Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy
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 a...
| Main Authors: | , , |
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| Format: | Journal Article |
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John Wiley & Sons
2012
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| Online Access: | http://hdl.handle.net/20.500.11937/27734 |
| _version_ | 1848752345541771264 |
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| author | Yu, Yu Rahmanto, Y. Richardson, D. |
| author_facet | Yu, Yu Rahmanto, Y. Richardson, D. |
| author_sort | Yu, Yu |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T08:07:09Z |
| format | Journal Article |
| id | curtin-20.500.11937-27734 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:07:09Z |
| publishDate | 2012 |
| publisher | John Wiley & Sons |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-277342023-02-22T06:24:18Z Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy Yu, Yu Rahmanto, Y. Richardson, D. 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. 2012 Journal Article http://hdl.handle.net/20.500.11937/27734 10.1111/j.1476-5381.2011.01526.x John Wiley & Sons unknown |
| spellingShingle | Yu, Yu Rahmanto, Y. Richardson, D. Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title | Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title_full | Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title_fullStr | Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title_full_unstemmed | Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title_short | Bp44mT: An orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| title_sort | bp44mt: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy |
| url | http://hdl.handle.net/20.500.11937/27734 |