title: Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice.
abstract: Recent studies have suggested that an anti-angiogenic agent could improve the inhibitory effects of standard chemotherapeutic drugs against tumor development. We previously reported that the clinically used copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited tumor growth. The aim of the current study was to examine the combined effect of trientine and methotrexate on the development and angiogenesis of xenograft human colorectal carcinoma (CRC) cells at clinically comparable low doses. When used individually, both trientine and methotrexate significantly suppressed CRC development along with inhibition of neovascularization in the tumor. A combination regimen of trientine and methotrexate exerted the most potent tumoricidal effect and led to 'tumor dormancy.' The combination of these agents also resulted in a marked suppression of the angiogenic factors, in particular the vascular endothelial growth factor and interleukin-8, and an increase of apoptosis in the tumor. In vitro studies revealed that neither trientine nor methotrexate was cytotoxic for tumor cells. On the other hand, the endothelial cell proliferation and tubular formation were significantly suppressed by these agents. The combined treatment of trientine and methotrexate at clinically comparable low doses could inhibit CRC development and angiogenesis, as well as suppress the angiogenic factors. Because both agents are widely used in clinical practice, the combination regimen may represent a potential new strategy for CRC therapy in the future.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, School of Medicine, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
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: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014266:Trientine / Q000008:administration & dosage / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D002614:Chelating Agents; D016209:Interleukin-8; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D014266:Trientine; D008727:Methotrexate