| Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice. | |
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MedLine Citation:
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PMID: 20473609 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: PR-104, a bioreductive prodrug in clinical trial, is a phosphate ester which is rapidly metabolized to the corresponding alcohol PR-104A. This dinitrobenzamide mustard is activated by reduction to hydroxylamine (PR-104H) and amine (PR-104M) metabolites selectively in hypoxic cells, and also independently of hypoxia by aldo-keto reductase (AKR) 1C3 in some tumors. Here, we evaluate reductive metabolism of PR-104A in mice and its significance for host toxicity. METHODS: The pharmacokinetics of PR-104, PR-104A and its reduced metabolites were investigated in plasma and tissues of mice (with and without SiHa or H460 tumor xenografts) and effects of potential oxidoreductase inhibitors were evaluated. RESULTS: Pharmacokinetic studies identified extensive non-tumor reduction of PR-104A to the 5-amine PR-104H (identity of which was confirmed by chemical synthesis), especially in liver. However, high concentrations of PR-104H in tumors that suggested intra-tumor activation is also significant. The tissue distribution of PR-104M/H was broadly consistent with the target organ toxicities of PR-104 (bone marrow, intestines and liver). Surprisingly, hepatic nitroreduction was not enhanced when the liver was made more hypoxic by hepatic artery ligation or breathing of 10% oxygen. A screen of non-steroidal anti-inflammatory drugs identified naproxen as an effective AKR1C3 inhibitor in human tumor cell cultures and xenografts, suggesting its potential use to ameliorate PR-104 toxicity in patients. However, neither naproxen nor the pan-CYP inhibitor 1-aminobenzotriazole inhibited normal tissue reduction of PR-104A in mice. CONCLUSIONS: PR-104 is extensively reduced in mouse tissues, apparently via oxygen-independent two-electron reduction, with a tissue distribution that broadly reflects toxicity. |
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Authors:
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Yongchuan Gu; Christopher P Guise; Kashyap Patel; Maria R Abbattista; Jie Li; Jie Lie; Xueying Sun; Graham J Atwell; Maruta Boyd; Adam V Patterson; William R Wilson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-15 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 67 ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-22 Completed Date: 2011-04-11 Revised Date: 2011-06-10 |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 543-55 Citation Subset: IM |
Affiliation:
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Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3-Hydroxysteroid Dehydrogenases
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metabolism* Animals Antineoplastic Agents / pharmacokinetics*, toxicity Cell Line, Tumor Electrons Enzyme Inhibitors / pharmacology Female Humans Hydroxyprostaglandin Dehydrogenases / metabolism* Lung Neoplasms / drug therapy, pathology Mice Mice, Nude Nitrogen Mustard Compounds / pharmacokinetics*, toxicity Oxidation-Reduction Prodrugs Tissue Distribution Uterine Cervical Neoplasms / drug therapy, pathology Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Nitrogen Mustard Compounds; 0/PR-104; 0/PR-104A; 0/Prodrugs; EC 1.1.-/3-Hydroxysteroid Dehydrogenases; EC 1.1.1.-/AKR1C3 protein, human; EC 1.1.1.-/Hydroxyprostaglandin Dehydrogenases |
| Comments/Corrections | |
Erratum In:
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Cancer Chemother Pharmacol. 2011 May;67(5):1209 Note: Lie, Jie [corrected to Li, Jie] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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