Treatment of hepatocellular carcinoma by AdAFPep/rep, AdAFPep/p53, and 5-fluorouracil in mice.
Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by alpha-fetoprotein enhancer/promoter (AFPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 microg/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 microg) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents.


CONCLUSIONS
This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.
Sagawa
Tamotsu
T
Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Yamada
Yasuyuki
Y
Takahashi
Minoru
M
Sato
Yasushi
Y
Kobune
Masayoshi
M
Takimoto
Rishu
R
Fukaura
Junki
J
Iyama
Satoshi
S
Sato
Tsutomu
T
Miyanishi
Koji
K
Matsunaga
Takuya
T
Takayama
Tetsuji
T
Kato
Junji
J
Sasaki
Katsunori
K
Hamada
Hirofumi
H
Niitsu
Yoshiro
Y