Sagawa Tamotsu, Takahashi Minoru, Sato Tsutomu, Sato Yasushi, Lu Yue, Sumiyoshi Tetsuya, Yamada Yasuyuki, Iyama Satoshi, Fukaura Junki, Sasaki Katsunori, Hamada Hirofumi, Miyanishi Koji, Takayama Tetsuji, Kato Junji, Niitsu Yoshiro
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
Mol Ther. 2004 Dec;10(6):1043-50. doi: 10.1016/j.ymthe.2004.08.023.
Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which E1A 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 microl) 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 microl) 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.
肝脏是结肠癌转移的最优先部位。在本研究中，我们构建了一种自我复制的腺病毒，其中E1A由癌胚抗原（CEA）启动子驱动，E1B区域缺失E1B - 55K（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。我们首先证明了该病毒在各种产生CEA的人结肠癌细胞（M7609、HT - 29）中有效复制，并随后在体外裂解了被感染的细胞。然后我们证明，向裸鼠瘤内单次注射该病毒（1×10⁸ PFU/100微升）可使接种到裸鼠体内的皮下肿瘤（M7609）完全消退。此外，我们证明，通过尾静脉向裸鼠全身给药该病毒（1×10⁸ PFU/100微升），这些裸鼠在1周前已通过脾脏接种肿瘤细胞（结肠癌细胞系HT - 29）并在肝脏中出现明显的多处转移，能有效抑制转移灶的形成。治疗组小鼠的平均生存时间显著长于对照组。因此，在异种移植模型中，AdCEAp/Rep全身给药被认为对CEA阳性结肠癌的多处肝转移有效。
