Kinetic Evaluation of the Effect of Actinomycin D, Daunomycin, and Mitomycin C on Proliferating Cultured Leukemia L1210 Cells

Abstract

Proliferating cultured leukemia L1210 cells exposed to cytotoxic concentrations of actinomycin D, daunomycin, or mitomycin C are killed at a rate which is relatively dependent upon the concentrations used. On an equimolar basis, proliferating L1210 cells are equally sensitive to actinomycin D or daunomycin and are the least sensitive to mitomycin C. Nonproliferating L1210 cells are sensitive to these agents in vitro. The nonproliferating cells are the most sensitive to actinomycin D, less sensitive to daunomycin, and the least sensitive to mitomycin C. A comparison of the sensitivity of proliferating and nonproliferating L1210 cells to these agents indicate that proliferating cells are more sensitive than nonproliferating cells. The results of this study indicate that actinomycin D, daunomycin, and mitomycin C are neither cell-cycle-specific nor cell-cycle-stage-specific agents. This implies (a) that these drugs may be potentially effective in treating malignancies with low growth fractions and (b) that effective therapy with these agents may be enhanced by increasing the dosage up to the limits of acceptable toxicity to normal tissues.

RESPONSE OF MOUSE BONE MARROW COLONY FORMING UNITS IN DIFFERENT STAGES OF THE CELL CYCLE TO IN VITRO INCUBATION WITH MITOMYCIN‐C

“…Actually, the large amount of the normal CFU killed by the drug outside the S-phase cannot be accounted for without including the Go population. This observation was at variance with the difference in the toxic effects found between proliferative and non-proliferative mammalian tumour cells (Wilkoff et al, 1971), although their non-proliferating populations are stopped from growth (Schabel et al, 1965) in contrast to normal bone marrow CFU whose proliferation is balanced by death and differentiation. Cell culture studies have shown that GI (and G2) cells are sensitive to Mitomycin-C (Djordjevic & Kim, 1968).…”

“…In HeLa cell cultures, the drug has been found to be more toxic to cells other than those in the S-phase (Djordjevic & Kim, 1968). Some workers (Doi et al, 1967) have reported that the latter half of the GI-phase and first half of the S-period are highly sensitive to Mitomycin-C. Non-proliferative L1210 cells have been found to be much less sensitive to the agent than proliferative cells (Wilkoff, Lloyd & Dulmadge, 1971).…”