Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of 2'-deoxyribonucleoside 5'-triphosphates. As such, it represents a critical step in DNA replication and has been a target for the design of antitumor agents. A unique aspect of this enzyme is that it consists of two non-identical protein subunits which can be specifically and independently inhibited. Previous studies established that combinations of ribonucleotide reductase inhibitors, directed at each of the subunits, yielded synergistic inhibition of L1210 cell growth in culture and synergistic cytotoxicity of L1210 cells. It will be the specific aims of this project: to establish the biochemical basis for the synergistic effects induced by the combinations of ribonucleotide reductase; to study the subunit specificity of the reductase inhibitors of the N-hydroxy-N'-aminoguanidine and polyhydroxybenzene series; to study additional combinations of reductase inhibitors which include the N-hydroxy-N'-aminoguanidine and polyhydroxybenzene derivatives; to study the effects of combinations of ribonucleotide reductase inhibitors of L1210 cell growth in vivo; and to determine if there is selective toxicity between the tumor cells and host tissues for these combinations of ribonucleotide reductase inhibitors. The overall goal of this project is to establish combination chemotherapy directed at multiple sites of the same enzyme as an appropriate approach for the treatment of human tumors.
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