title: The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression.
abstract: It has been shown that angiogenesis plays an important role not only in tumor growth, but also in carcinogenesis. We previously reported that the copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited hepatocellular carcinoma (HCC) tumor growth. The aim of the current study was to elucidate the effect of trientine on liver enzyme-altered preneoplastic lesions in rats, especially in conjunction with angiogenesis alteration in the liver. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment, even at a clinically comparable low dose, significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions associated with a decrease in copper content in the liver. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of the preneoplastic lesions. On the contrary, the proliferative cell nuclear antigen (PCNA)-positive cells were not altered with or without trientine treatment. These results suggested that the copper-chelating agent, trientine, exerted chemopreventive effects against rat liver carcinogenesis due to the suppression of angiogenesis, and suggest that it might be useful clinically as a chemopreventive agent of HCC.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: Hiroo
authors.initials: H
authors.lastname: Imazu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens; D002455:Cell Division; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D004052:Diethylnitrosamine; D005982:Glutathione Transferase / Q000096:biosynthesis; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014266:Trientine / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D002273:Carcinogens; D002614:Chelating Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D003300:Copper; D005982:Glutathione Transferase; D014266:Trientine