title: Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor.
abstract: OBJECTIVE
  The implication of matrix metalloproteinases (MMPs) in the major stages of cancer progression has fueled interest in the design of synthetic MMP inhibitors (MMPIs) as a novel anticancer therapy. Thus far, drugs used in clinical trials are broad-spectrum MMPIs the therapeutic index of which proved disappointingly low. The development of selective MMPIs for tumor progression-associated MMPs is, thus, likely to offer improved therapeutic possibilities.
  
  
  METHODS
  The anti-invasive capacity of a series of pyrimidine-trione derivatives was tested in vitro in a chemoinvasion assay, and the most potent compound was further evaluated in vivo in different human tumor xenograft models. The activity of this novel selective MMPI was compared with BB-94, a broad-spectrum inhibitor.
  
  
  RESULTS
  Ro-28-2653, an inhibitor with high selectivity for MMP-2, MMP-9, and membrane type 1 (MT1)-MMP, showed the highest anti-invasive activity in vitro. In vivo, Ro-28-2653 reduced the growth of tumors induced by the inoculation of different cell lines producing MMPs and inhibited the tumor-promoting effect of fibroblasts on breast adenocarcinoma cells. Furthermore, Ro-28-2653 reduced tumor vascularization and blocked angiogenesis in a rat aortic ring assay. In contrast, BB-94 up-regulated MMP-9 expression in tumor cells and promoted angiogenesis in the aortic ring assay.
  
  
  CONCLUSIONS
  Ro-28-2653, a selective and orally bioavailable MMPI with inhibitory activity against MMPs expressed by tumor and/or stromal cells, is a potent antitumor and antiangiogenic agent. In contrast to broad-spectrum inhibitors, the administration of Ro-28-2653 was not associated with the occurrence of adverse side effects that might hamper the therapeutic potential of these drugs.
authors.affiliation: Laboratory of Tumor and Development Biology, University of Liège, Centre Hospitalier Universitaire, Liège, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Maquoi
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.forename: Laetitia
authors.initials: L
authors.lastname: Devy
authors.forename: Fabrice
authors.initials: F
authors.lastname: Olivier
authors.forename: Francis
authors.initials: F
authors.lastname: Frankenne
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Krell
authors.forename: Frank
authors.initials: F
authors.lastname: Grams
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D020778:Matrix Metalloproteinase 2