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

    Access Status
    Open access via publisher
    Authors
    Yu, Yu
    Rahmanto, Y.
    Richardson, D.
    Date
    2012
    Type
    Journal Article
    
    Metadata
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    Citation
    Yu, Y. and Rahmanto, Y. and Richardson, D. 2012. Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy. British Journal of Pharmacology. 165 (1): pp. 148-166.
    Source Title
    British Journal of Pharmacology
    DOI
    10.1111/j.1476-5381.2011.01526.x
    ISSN
    0007-1188
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/27734
    Collection
    • Curtin Research Publications
    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.

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    • Thiosemicarbazone Iron Chelator: Evaluation of the anti-cancer activity and mechanisms of action
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      Previous studies demonstrated that thiosemicarbazone iron chelator possessed potent and selective anti-cancer activity. In this study, the in vitro and in vivo anti-tumor efficacy and tolerability of 2-benzoylpyridine ...
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      The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also ...
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      Cancer is one of the leading causes of death worldwide and there is an increasing need for novel anti-tumor therapeutics with greater selectivity and potency. A new strategy in the treatment of cancer has focused on ...
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