Studies on the differential mechanisms of inhibition of ribonucleotide reductase by specific inhibitors of the non-heme iron subunit.

The data presented here show that while the non-heme iron subunit of ribonucleotide reductase is inhibited by IMPY, hydroxyurea and MAIQ, the mechanism of inhibition by hydroxyurea and IMPY is distinct from that for MAIQ. This difference in mechanisms is expressed not only in effects of iron-chelating agents on enzyme activity and of L1210 cell growth in culture, but also in differences in responses to catalase and peroxidase. Further, these data suggest that the inhibition of reductase activity by IMPY and IMPY/iron-chelator occurs through different pathways. The same conclusion can be drawn for the inhibition of reductase by hydroxyurea and hydroxyurea/iron-chelator. It is clear that additional studies will be required to understand the exact mechanism by which hydroxyurea or IMPY and the thiosemicarbazones inhibit the non-heme iron component of ribonucleotide reductase. It will also be necessary to better define the pathways of inhibition of reductase activity by IMPY and the IMPY/iron-chelator combination (or hydroxyurea and hydroxyurea/iron-chelator combination). From these studies may come information which will allow these antitumor agents to have greater utilization in the clinical management of neoplastic diseases.