Cell death and free radicals: a mechanism for hydroxyurea teratogenesis

Hydroxyurea is a drug which causes birth defects in a variety of animals. Its pharmacologic actions include rapid killing of proliferating cells and profound inhibition of the synthesis of DNA. The mechanism whereby hydroxyurea produces teratogenesis is unresolved although it is related to the pharmacologic actions. Careful reading of the scientific literature discloses several putative mechanisms for the teratogenic action of hydroxyurea, which account for the inhibited synthesis of DNA, but do not explain the rapid onset of cell death. This paper presents a hypothesis that hydroxyurea causes rapid cell death through the initiation of uncontrolled free radical chain reactions. In vitro biochemical experiments have demonstrated the ability of compounds containing a hydroxylamine group (such as hydroxyurea) to form H2O2 and intermediate free radicals in biological fluids. Free radicals propagate themselves through chain reactions and can react swiftly and indiscriminately with the macromolecules quickly by inactivating enzymes, cross-linking DNA, and altering membrane functions through lipid auto-oxidation. Preliminary experiments utilizing an antioxidant to counteract the free radical effects appear to support the hypothesis that the rapid cell death is caused by aberrant free radical reactions.