Telomerase-Specific Virotheranostics for Human Head and Neck Cancer
Telomerase-Specific Virotheranostics for Human Head and Neck Cancer
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DOI：
10.1158/1078-0432.ccr-08-2690
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发表时间：
2009-04-01
影响因子：
11.5
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Kurihara, Yuji;Watanabe, Yuichi;Fujiwara, Toshiyoshi
目的：头颈部鳞状细胞癌（SCCHN）患者的长期预后仍然不令人满意，尽管在联合治疗方式的进步。SCCHN的特点是局部扩散，它是临床上可及的，使其成为一个有吸引力的目标，肿瘤内的生物therapy.Experimental设计：OBP-301是一种5型腺病毒，其中含有复制盒，人端粒酶逆转录酶启动子驱动E1基因的表达。OBP-401含有复制盒和绿色荧光蛋白（GFP）基因。通过30-[1-（苯氨基羰基）-3，4-四唑]-双（4-甲氧基-6-硝基）苯磺酸钠水合物测定法在体外和原位异种移植模型中评价了OBP-301的抗肿瘤作用。结果：瘤内注射OBP-301可使原位移植于BALB/c nu/nu小鼠舌内的人SCCHN肿瘤缩小，并可通过口服恢复体重。OBP-401体外感染后GFP表达水平可能作为端粒酶特异性病毒治疗结果的阳性预测标志物。此外，全身荧光成像显示，肿瘤内注射OBP-401可以使转移淋巴结可视化，表明病毒能够运输到区域淋巴区并在肿瘤病变中选择性复制，导致转移淋巴结中的GFP表达和细胞死亡。这些结果说明了端粒酶特异性溶瘤病毒作为一种新的治疗和诊断方法的潜力，称为治疗诊断学，用于人类SCCHN。
Purpose: Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies.Experimental Design: OBP-301 is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl) -3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401.Results: Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 Could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes.Conclusions: These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.