DNA Synthesis in Normal and Leucemie Cells as Related to Therapy with Cytotoxic Drugs

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Abstract
Enzymatic investigations of DNA synthesis in normal and leucemie cells in the blood and in the bone marrow show only qualitative differences which are mainly dependent on the proliferative activity of the investigated cell population. Under therapy with cytotoxic drugs in sensitive leucemie cells, characteristic changes of DNA syn- thesis can be observed: (1) By methotrexate dihydrofolate reductase and the incorporation of deoxyuridine (UdR) into DNA are inhibited. This is based on the blockade of the de novo synthesis of thymine methyl groups. An increased utilization of deoxythymidine (TdR) for DNA synthesis in resistant cells is explained by a reduction of the negative feedback control of thymidine kinase (TdR-K) by thymidinetriphosphate (TTP). (2) By cytosine arabinoside, the incorporation of UdR and TdR is decreased, as the synthesis of TTP and deoxycytidine triphosphate (dCTP) - both substrates of DNA polymerase - is inhibited. Therefore, and by inhibition of DNA polymerase, despite the increased activity of thymidine kinase, TdR cannot be utilized for DNA synthesis. (3) Dauno-Rubidomycin and Adriamycin cause a decrease of DNA and RNA synthesis in sensitive leucemie cells. (4) Corticosteroids are mainly effective in lymphoblastic leukaemias. A rapid fall in TdR-K activity during treatment with prednisolone is the first observed sign of sensitivity. (5) Combination of determination of enzyme activities affected by different cytotoxic drugs in cytolysates of the cells and of incorporation rates of radioactive-labeled DNA precursors in cell cultures before and in the beginning of a specific therapy favour the judgement of sensitivity of the leucemie cells on a biochemical basis.

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