title: CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo.
abstract: OBJECTIVE
  We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo.
  
  
  METHODS
  CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 μm; 2) in ATC cells at the concentrations of 10, 30, and 50 μm; and 3) in an ATC cell line (AF) in CD nu/nu mice.
  
  
  RESULTS
  CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P < 0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 μm in normal thyroid follicular cells (P < 0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA) and inhibited migration (P < 0.01) and invasion (P < 0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg · d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues.
  
  
  CONCLUSIONS
  The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.
authors.affiliation: Department of Internal Medicine, University of Pisa, School of Medicine, Via Roma, 67, 56100, Pisa, Italy. alessandro.antonelli@med.unipi.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonelli
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Silvia Martina
authors.initials: SM
authors.lastname: Ferrari
authors.forename: Poupak
authors.initials: P
authors.lastname: Fallahi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ruffilli
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Domenicantonio
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Michele
authors.initials: M
authors.lastname: Minuto
authors.forename: Simona
authors.initials: S
authors.lastname: Piaggi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.forename: Greta
authors.initials: G
authors.lastname: Alì
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.forename: Piero
authors.initials: P
authors.lastname: Berti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015507:Drugs, Investigational / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012439:Saccharin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C572631:4-chloro-N-(1,1,3-trioxo-2,3-dihydrobenzo(d)isothiazol-4-yl)benzamide; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D015507:Drugs, Investigational; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D012439:Saccharin