Adenovirus vector covalently conjugated to polyethylene glycol with a cancer-specific promoter suppresses the tumor growth through systemic administration.
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 Adv 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 Adv with suitable efficacy and safety for systemic cancer gene therapy against both metastatic and primary tumors.
Yao
Xinglei
X
Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Yoshioka
Yasuo
Y
Morishige
Tomohiro
T
Eto
Yusuke
Y
Narimatsu
Shogo
S
Mizuguchi
Hiroyuki
H
Mukai
Yohei
Y
Okada
Naoki
N
Nakagawa
Shinsaku
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002277:Carcinoma / Q000628:therapy; D003110:Colonic Neoplasms / Q000628:therapy; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics / Q000627:therapeutic use; D019076:Transgenes
D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D008156:Luciferases; D013937:Thymidine Kinase; D019098:Telomerase