Research on DNA biosynthesis in human hematologic malignant cells.

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The role of de novo and salvage pathways for DNA biosynthesis in human hematologic malignant cells was investigated to provide further informations for appropriate chemotherapy. The activities of ribonucleotide reductase and thymidine kinase, and the thymidine incorporation rate were measured in 16 cultured human hematologic malignant cell lines with different cell proliferation rates. A close correlation was found between the cell proliferation rate and ribonucleotide reductase activity, but not thymidine kinase activity or the thymidine incorporation rate. These results indicate that in cultured human malignant cells a high potential for proliferation may depend mainly on the de novo pyrimidine pathway of DNA biosynthesis. Then, the extent of use and role of the salvage pathway of pyrimidine metabolism for DNA biosynthesis in the growth of human hematologic malignant cells were studied by examining the effect of dipyridamole, an effective blocker of this salvage pathway on their growth. The data indicate that the salvage pathway for deoxynucleotide supply is more important in peroxidase-positive non-lymphoid cell lines than in lymphoid cell lines. Blockers of salvage pathway like dipyridamole which has not been used might be useful clinically. Next, the component of ribonucleotide reductase was investigated. Ribonucleotide reductase is concisted of M1-subunit "effector binding subunit" and M2-subunit "nonhem iron subunit". It became clear that the amount of M1-subunit was more than that of M2-subunit in any hematologic malignant cells. Therefore, the use of specific inhibitor of M2-subunit might provide more potential inhibitory effect of cellular proliferation.