METABOLISM AND METABOLIC ACTIONS OF 4'-THIOTHYMIDINE IN L121O CELLS

4'-Thiothymidine (S-dThd) is a potent inhibitor of L1210 cell growth a nd is active against P388 leukemia in mice. Because of these activitie s and its novel structure, we have begun studies of its metabolism and metabolic actions in L1210 cells in order to understand its mechanism of cytotoxicity. S-dThd inhibited the incorporation of radiolabeled p recursors into DNA, but did not inhibit the incorporation of either ur idine or leucine into RNA or protein, respectively, which indicated th at the mechanism of its toxicity was due to its inhibition of DNA synt hesis. S-dThd did not decrease the concentration of any of the natural deoxynucleoside triphosphates, which indicated that its cytotoxicity was not due to the inhibition of ribonucleotide reductase. S-dThd was readily phosphorylated and used as a substrate for DNA synthesis. Beca use the rate of incorporation of S-dThd into DNA was 20% that of thymi dine, it is likely that the mechanism of action of S-dThd is not due t o inhibition of DNA polymerases by the 5'-triphosphate of S-dThd, but instead to its incorporation into the DNA and its subsequent disruptio n of some function of DNA.