Ribonucleotide Reductase and Cell Proliferation

Abstract

The relationship between ribonucleotide reductase and tumor growth rate was measured in a series of rat hepatomas of different growth rates. An excellent correlation was found between tumor growth rate and the specific activity of ribonucleotide reductase. Differences of 200-fold in enzyme specific activities exist between the very fast and the slow growing hepatomas. This represents the largest enhancement of any enzyme activity in these tumors. No activity was detected in either normal rat liver or liver from a tumor-bearing animal although 1/500 of the enzyme level in the rapid tumor could have been detected. The thioredoxin-thioredoxin reductase complex which serves as the hydrogen donor for this reaction was eliminated as a contributory factor for these differences in activities because this complex is found at comparable levels in both fast growing tumor and normal liver extracts. Two other enzymes involved in deoxyribonucleotide synthesis, thymidylate synthetase and thymidine kinase, did not exhibit such a close degree of correlation with tumor growth rate. Thymidylate synthetase activity was found to be less markedly enhanced with only a 15- to 20-fold difference between the slow and fast growing tumors. Thymidine kinase exhibited differences of activity of approximately 40-fold. These data, as well as other evidence, indicate that the ribonucleotide reductase reaction is a rate-limiting step in DNA synthesis and cell division and that enzyme synthesis and degradation may be involved in control of this reaction.