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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. [ABSTRACT FROM AUTHOR]

PR-104 is a “pre-prodrug” designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors. Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated. Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m2. The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m2. One of six patients treated at 1,100 mg/m2 experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m2 were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses ≥550 mg/m2. The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species. PR-104 was well tolerated at a dose of 1,100 mg/m2 administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration–time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m2 and further trials are underway. [ABSTRACT FROM AUTHOR]