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Evaluation of Combinations of Drugs That Inhibit Ehrlich Tumor Cell Ribonucleotide Reductase¹

Department of Biochemistry, College of Medicine, University of South Florida, Tampa, Florida 33612

The nature of the inhibition of Ehrlich tumor cell ribonucleotide reductase by combinations of agents directed at the nonheme iron-containing component and the effector-binding component was studied with the use of isobolograms. From these studies, it was determined that the combinations of pyrazoloimidazole (IMPY) and dialdehyde of inosine, IMPY and deoxyguanosine triphosphate (dGTP), IMPY and deoxyadenosine triphosphate (dATP), and IMPY and deoxythymidine triphosphate (dTTP) gave synergistic inhibition of cytidine diphosphate reductase. The combination of dATP and dGTP also gave synergistic inhibition. The combinations of hydroxyurea and IMPY, 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ) and IMPY, and dialdehyde of inosine and dialdehyde derivative of 5'-deoxyinosine gave antagonistic inhibition. Other combinations utilizing MAIQ and dATP, MAIQ and dGTP, MAIQ and dTTP, hydroxyurea and dGTP, and hydroxyurea and dTTP gave inhibition which was additive.

¹ This research was supported by Grant CA27398 from the USPHS, National Cancer Institute, and the Phi Beta Psi Sorority.

² To whom requests for reprints should be addressed.

Received 10/31/80. Accepted 1/26/81.