An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy
An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy
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DOI：
10.1038/nbt0598-444
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发表时间：
1998-05-01
影响因子：
46.9
通讯作者：
Chiocca, EA
中科院分区：
文献类型：
--
作者：
Chase, M;Chung, RY;Chiocca, EA
设计具有灭活病毒核糖核苷酸还原酶（Hsrr，ICP 6）的单纯疱疹病毒1型（HSV-1）以靶向具有上调的哺乳动物核糖核苷酸还原酶（mRR）的肿瘤细胞，所述mRR是一种其表达受p16/pRB肿瘤抑制途径调节的酶。通过敲除Hsrr并插入负责前药环磷酰胺和异环磷酰胺生物活化的大鼠CYP 2B 1转基因产生重组HSV-1。突变病毒在表达mRR的大鼠和人类肿瘤细胞中选择性复制。添加环磷酰胺可增强对培养的肿瘤细胞和在无胸腺小鼠中建立的皮下肿瘤异种移植物的溶瘤作用。
Herpes simplex viruses type 1 (HSV-1) with an inactivated viral ribonucleotide reductase (Hsrr, ICP6) were designed to target tumor cells with upregulated mammalian ribonucleotide reductase (mRR), an enzyme whose expression is regulated by the p16/pRB tumor suppressor pathway. A recombinant HSV-1 was generated by knock-out of Hsrr and insertion of the rat CYP2B1 transgene responsible for the bioactivation of the prodrugs, cyclophosphamide and ifosfamide. The mutant virus replicated selectively in rat and human tumor cells that express mRR. Addition of cyclophosphamide potentiated oncolytic effects against cultured tumor cells and subcutaneous tumor xenografts established in athymic mice.