cancer Res. 1996 Sep 15;56(18):4087-95.
Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using 131I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodo-uracil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-type RG2 glioma or W256 mammary carcinoma cells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had been transduced in vitro with the HSV1-tk gene) into the opposite flank. In some animals, HSV1-tk gene transduction of the pre-established wild-type tumors was accomplished in vivo by direct intratumoral injection of retroviral vector-producer cells. Imaging studies were performed 2 weeks after tumor transduction to allow time for production and spread of the retroviruses through the tumor and for sufficient growth and increase in size of the tumors to facilitate imaging. The gamma camera and SPECT images revealed highly specific localization of [131I]FIAU-derived radioactivity to areas of HSV1-tk gene expression at 24, 36, and 48 h after i.v. administration of 1.6-2.8 mCi of [131I]FIAU. Comparative analysis of quantitative autoradiographic images obtained from the same tumors confirmed that the high levels of [131I]FIAU-derived radioactivity (> 1% dose) were localized to areas of HSV1-tk gene expression demonstrated by immunohistochemical staining for HSV1-tk protein. In contrast, significantly lower levels of [131I]FIAU-derived radioactivity (< 0.01%) were observed in the surrounding nontransduced tumor tissue, contralateral wild-type tumors, and other tissues that showed no immunohistochemical staining for the HSV1-tk protein. The magnitude of FIAU accumulation in RG2TK+, W256TK+, and wild-type tumors corresponded to the in vitro ganciclovir sensitivity of the cell lines used to produce these tumors, which indicates that the magnitude of FIAU accumulation reflects the level of HSV1-tk gene expression. We suggest that "clinically relevant" levels of HSV1-tk gene expression in transfected tissue can be imaged with [131I]FIAU and a gamma camera or SPECT, and that a significant improvement in imaging sensitivity and resolution is expected with [124I]FIAU and PET.
利用临床γ相机和单光子发射断层扫描（SPECT），采用131I标记的2'-氟-2'-脱氧-1-β-D-阿拉伯呋喃糖基-5-碘尿嘧啶（FIAU），可对单纯疱疹病毒1型胸苷激酶（HSV1-tk）基因表达进行无创成像。在携带皮下肿瘤的大鼠身上进行了研究。通过将野生型RG2胶质瘤或W256乳腺癌细胞注射到一侧胁腹，将RG2TK+胶质瘤或W256TK+乳腺癌细胞（已在体外转导HSV1-tk基因）注射到对侧胁腹来产生肿瘤。在一些动物中，通过向预先建立的野生型肿瘤内直接注射逆转录病毒载体产生细胞，在体内完成HSV1-tk基因转导。在肿瘤转导后2周进行成像研究，以便有时间让逆转录病毒在肿瘤中产生和扩散，以及让肿瘤充分生长和增大以利于成像。γ相机和SPECT图像显示，在静脉注射1.6 - 2.8 mCi的[131I]FIAU后24、36和48小时，[131I]FIAU衍生的放射性高度特异性地定位于HSV1-tk基因表达区域。对从相同肿瘤获得的定量放射自显影图像的比较分析证实，高水平的[131I]FIAU衍生放射性（>1%剂量）定位于通过HSV1-tk蛋白免疫组织化学染色显示的HSV1-tk基因表达区域。相比之下，在周围未转导的肿瘤组织、对侧野生型肿瘤以及其他未显示HSV1-tk蛋白免疫组织化学染色的组织中，观察到[131I]FIAU衍生放射性水平显著较低（<0.01%）。FIAU在RG2TK+、W256TK+和野生型肿瘤中的积累程度与用于产生这些肿瘤的细胞系的体外更昔洛韦敏感性相对应，这表明FIAU积累程度反映了HSV1-tk基因表达水平。我们认为，转染组织中“临床相关”水平的HSV1-tk基因表达可用[131I]FIAU和γ相机或SPECT进行成像，并且预计使用[124I]FIAU和PET可显著提高成像灵敏度和分辨率。
