title: Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer.
abstract: Activation of nuclear factor-κB (NF-κB) has been implicated in metastasis of pancreatic cancer. We investigated the effects of the novel NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on the inhibition of liver metastasis of pancreatic cancer in a mouse model of clinical liver metastasis. Nude mice were xenografted by intra-portal-vein injection with the human pancreatic adenocarcinomas cell line AsPC-1 via small laparotomy. Mice were treated with DHMEQ and gemcitabine (GEM), alone or in combination. The combination of GEM + DHMEQ showed a stronger antitumor effect than either monotherapy. Apoptosis induction in the metastatic foci was greatest in the DHMEQ + GEM group. Significant reductions in the numbers of neovessels were also seen in the DHMEQ and/or GEM groups. Cell growth inhibition assays revealed no synergistic effect of combination therapy, although each monotherapy had an individual cytotoxic effect. Combination therapy produced the greatest inhibition of tumor cell invasiveness in chemoinvasion assay. In addition, combination therapy significantly down-regulated the expression level of matrix metalloproteinase (MMP)-9 mRNA in AsPC-1 cells. DHMEQ also markedly down-regulated interleukin-8 and MMP-9, while GEM caused moderate down-regulation of vascular endothelial growth factor in metastatic foci, demonstrated by quantitative reverse transcription-polymerase chain reaction. These results demonstrate that DHMEQ can exert anti-tumor effects by inhibiting angiogenesis and tumor cell invasion, and by inducing apoptosis. Combination therapy with DHMEQ and GEM also showed potential efficacy. DHMEQ is a promising drug for the treatment of advanced pancreatic cancer.
authors.affiliation: Department of Surgery, Kitasato Institute Hospital, 5-9-1 Shirogane, Minato-ku, Tokyo 108-8642, Japan. k1suzuki@me.com
authors.forename: Keiichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Koichi
authors.initials: K
authors.lastname: Aiura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsuda
authors.forename: Osamu
authors.initials: O
authors.lastname: Itano
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D003512:Cyclohexanones; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; C464444:dehydroxymethylepoxyquinomicin; D003841:Deoxycytidine; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000093542:Gemcitabine