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

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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 3 Pg. 543-55 (Mar 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20473609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Nitrogen Mustard Compounds
• PR-104
• PR-104A
• Prodrugs
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3

Topics

• 3-Hydroxysteroid Dehydrogenases (metabolism)
• Aldo-Keto Reductase Family 1 Member C3
• 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