Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector.
An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy.
Guan
Min
M
Division of Hepatology and Gene Therapy, School of Medicine, Centro de Investigación Médica Aplicada, University of Navarra, 31008 Pamplona, Spain.
Rodriguez-Madoz
Juan R
JR
Alzuguren
Pilar
P
Gomar
Celia
C
Kramer
M Gabriela
MG
Kochanek
Stefan
S
Prieto
Jesus
J
Smerdou
Cristian
C
Qian
Cheng
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D051381:Rats; D011915:Rats, Inbred BUF; D012672:Semliki forest virus / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000235:genetics
D007376:Interleukin-2; D000509:alpha-Fetoproteins