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- Title
A Strategy for Selective O<sup>6</sup> -Alkylguanine-DNA Alkyltransferase Depletion Under Hypoxic Conditions.
- Authors
Penketh, Philip G.; Shyam, Krishnamurthy; Baumann, Raymond P.; Ishiguro, Kimiko; Patridge, Eric V.; Zhu, Rui; Sartorelli, Alan C.
- Abstract
Cellular resistance to chemotherapeutics that alkylate the O-6 position of guanine residues in DNA correlates with their O6-alkylguanine-DNA alkyltransferase activity. In normal cells high [ O6-alkylguanine-DNA alkyltransferase] is beneficial, sparing the host from toxicity, whereas in tumor cells high [ O6-alkylguanine-DNA alkyltransferase] prevents chemotherapeutic response. Therefore, it is necessary to selectively inactivate O6-alkylguanine-DNA alkyltransferase in tumors. The oxygen-deficient compartment unique to solid tumors is conducive to reduction, and could be utilized to provide this selectivity. Therefore, we synthesized 2-nitro-6-benzyloxypurine, an analog of O6-benzylguanine in which the essential 2-amino group is replaced by a nitro moiety, and 2-nitro-6-benzyloxypurine is >2000-fold weaker than O6-benzylguanine as an O6-alkylguanine-DNA alkyltransferase inhibitor. We demonstrate oxygen concentration sensitive net reduction of 2-nitro-6-benzyloxypurine by cytochrome P450 reductase, xanthine oxidase, and EMT6, DU145, and HL-60 cells to yield O6-benzylguanine. We show that 2-nitro-6-benzyloxypurine treatment depletes O6-alkylguanine-DNA alkyltransferase in intact cells under oxygen-deficient conditions and selectively sensitizes cells to laromustine (an agent that chloroethylates the O-6 position of guanine) under oxygen-deficient but not normoxic conditions. 2-Nitro-6-benzyloxypurine represents a proof of concept lead compound; however, its facile reduction (E1/2- 177 mV versus Ag/AgCl) may result in excessive oxidative stress and/or the generation of O6-alkylguanine-DNA alkyltransferase inhibitors in normoxic regions in vivo.
- Subjects
GUANINE; TRANSFERASES; DNA; HYPOXEMIA; CANCER chemotherapy; ENZYME kinetics; CANCER cells; PRODRUGS
- Publication
Chemical Biology & Drug Design, 2012, Vol 80, Issue 2, p279
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2012.01401.x