The Effect of Dose Interval on the Survival of L1210 Leukemic Mice Treated with DNA Synthesis Inhibitors1

The survival of L1210 leukemic C57BL/6 X DBA2 F! mice has been studied as a function of the time interval between two i.p. doses of DNA synthesis inhibitors (1-0-D-arabinofuranosylcytosine, hydroxyurea, sodium camptothecin, and 5-hydroxy-2-formylpyridine thiosemicarbazone). In general, life-span increases that were observed with single doses of these agents (i.e., a time interval of zero) were consistent with the cell kill expected (approximately 66 to 86%) for an S-phase-specific agent with a short effective contact time. The therapeutic effect appeared to be a function of the interval between the two doses. When optimal time intervals between two doses were used, cell kills in excess of 99% were achieved. In some cases, enhanced therapeutic ratios (increase in life-span compared to host weight loss) were achieved by judicious choice of the dose interval. It was possible in most cases to correlate the optimal interval for maximal cell kill with the time required for the maximal recovery of the ability of the peritoneal ascites LI210 cells to incorporate tritiated thymidine into DNA after the initial dose of the agent. The results are discussed in terms of a simple model based on cell-cycle kinetic parameters. eradicate the entire LI210 cell population with only 2 optimally spaced doses of an S-phase-specific agent (i.e., an agent that kills cells only when the cells are exposed to it during the DNA-synthetic phase of the cell cycle). An initial exposure to the agent should kill the S-phase cells of the asynchronous population. One could then wait an appropriate time until the partially "synchronized" surviving cells (i.e.,