title: Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selective antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide.
abstract: The 1,2,4-benzotriazine 1,4-dioxides are an important class of potential anticancer drugs that selectively kill the low-oxygen (hypoxic) cells found in solid tumors. These compounds undergo intracellular one-electron enzymatic reduction to yield an oxygen-sensitive drug radical intermediate that partitions forward, under hypoxic conditions, to generate a highly reactive secondary radical that causes cell killing DNA damage. Here, we characterized bioreductively activated, hypoxia-selective DNA-strand cleavage by 1,2,4-benzotriazine 1,4-dioxide. We found that one-electron enzymatic activation of 1,2,4-benzotriazine 1,4-dioxide under hypoxic conditions in the presence of the deuterium atom donor methanol-d4 produced nondeuterated mono-N-oxide metabolites. This and the results of other isotopic labeling studies provided evidence against the generation of atom-abstracting drug radical intermediates and are consistent with a DNA-damage mechanism involving the release of hydroxyl radical from enzymatically activated 1,2,4-benzotriazine 1,4-dioxides.
authors: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors: Xiulong
authors: X
authors: Shen
authors: Anuruddha
authors: A
authors: Rajapakse
authors: Fabio
authors: F
authors: Gallazzi
authors: Venkatraman
authors: V
authors: Junnotula
authors: Tarra
authors: T
authors: Fuchs-Knotts
authors: Rainer
authors: R
authors: Glaser
authors: Kent S
authors: KS
authors: Gates
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D053837:DNA Cleavage / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism*; D007553:Isotope Labeling; D015394:Molecular Structure; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000594455:1,2,4-benzotriazine 1,4-di-N-oxide; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D014227:Triazines