Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen
Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen
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DOI：
10.1158/0008-5472.can-03-3431
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发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Tanabe, KK
中科院分区：
文献类型：
--
作者：
Kasuya, H;Pawlik, TM;Tanabe, KK
复制条件病毒在称为病毒溶瘤的过程中破坏肿瘤。这种癌症治疗策略的一个重要先决条件是使用优先在肿瘤细胞中复制的病毒。在这项研究中，DF 3/MUC 1启动子/增强子序列用于调节γ（1）34.5的表达，以驱动单纯疱疹病毒1型（HSV-1）突变体（DF 3 γ 34.5）优先在DF 3/MUC 1阳性细胞中复制。HSV-1 γ（1）34.5的功能是使延伸起始因子2 α去磷酸化，这是HSV-1稳健复制的重要步骤。DF 3 γ 34.5感染细胞后，在DF 3/MUC 1阳性细胞中优先观察到延伸起始因子2a磷酸酶活性和病毒复制，但在DF 3/MUC 1阴性细胞中未观察到。γ（1）34.5功能的调节导致在表达DF 3/MUC 1的癌细胞中优先复制，限制体内生物分布，以及如通过LD 50评估的较低毒性。在血管内灌注人肝标本后，在DF 3/MUC 1阳性肝肿瘤中观察到DF 3 γ 34.5的优先复制。DF 3 γ 34.5对裸鼠移植瘤有明显的抗肿瘤作用。通过DF 3/MUC 1启动子调节γ（1）34.5是开发用于病毒溶瘤的HSV-1突变体的有前景的策略。
Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of gamma(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2a phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD50. Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.