title: Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy.
abstract: OBJECTIVE
  Our previous studies demonstrated that a thiosemicarbazone iron chelator (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; Dp44mT) possesses potent and selective anti-cancer activity but led to cardiotoxicity at non-optimal doses. In this study, we examined the in vivo anti-tumour efficacy and tolerability of a new-generation 2-benzoylpyridine thiosemicarbazone iron chelator (2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes.
  
  
  METHODS
  BpT chelators were tested in vitro against human lung cancer cells (DMS-53) and in vivo in DMS-53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron-regulated molecules involved in growth and cell cycle control were investigated.
  
  
  RESULTS
  Administration of Bp44mT by either route resulted in marked dose-dependent inhibition of tumour growth. When administered at 50 mg·kg(-1) via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle-treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator-treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated.
  
  
  CONCLUSIONS
  This is the first study to show that Bp44mT can be given orally with potent anti-tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: Y
authors.initials: Y
authors.lastname: Suryo Rahmanto
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007275:Injections, Intravenous; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011725:Pyridines / Q000145:classification / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000145:classification / Q000494:pharmacology*
chemical_list: C559854:2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones