DNA cross-links are amongst the most severe forms of DNA damage. The experimental anticancer pre-prodrug PR-104 induces toxicity by forming DNA interstrand cross-links (ICLs) following systemic hydrolysis and reductive bioactivation by hypoxia-associated oxidoreductases or aldo-keto reductase 1C3 (AKR1C3). The goal of this study was to identify the chemical structures of DNA cross-links formed by PR-104A and by its metabolites. The experimental strategy involved evaluating reactions between 15-mer DNA duplexes, the prodrug, and AKR1C3 by tandem mass spectrometry. The results suggest the formation of 1) adenine-adenine intrastrand cross-links directly, and also interstrand by the corresponding hydroxylamine; 2) guanine-adenine ICLs directly and by the hydroxylamine; 3) guanine-guanine intra- and interstrand cross-links directly and when the 5-nitro group is reduced; and 4) distinct patterns of preferential 1,2- vs. 1,3-cross-links formation. The profile of cross-links provides a chemical basis for the relevance of hypoxia and AKR1C3 expression for affecting drug potency in cells.

DNA cross-linking by the anticancer prodrug PR-104A in oligonucleotides

254th National Meeting (2017)

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