Combination of interferon-beta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis.
OBJECTIVE
Angiogenesis is now recognized as a crucial step in the development of tumors, including hepatocellular carcinoma (HCC). The aim of this study was to elucidate the combined effect of the clinically used angiotensin I-converting enzyme (ACE) inhibitor, perindopril (PE), and IFN-beta on the development and angiogenesis of murine HCC at clinically comparable low doses.


METHODS
PE and IFN were administered at doses of 2 mg/kg/day and 1 x 10(4) IU/twice a week, respectively.


RESULTS
Both PE and IFN significantly suppressed HCC development and inhibited neovascularization in the tumor, although the effect of low-dose IFN was weaker than that of PE. A combination regimen of PE plus IFN was effective; IFN significantly augmented the tumoricidal effect of PE. These inhibitory effects of PE plus IFN could be detected even on established tumors. The potent angiogenic factor, vascular endothelial growth factor, was markedly suppressed by combined treatment with PE and IFN, whereas these agents produced a marked increase of apoptosis in the tumor. The in vitro studies exhibited that PE and IFN inhibited endothelial cell tubular formation. IFN also suppressed endothelial cell proliferation, whereas neither IFN nor PE showed any inhibitory effect on proliferation of HCC cells.


CONCLUSIONS
The combination treatment of PE and IFN at clinically comparable low doses could inhibit HCC development and angiogenesis and suppress vascular endothelial growth factor as well. Because both agents are widely used in clinical practice, this combination regimen may represent a potential new strategy for HCC therapy in the future.
Noguchi
Ryuichi
R
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Yoshiji
Hitoshi
H
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Mitoro
Akira
A
Tsujinoue
Hirohisa
H
Imazu
Hiroo
H
Masaki
Tsutomu
T
Fukui
Hiroshi
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000517:prevention & control*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020913:Perindopril / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D042461:Vascular Endothelial Growth Factor A; D016899:Interferon-beta; D020913:Perindopril