Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy

Br J Pharmacol. 2012 Jan;165(1):148-66. doi: 10.1111/j.1476-5381.2011.01526.x.


Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Humans
  • Injections, Intravenous
  • Iron Chelating Agents / pharmacology*
  • Lung Neoplasms / drug therapy
  • Mice
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Pyridines / classification
  • Pyridines / pharmacology*
  • Thiosemicarbazones / classification
  • Thiosemicarbazones / pharmacology*


  • 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone
  • Antineoplastic Agents
  • Iron Chelating Agents
  • Pyridines
  • Thiosemicarbazones