Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization
Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization
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DOI：
10.1089/10430340050016166
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发表时间：
2000-01-01
影响因子：
4.2
通讯作者：
Freytag, SO
中科院分区：
文献类型：
--
作者：
Rogulski, KR;Wing, MS;Freytag, SO
复制型腺病毒可以提供一种高效的手段，将治疗基因传递到肿瘤。以前，我们在体外评估了一个复制型腺病毒（AdS-CD/TKrep）含有胞嘧啶脱氨酶（CD）/单纯疱疹病毒1型胸苷激酶（HSV-1 TK）融合基因，允许裂解病毒治疗结合双自杀基因治疗。CD/5-FC和HSV-1 TK/GCV酶/前药系统均增强了AdS-CD/TKrep病毒在体外的肿瘤细胞特异性细胞病变效应，并使细胞对辐射敏感。为了在体内扩展这些体外发现，我们评估了Ad 5-CD/TKrep病毒与双前药疗法和放射疗法组合的抗肿瘤活性。Ad 5-CD/TKrep病毒对C33 A宫颈癌异种移植物独立地表现出显著的抗肿瘤活性。治疗结果显着改善与全身性管理的双重，而不是单一的，前体药物（5-FC + GCV）治疗。当用于新辅助治疗时，Ad 5-CD/TKrep介导的双自杀基因治疗显著增强了放射治疗的有效性。Ad 5-CD/TKrep病毒、双自杀基因和放射治疗的三模式方法产生了显著的肿瘤消退，最终100%的肿瘤治愈。这些结果表明了三模式方法的高治疗潜力，并为未来的临床试验提供了坚实的基础。
Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (AdS-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the AdS-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials.