title: Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts.
abstract: A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3'-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a "5 days on, 2 days off" regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.
authors.affiliation: Hypoxia and Therapeutics Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Roben G
authors.initials: RG
authors.lastname: Gieling
authors.forename: Muhammad
authors.initials: M
authors.lastname: Babur
authors.forename: Lupti
authors.initials: L
authors.lastname: Mamnani
authors.forename: Natalie
authors.initials: N
authors.lastname: Burrows
authors.forename: Brian A
authors.initials: BA
authors.lastname: Telfer
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Kaye J
authors.initials: KJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002256:Carbonic Anhydrases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D009368:Neoplasm Transplantation; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: C575288:4-(3'-(3',5'-dimethylphenyl)ureido)phenyl sulfamate; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D010671:Phenylurea Compounds; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII