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.
- 1,2,4 benzotriazine 1,4 dioxide,
- deuterium,
- hydroxyl radical,
- methanol,
- 1,2,4-benzotriazine 1,4-di-N-oxide,
- amine oxide,
- antineoplastic agent,
- triazine derivative,
- controlled study,
- cytotoxicity,
- DNA cleavage,
- DNA damage,
- DNA strand,
- enzyme activation,
- isotope labeling,
- anoxia,
- chemical structure,
- chemistry,
- DNA cleavage,
- drug effects,
- metabolism,
- Anoxia,
- Antineoplastic Agents,
- Cyclic N-Oxides,
- DNA Cleavage,
- Isotope Labeling,
- Molecular Structure,
- Triazines
Available at: http://works.bepress.com/rainer-glaser/113/