Combination with low-dose gemcitabine and hTERT-promoter-dependent conditionally replicative adenovirus enhances cytotoxicity through their crosstalk mechanisms in pancreatic cancer.
To overcome the limited clinical efficacy of conditionally replicative adenoviruses (CRAds), we investigated the effects of combination therapy with gemcitabine (GEM) and the hTERT-promoter-dependent CRAd (hTERT-CRAd), Ad5/3hTERTE1. This combination therapy exhibited enhanced cytotoxic effects on pancreatic cancer both in vitro and in vivo. Furthermore, we revealed that this enhancement effect was due to the multiple bidirectional interactions between hTERT-CRAd and GEM. The GEM-sensitizing effect of E1 expression derived from hTERT-CRAd, and the enhancement effect by GEM on hTERT promoter activity which led to the increase of adenovirus E1 and viral infectivity. This combination therapy may be a promising therapeutic approach for pancreatic cancer.
Onimaru
Manabu
M
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan.
Ohuchida
Kenoki
K
Nagai
Eishi
E
Mizumoto
Kazuhiro
K
Egami
Takuya
T
Cui
Lin
L
Sato
Norihiro
N
Uchino
Junji
J
Takayama
Koichi
K
Hashizume
Makoto
M
Tanaka
Masao
M
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014162:Transfection; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D017500:Adenovirus E1A Proteins; D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D003841:Deoxycytidine; C509186:TERT protein, human; D019098:Telomerase; D000093542:Gemcitabine