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

Abstract

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.

• Authors: Y Yu, Y Suryo Rahmanto, D R Richardson
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 165 Issue 1 Pg. 148-66 (Jan 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 21658021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

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

Topics

• 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, pharmacology)
• Thiosemicarbazones (classification, pharmacology)