Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters.
Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters.
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DOI：
10.1038/cgt.2014.13
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发表时间：
2014-04
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
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针对溶瘤腺病毒（Ad）载体的免疫应答被认为限制了载体抗肿瘤功效。在具有免疫活性并且其肿瘤和正常组织允许基于Ad 5的溶瘤Ad载体复制的叙利亚仓鼠中，用高剂量环磷酰胺治疗以抑制免疫系统并发挥化疗作用增强Ad载体抗肿瘤功效。然而，长期环磷酰胺治疗和免疫抑制可导致贫血和载体扩散到正常组织。在这里，我们采用了三个周期的短暂高剂量环磷酰胺给药加上肿瘤内注射溶瘤Ad载体VRX-007，然后从环磷酰胺中撤出。每个周期持续4-6周。该方案允许仓鼠保持健康，因此研究可持续约100天。在整个研究过程中，肿瘤得到了很好的抑制。对于免疫活性仓鼠，载体最初延缓肿瘤生长，但3-4周后肿瘤恢复快速生长，进一步注射载体无效。用Ad 5预免疫仓鼠防止了载体从肿瘤溢出到肝脏，但仍然允许有效的长期抗肿瘤功效。我们的研究结果表明，可能会开发一种临床方案，采用短暂化疗加瘤内载体注射的周期，以达到显着的抗肿瘤疗效，同时最大限度地减少细胞抑制治疗的副作用。
Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. In Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long term cyclophosphamide treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here we employed three cycles of transient high-dose cyclophosphamide administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal from cyclophosphamide. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment.
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影响因子：
5.4
作者：
Dhar, Debanjan;Spencer, Jacqueline F.;Wold, William S. M.
通讯作者：
Wold, William S. M.
影响因子：
11.5
作者：
Qiao, Jian;Wang, Hongxun;Harrington, Kevin
通讯作者：
Harrington, Kevin
影响因子：
12.4
作者：
Lamfers, Martine L. M.;Fulci, Giulia;Chiocca, E. Antonio
通讯作者：
Chiocca, E. Antonio
DOI：
10.1038/mt.2008.162
发表时间：
2008-10
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
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影响因子：
12.4
作者：
Koski, Anniina;Kangasniemi, Lotta;Hemminki, Akseli
通讯作者：
Hemminki, Akseli