Specific inhibition of the subunits of ribonucleotide reductase as a new approach to combination chemotherapy

Abstract Ribonucleotide reductase activity can be inhibited by agents such as hydroxyurea, guanazole, IMPY, MAIQ, IQ, Inox, 5′-deoxyinox and various deoxyribonucleoside triphosphates. Since the reductase from mammalian cells could be separated into its non-identical components (non-heme iron subunit and effector binding subunits), it was possible to show that these inhibitors are specifically directed toward only one of the subunits. It was show that the inhibition of reductase by hydroxyurea, guanazole and IMPY was potentiated by the iron-chelating agents EDTA, Desferal and 8-hydroxyquinoline while the inhibition by MAIQ and IQ was reversed by the iron-chelating agents. Combinations of reductase inhibitors such as IMPY/dGTP, IMPY/Inox and hydroxyurea/dATP gave synergistic inhibition while combinations of MAIQ/IMPY and IMPY/hydroxyurea caused antagonistic effects. However, it was not possible to predict a priori which combinations would lead to the anticipated results.