M. Moehler et al., Effective infection, apoptotic cell killing and gene transfer of human hepatoma cells but not primary hepatocytes by parvovirus H1 and derived vectors, CANC GENE T, 8(3), 2001, pp. 158-167
Autonomous parvoviruses preferentially replicate in and kill in vitro-trans
formed cells and reduce the incidence of spontaneous and implanted tumors i
n animals. Because of these natural oncotropic and oncolytic properties, pa
rvoviruses deserve to be considered as potential antitumor vectors. Here, w
e assessed whether parvovirus H1 is able to kill human hepatoma cells by in
duction of apoptosis but spares primary human liver cells, and whether the
former cells can efficiently be transduced by H1 virus-based vectors. Cell
death, infectivity, and transgene transduction were investigated in Hep3B,
HepG2, and Huh7 cells and in primary human hepatocytes with natural and rec
ombinant H1 virus. All hepatoma cells were susceptible to H1 virus-induced
cytolyis. Cell death correlated with H1 virus DNA replication, nonstructura
l protein expression, and with morphological features of apoptosis. H1 viru
s-induced apoptosis was more pronounced in p53-deleted Hep3B and p53-mutate
d Huh7 cells than in HepG2 cells which express wild-type p53. In Hep3B cell
s, apoptosis was partially inhibited by DEVD-CHO, a caspase-3 inhibitor. In
contrast, H1 virus-infected primary hepatocytes were neither positive for
nonstructural protein expression nor susceptible to H1 virus-induced killin
g. infection with a recombinant parvovirus vector carrying the luciferase g
ene under control of parvovirus promoter P38 led to higher transgene activi
ties in hepatoma cells than in the hepatocytes. Taken together, H1 virus ki
lls human hepatoma cells at low virus multiplicity but not primary hepatocy
tes. Thus, recombinant H1 viruses carrying antitumor transgenes may be cons
idered as potential therapeutic options for the treatment of hepatocellular
carcinomas.