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01-03-2011 | Original Article

Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice

Authors: Yongchuan Gu, Christopher P. Guise, Kashyap Patel, Maria R. Abbattista, Jie Lie, Xueying Sun, Graham J. Atwell, Maruta Boyd, Adam V. Patterson, William R. Wilson

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2011

Abstract

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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Title: Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice
Authors: Yongchuan Gu
Christopher P. Guise
Kashyap Patel
Maria R. Abbattista
Jie Lie
Xueying Sun
Graham J. Atwell
Maruta Boyd
Adam V. Patterson
William R. Wilson
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1354-5

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