Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, Kyo S, Kondo S
Center for Surgery Research, Cleveland Clinic Foundation, OH 44195, USA.
Hum Gene Ther. 2000 Jul 1;11(10):1397-406. doi: 10.1089/10430340050057477.
Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the ability to undergo apoptosis are promising for the treatment of tumor cells. We have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to explore a tumor-specific expression system of these genes. In the present study, we developed the telomerase-specific transfer system of apoptosis-inducible genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor-specific expression system of vectors. We demonstrate here that by using the hTERT promoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not seen in normal fibroblast cells without telomerase activity. Furthermore, treatment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construct inhibited tumor growth significantly because of induction of apoptosis (p < 0.01). The telomerase-specific expression of apoptosis-inducible genes afforded by the hTERT promoter, therefore, may be a novel and promising targeting approach for the treatment of tumors with telomerase activity.
细胞凋亡是一种由基因编码的细胞死亡过程，是一条可能在肿瘤细胞中被破坏的途径。因此，恢复细胞凋亡能力的疗法有望用于治疗肿瘤细胞。我们已经证明，诱导凋亡基因的转移通过诱导细胞凋亡在体外和体内抑制肿瘤生长。然而，为了将细胞凋亡的诱导限制在肿瘤细胞中，我们需要探索这些基因的肿瘤特异性表达系统。在本研究中，我们利用人端粒酶催化亚基（hTERT）基因的启动子，开发了诱导凋亡基因的端粒酶特异性转移系统。大约90%的肿瘤具有端粒酶活性，而大多数正常细胞不表达该活性。这些观察结果表明，端粒酶是载体肿瘤特异性表达系统特别有吸引力的靶点。我们在此证明，通过使用hTERT启动子驱动的半胱天冬酶-8表达载体（hTERT/半胱天冬酶-8），细胞凋亡被限制在广泛的端粒酶阳性肿瘤细胞中，而在没有端粒酶活性的正常成纤维细胞中未见。此外，用hTERT/半胱天冬酶-8构建体处理裸鼠皮下肿瘤，由于诱导细胞凋亡，显著抑制了肿瘤生长（p < 0.01）。因此，hTERT启动子提供的诱导凋亡基因的端粒酶特异性表达可能是一种用于治疗具有端粒酶活性肿瘤的新颖且有前景的靶向方法。
