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Mechanism of the Inhibition of DNA Biosynthesis by 4,4'-Diacetyldiphenylurea-bis(guanylhydrazone) in Leukemia L1210 Cells¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14203

Following the i.p. administration of a single therapeutic dose of 4,4'-diacetyldiphenyluria bis(guanylhydrazone) (DDUG), the incorporation of formate-¹⁴C and of thymidine-¹⁴C into the DNA of ascitic leukemia L1210 cells was inhibited to about the same extent. In a cell-free system, the DNA synthesis catalyzed by DNA polymerase from L1210 cells was also inhibited by DDUG; this inhibition was similar regardless of whether the enzyme was from L1210 sensitive or resistant to DDUG or whether the DNA template was from calf thymus or from L1210. The degree of inhibition was directly proportional to the ratio of concentrations of DDUG and DNA template and was independent of the enzyme concentration. A 50% inhibition occurred at the ratio of 1 mole of DDUG to about 10 nucleotides of calf thymus DNA. In drug-sensitive L1210 cells exposed to 200 µM DDUG for 30 min in vitro, the incorporation of thymidine-¹⁴C into DNA was completely stopped within 10 min and a rapid decrease occurred in the label of thymidine nucleotides. At the same time, the label in the thymidine pool remained high and constant. ¹⁴C-labeled nucleotides of thymidine were found to leak from DDUG-treated cells. In cell-free systems, DDUG had no effect on the conversion of thymidine to thymidine 5'-triphosphate or the breakdown of thymidine 5'-triphosphate to thymidine.

¹ This investigation was supported in part by Research Grant CA-10805 and Core Program Grant CA-13038 from the National Cancer Institute, USPHS.

Received 2/ 5/73. Accepted 6/ 4/73.

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