Combination chemotherapy directed at the components of nucleoside diphosphate reductase.

It would be expected that drugs directed at the rate-limiting step in a key metabolic pathway in tumor cell proliferation would provide a useful basis for therapy of neoplasms. Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of dNTP's for DNA synthesis. Further, ribonucleotide reductase is composed of two non-identical protein subunits (non-heme iron and effector-binding subunits) which can be specifically and independently inhibited. As a result, combinations of drugs specifically directed at each of the subunits of ribonucleotide reductase have been shown to cause synergistic inhibition of L1210 cell growth in culture and synergistic cell kill. This approach offers a novel basis for the design of combination chemotherapy.