Ribonucleotide reductase as a chemotherapeutic target.

Ribonucleotide reductase, because of the critical role that it plays in DNA replication and the specific properties of the protein subunits, provides a unique metabolic target for chemotherapeutic approaches to cancer treatment. Combinations of ribonucleotide reductase inhibitors resulted in synergistic inhibition of cell growth with concurrent cytotoxicity. The drugs in this combination were targeted at the individual subunits (non-heme iron and effector-binding) of ribonucleotide reductase and at the differential sensitivities of the substrate reductions to these agents. The reduction of the intracellular pools of all four dNTPs through the direct inhibition of ribonucleotide reductase has the effect of reducing DNA polymerase activity in a sigmoidal manner rather than in a hyperbolic fashion due to the requirement of DNA polymerase for all four substrates. As a result relatively small decreases in the intracellular concentrations of the dNTPs cause remarkably large decreases in DNA synthesis and hence cell replication. It appears that there may be a relationship between the capability of the cell to synthesize DNA at a minimal absolute rate and cell viability. That is, if DNA synthesis is decreased to or below a specific level, then the processes leading to cell death takes precedence over the tendency of the cell to complete DNA replication leading to cell division.