ESR studies of structure and kinetics of radicals from hydroxyurea. An antitumor drug directed against ribonucleotide reductase

Hydroxyurea (HU) is a clinically applied antineoplastic drug, which quenches tyrosine radicals in the active site of ribonucleotide reductase (RR) and inhibits DNA synthesis in proliferating cells. Under oxidizing conditions (Cu2+ or H2O2) long-lived radicals from HU have been found by ESR. The structure of HU radicals was established to be: (formula; see text). The kinetics of formation and decay of HU radicals after reaction of HU with H2O2 is complex; it exhibits a lag-phase, a maximum, and a decay, all depending on the concentration of HU. Biological consequences of HU radicals for the inhibition of RR as well as their role in cytotoxic events during chemotherapy of cancer are discussed.