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Experimental Therapeutics |
Calydon, Inc., Sunnyvale, California 94089
Hepatocellular carcinoma (HCC) is the third leading cause of cancer
death in the world. Tumor resection remains the only curative treatment
but is often not possible because of advanced stage and frequently
unsuccessful because of intrahepatic or distant tumor recurrence.
-Fetoprotein (AFP), a tumor marker currently used for the
diagnosis and management of HCC, is an oncofetal protein expressed in a
majority of HCCs but rarely in normal hepatocytes. Because AFP
gene expression is tightly regulated at the level of
transcription, AFP transcriptional regulatory elements (TRE) are
excellent candidates for generating HCC-specific oncolytic
adenoviruses. We devised a new strategy for the AFP TRE to control an
artificial E1A-IRES-E1B bicistronic cassette in an adenovirus 5 vector
(Ad5) and constructed an HCC-specific oncolytic virus, CV890. In
vitro, CV890 expression of the E1A and
E1B genes, virus replication, and cytopathic effects
were examined by Northern blot, Western blot, virus yield assay, and
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in
AFP-producing cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5, and SNU449),
non-AFP-producing cell lines (Sk-Hep-1, Chang liver cell, LNCaP,
HBL-100, PA-1, UM-UC-3, SW 780, Colo 201, and U118 MG), and
non-AFP-producing human primary cells (lung fibroblast, bladder smooth
muscle, and mammary epithelial). CV890 efficiently replicates in and
destroys AFP-producing HCC cells as well as wild-type Ad5, but
replication is highly attenuated in non-AFP-producing HCC cells or
non-HCC cells. CV890 produced 5,000–100,000-fold less virus than
wild-type Ad5 in non-AFP-producing cells. CV890 was attenuated 100-fold
more than CV732, a virus containing the AFP TRE driving the
E1A gene alone, in non-AFP-producing cells. These
studies demonstrated that expression of both E1A and
E1B genes under the control of a bicistronic
AFP-E1A-IRES-E1B cassette yielded improvements in virus specificity
equivalent to driving the E1A and E1B
genes with two independent TREs yet requires only one TRE thereby
conserving genomic space within the virus. Significantly, CV890
produced nearly the same yield of virus in cells that produced AFP over
a 75-fold range, from a low of 60 ng AFP/106 cells/10 days
to as high as 4585 ng AFP/106 cells/10 days. In
vivo, antitumor efficacy of CV890 was examined in
BALB/c-nu/nu mice containing large s.c. HepG2 or Hep3B
tumor xenografts. Tumor volume of distant xenografts dropped below
baseline 4 weeks after a single i.v. injection. Combination of CV890
with doxorubicin demonstrated synergistic antitumor efficacy, yielding
complete elimination of distant Hep3B tumors 4 weeks after a single
i.v. administration of both compounds. Our results support the clinical
development of CV890 as an antineoplastic agent for the treatment of
localized or metastatic HCC.
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