Kinetics of cytotoxicity of VM-26 and VP-16-213 on L1210 leukemia and hematopoietic stem cells.

The in vivo effects of VM-26 and VP-16-213 upon hematopoietic stem cells and L1210 leukemia cells were quantitated using the spleen-colony assay technique. The effect of VM-26 on leukemia cells was further quantitated using an endpoint dilution assay. The dose-response curves for leukemic clonogenic cells for both agents when given by iv injection were exponential and biphasic, indicating the existence of two populations. The survival of leukemia cells when VM-26 was administered as a 24-hour infusion was less than that found for equivalent doses administered as single injections. The survival kinetics with respect to time for a low dose (0.02 mg/mouse) and a high dose (0.15 mg/mouse) of VM-26 were similar in that the decrease in survival was rapid, reaching a maximum effect within 4 hours after administration. With the low dose, repopulation of the femoral marrow started immediately, whereas with the high dose, there was a 20-hour delay in repopulation. The data from the increase in lifespan studies were in excellent agreement with the quantitative assays. The dose-response curves for the normal hematopoietic clonogenic cells were also exponential, but these cells were much less sensitive to the agents than were the leukemia cells.