Discussion Mammalian Cell Killing by Inhibitors of DNA Synthesis

During the course of his discussion this afternoon, Dr. Philips mentioned two agents, hydroxyurea and cytosine arabinoside which appeared to bring about rapid destruction of the cells of the intestinal lining. Like a number of other groups we have been interested in the effects of these compounds and others on mammalian cells in tissue culture. In agreement with the observation of Dr. Philips and others (1, 2, 3) we have observed that with these two compounds there is a class of cells which are rapidly killed by the compounds and these are cells in the S phase. There is, however, a second mode of killing which is not restricted to cells in the S phase and which is not apparent until much later times in the cell cycle, times which are approximately equal to the times required for a cell to pass from the beginning of S through S and G2 and into mitosis (2, 3, 4). After this length of exposure to the drug there appears to be a rapid and almost exponential decline in the fraction of viable cells. This paper presents some data and questions which we feel bear on the nature of these two types of killing.