Adenovirus Vector Covalently Conjugated to Polyethylene Glycol with a Cancer-Specific Promoter Suppresses the Tumor Growth through Systemic Administration

作者：Yao Xinglei; Yoshioka Yasuo^*; Morishige Tomohiro; Eto Yusuke; Narimatsu Shogo; Mizugguchi Hiroyuki; Mukai Yohei; Okada Naoki; Nakagawa Shinsaku

来源：Biological & Pharmaceutical Bulletin, 2010, 33(6): 1073-1076.

• bioconjugation
• gene therapy
• polymer

Cancer gene therapy with adenovirus vectors (Adv) is limited to local administration because systemic administration of Adv produces a weak therapeutic effect and severe side effects. Previously, we generated a dual cancer-specific Ads' system by using Adv covalently conjugated to polyethylene glycol (PEG) for transductional targeting and the telomere reverse transcriptase (TERT) promoter as a cancer-specific promoter for transcriptional targeting (PEG-Ad-TERT). We demonstrated that systemic administration of PEG-Ad-TERT showed superior antitumor effects against lung metastatic cancer with negligible side effects. Here, we investigated the therapeutic efficacy of systemic administration of PEG-Ad-TERT for the treatment of primary tumors. We first evaluated the transgene expression of PEG-Ad-TERT containing the luciferase gene (PEG-Ad-TERT/Luc) in primary tumors. Systemic administration of PEG-Ad-TERT/Luc resulted high transgene expression, similar to that observed in tumors for the conventional cytomegalovirus (CMV) promoter-driven Adv containing the luciferase gene (Ad-CMV/Luc). By comparison, transgene expression was 2500-fold lower than that of Ad-CMV/Luc in liver. We then examined the therapeutic effect of systemic administration of PEG-Ad-TERT containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/HSVtk) for the treatment of primary tumors. We showed that PEG-Ad-TERT/HSVtk produced a notable antitumor effect against primary tumors with negligible side effects. These results demonstrated that PEG-Ad-TERT can be regarded as a prototype Ads' with suitable efficacy and safety for systemic cancer gene therapy against both metastatic and primary tumors.

• 出版日期2010-6