Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model
Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model
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DOI：
10.1038/cgt.2008.3
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发表时间：
2008-05-01
影响因子：
6.4
通讯作者：
Kumon, H.
中科院分区：
文献类型：
--
作者：
Huang, P.;Watanabe, M.;Kumon, H.
我们之前构建了OBP-301（端粒酶特异性复制能力腺病毒，带有人端粒酶逆转录酶启动子），通过诱导人非小细胞肺癌和结直肠癌细胞的细胞裂解，显示出很强的抗癌作用。为了研究OBP-301在前列腺癌治疗中的效用，我们在此评估了OBP-301的细胞杀伤和抗肿瘤作用。首先，利用OBP-401（端粒溶素绿色荧光蛋白（GFP））证实了体外htert特异性腺病毒在人前列腺癌细胞（LNCaP、PC3、DU145）中的转导作用。在人前列腺正常细胞（PrEC, PrSC）中未检测到GFP转导。与此一致的是，OBP-301的细胞杀伤作用仅在癌细胞中观察到。其次，使用裸鼠体内皮下LNCaP肿瘤模型，我们证明三次瘤内OBP-301注射（每个肿瘤10(7)PFU x 3天）足以根除可检测到的LNCaP前列腺肿瘤。我们还证明，在肿瘤模型的两侧，用OBP-301治疗可显著抑制对侧LNCaP肿瘤的生长。组织学和免疫组织化学分析显示肿瘤两侧弥漫性溶瘤变性和腺病毒E1A蛋白表达。因此，原位给药OBP-301可能是一种很有前途的治疗前列腺癌及其转移性病变的策略。
We previously constructed OBP-301 ( Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase ( hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells ( LNCaP, PC3, DU145) was confirmed using OBP-401 ( Telomelysin-green fluorescent protein ( GFP)). There was no detectable GFP transduction in the human prostate normal cells ( PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections ( 10(7) PFU per tumor x 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.