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.
Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Xinglei
X
Yao
Yasuo
Y
Yoshioka
Tomohiro
T
Morishige
Yusuke
Y
Eto
Shogo
S
Narimatsu
Hiroyuki
H
Mizuguchi
Yohei
Y
Mukai
Naoki
N
Okada
Shinsaku
S
Nakagawa
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