Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter
Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter
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DOI：
10.1016/j.ymthe.2004.08.023
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发表时间：
2004-12-01
影响因子：
12.4
通讯作者：
Niitsu, Y
中科院分区：
文献类型：
--
作者：
Sagawa, T;Takahashi, M;Niitsu, Y
肝脏是结肠癌转移的首选部位。在本研究中，我们构建了一种自我复制的腺病毒，其中EIIA由CEA启动子驱动，E1 B-55 K从E1 B区域缺失（AdCEAp/Rep），并在小鼠异种移植模型中研究了其对人结肠癌细胞多处转移的影响。我们首先在各种CEA产生的人结肠癌细胞（M7609，HT-29）中显示了病毒的有效复制，随后在体外裂解了感染的细胞。然后，我们证明了单次瘤内注射病毒（1 × 10（8）PFU/100穆尔）可诱导接种到裸鼠体内的皮下肿瘤（M7609）完全消退。此外，我们证明了通过尾静脉向裸鼠全身给予病毒（1 × 10（8）PFU/100穆尔）有效地抑制了转移的形成，所述裸鼠在1周前已经通过脾脏接种了肿瘤细胞（结肠癌细胞系HT-29），并且在肝脏中显示出明显的多个转移。治疗组小鼠的平均存活时间明显长于对照组。因此，AdCEAp/Rep的全身施用被认为对异种移植物模型中CEA阳性结肠癌的多个肝转移有效。
Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which EIIA is driven by a CEA promoter and E1B-55K is deleted from the E1B region (AdCEAp/Rep) and examined its effects on multiple metastases of a human colon cancer cell in a mouse xenograft model. We first showed effective replication of the virus in various CEA-producing human colon cancer cells (M7609, HT-29) and subsequent lysis of the infected cells in vitro. We then demonstrated that a single intratumoral injection of the virus (1 x 10(8) PFU/100 mul) induced a complete regression of subcutaneous tumors (M7609) inoculated into nude mice. Further, we demonstrated that systemic administration of the virus (1 x 10(8) PFU/100 mul) through the tail vein to nude mice, which 1 week prior had been inoculated with tumor cells (colon carcinoma cell line HT-29) via the spleen and showed apparent multiple metastases in the liver, effectively suppressed the metastasis formation. The mean survival time of the treated mice was significantly longer than that of the controls. Thus, the systemic administration of AdCEAp/Rep was considered to be effective on multiple liver metastases of CEA-positive colon cancer in a xenograft model.