Thanks, Collin and Jason, here's the abstract. In my experience, Cancer Research is not a particularly discriminating journal.......
Cancer Res 2001 Sep 1;61(17):6428-6436
A hepatocellular carcinoma-specific adenovirus variant, cv890, eliminates
distant human liver tumors in combination with doxorubicin.
Li Y, Yu DC, Chen Y, Amin P, Zhang H, Nguyen N, Henderson DR.
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.
alpha-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/10(6) cells/10 days to as high as 4585 ng AFP/10(6)
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. |
