In Vivo Biological Purging for Lymph Node Metastasis of Human Colorectal Cancer by Telomerase-Specific Oncolytic Virotherapy
In Vivo Biological Purging for Lymph Node Metastasis of Human Colorectal Cancer by Telomerase-Specific Oncolytic Virotherapy
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DOI：
10.1097/sla.0b013e3181deb69d
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发表时间：
2010-06-01
影响因子：
9
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Kojima, Toru;Watanabe, Yuichi;Fujiwara, Toshiyoshi
背景/目的：本研究的目的是开发一种微创的靶向淋巴结转移的方法来治疗人胃肠道肿瘤。淋巴道浸润是癌细胞播散的主要途径，局部淋巴结的充分治疗是恶性肿瘤患者根治性治疗的必要条件。方法：人端粒酶逆转录酶（Human telomerase reverse transcription，hTERT）是端粒酶的催化亚单位，在癌细胞中高度活跃，而在大多数正常体细胞中处于静止状态。OBP-301（端粒溶素）是具有溶瘤效力的减毒腺病毒，其含有hTERT启动子元件以调节病毒复制。我们检查是否OBP-301注射到原发肿瘤可能是有用的清除局部淋巴结的微转移在原位结直肠癌model.Results：OBP-301被intratumorously注射到HT 29肿瘤orthotopically植入到BALB/c nu/nu小鼠的直肠。通过使用针对人类特异性Alu序列的高灵敏度定量PCR分析，我们发现OBP-301导致病毒扩散到区域淋巴区，并在肿瘤病变中选择性复制，导致转移性淋巴结中肿瘤细胞特异性死亡。此外，虽然手术切除原发性肿瘤增加了淋巴结转移的趋势，术前瘤内注射病毒显着降低淋巴结transferation.Conclusions：我们的研究结果表明，瘤内注射OBP-301介导有效的在体内清除转移性肿瘤细胞从区域淋巴结，这可能有助于优化治疗人类癌症，特别是胃肠道恶性肿瘤。
Background/Objective: The aim of this study was to develop a less invasive way of targeting lymph node metastasis for the treatment of human gastrointestinal cancer. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with malignancies.Methods: Human telomerase reverse transcription (hTERT) is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. OBP-301 (Telomelysin) is an attenuated adenovirus with oncolytic potency that contains the hTERT promoter element to regulate viral replication. We examined whether OBP-301 injected into the primary tumor might be useful for purging micrometastasis from regional lymph nodes in an orthotopic colorectal cancer model.Results: OBP-301 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice. By using a highly sensitive quantitative PCR analysis that targets the human-specific Alu sequence, we showed that OBP-301 caused viral spread into the regional lymphatic area and selectively replicated in neoplastic lesions, resulting in tumor-cell-specific death in metastatic lymph nodes. Moreover, although the surgical removal of primary tumors increased the tendency of lymph node metastasis, preoperative intratumoral injection of virus significantly reduced lymph node metastasis.Conclusions: Our results indicate that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human cancer, especially gastrointestinal malignancies.