Transthyretin-driven oncolytic adenovirus suppresses tumor growth in orthotopic and ascites models of hepatocellular carcinoma.
Strategies to increase antitumor efficacy of oncolytic adenoviruses are actively investigated. We have previously shown that E1B-55 kDa-deleted adenovirus, designated Ad5WS1, has therapeutic potential for treating hepatocellular carcinoma (HCC). To achieve HCC-restricted replication of oncolytic adenovirus, we generated Ad5WS2, an E1B-55 kDa-deleted adenovirus with its E1A gene driven by the liver-specific transthyretin promoter. Our results showed that Ad5WS2 could replicate within tumor cells where the transthyretin gene was expressed. Mouse transthyretin promoter was active in murine and human HCC cells, but relatively quiescent in cells of non-liver origin. Ad5WS2 caused severe cytolytic effect on HCC cells, but was much attenuated in non-HCC cells. Peritoneal administration of Ad5WS2 into mice bearing liver tumors grown in ascites resulted in enhanced survival. In an orthotopic HCC model, Ad5WS2, when systemically administered, exerted higher antitumor effects than Ad5WS1. Lack of viral replication in normal organs and minimal hepatic toxicity was noted after Ad5WS2 treatment. Furthermore, the antitumor effect of Ad5WS2 could be enhanced when combined with chemotherapeutic agent cisplatin in the ascites tumor model. These results suggest that E1B-55 kDa-deleted adenovirus driven by the transthyretin promoter may be a safer and more efficacious oncolytic agent for the treatment of primary and metastatic HCC.
Hsieh
Jeng-Long
JL
Department of Nursing, Chung Hwa University of Medical Technology, Jen-Te County, Tainan Hsien, Taiwan.
Lee
Che-Hsin
CH
Teo
Min-Li
ML
Lin
Yih-Jyh
YJ
Huang
Yen-Sung
YS
Wu
Chao-Liang
CL
Shiau
Ai-Li
AL
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001201:Ascites / Q000473:pathology / Q000821:virology; D006528:Carcinoma, Hepatocellular / Q000628:therapy* / Q000821:virology; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy* / Q000821:virology; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D011228:Prealbumin / Q000235:genetics*; D011401:Promoter Regions, Genetic
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; D011228:Prealbumin; D002945:Cisplatin