PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non-small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. Cancer Res; 70(4); 1573-84.
Glyceryl-ether monooxygenase (1-alkyl-sn-glycerol,tetrahydropteridine: oxygen oxidoreductase, EC 1.14.16.5) catalyzes the oxidative cleavage of 1-O-alkyl glycerol or glycol derivatives to a long-chain aldehyde and the glycerol or glycol derivative. The specificity for tetrahydropterins of a similar, perhaps identical, enzyme that cleaves O-hexadecyl ethylene glycol in rat liver microsomes was examined with the use of an assay based on [1-3H]ethylene glycol formation from 2-hexadecyloxy [1-3H]ethan-1-ol. Several tetrahydropterin derivatives are effective electron donors for this reaction, and 2,4,5-triamino-6-hydroxypyrimidine is somewhat effective, but NADH, NADPH, ascorbate, reduced dichlorophenolindophenol and glutathione are inactive. Tetrahydropterin derivatives differ from each other in apparent Km and apparent Vmax. The order of increasing apparent Km values is tetrahydropterin approximately 6-methyltetrahydropterin approximately tetrahydrobiopterin less than 6.7-dimethyltetrahydropterin less than tetrahydrofolate. The order of increasing apparent Vmax values is tetrahydrofolate approximately tetrahydropterin less than 6-methyltetrahydropterin approximately tetrahydrobiopterin approximately 6,7-dimethyltetrahydropterin. Results obtained with the use of a spectrophotometric assay, in which tetrahydropterin oxidation is coupled to NADH oxidation by dihydropteridine reductase (NAD(P)H: 6,7-dihydropteridine oxidoreductase, EC 1.6.99.7), indicated that the ratio of 6,7-dimethyltetrahydropterin or 6-methyltetrahydropterin oxidized to ether lipid degraded is about 1.1 to 1.3. Unlike cytochrome P-450-dependent hydroxylases, this alkyl glycol-ether monooxygenase is not inhibited by carbon monoxide. 1-O-hexadecyl-rac-glycerol (chimyl alcohol) competitively inhibits the oxidation of the glycol ether indicating that the same enzyme probably catalyzes the oxidation of both O-alkyl glycol and 1-O-alkyl glycerol.
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