title: Downregulation of matrix metalloprotease-9 and urokinase plasminogen activator by TX-1877 results in decreased tumor growth and metastasis on xenograft model of rectal cancer.
abstract: OBJECTIVE
  It is well known that hypoxic milieu is the primary cancer environment. Therefore, tumor hypoxia is considered to be a potential therapeutic target. In the present study, we investigated the antitumor and antimetastatic effect of hypoxic cell radiosensitizer, TX-1877 on xenograft model of rectal cancer.
  
  
  METHODS
  Nude mice bearing subcutaneously or orthotopically implanted human colon cancer cell lines HCT-116 and HT-29 were treated with TX-1877, irradiation or TX-1877 with irradiation. Tumor volume, survival, expression of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9 and urokinase-type plasminogen activator (uPA) and incidence of lymph node metastasis were evaluated in treatment versus control group.
  
  
  RESULTS
  In subcutaneous model, tumor treated with TX-1877 and irradiation showed significant reductions in volume (P < 0.05 vs. control, TX-1877 or irradiation group). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that TX-1877 significantly inhibited expression of the MMP-9 and uPA. These treatments also inhibited the para-aortic lymph node metastasis, however, did not prolong the survival in orthotopic model.
  
  
  CONCLUSIONS
  These data show that the treatment of TX-1877 with irradiation decreased growth of human rectal cancer and, furthermore, suppressed lymph node metastasis.
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. kota166@clin.med.tokushima-u.ac.jp
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyake
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.forename: Masanori
authors.initials: M
authors.lastname: Nishioka
authors.forename: Koji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Erdenebulgan
authors.initials: E
authors.lastname: Batmunkh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D000860:Hypoxia; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D051381:Rats; D012004:Rectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: C115855:2-nitroimidazole acetamide; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014568:Urokinase-Type Plasminogen Activator; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9