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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.

Proliferating cultured P388 cells exhibited a greater degree of sensitivity to adriamycin than did proliferating cultured L1210 cells, although both leukemia cell populations had approximately the same doubling time. The rate of reduction in viability when cultured L1210 cell populations were exposed to adriamycin (0.0625-2.0 microgram/ml, concentrations that are comparable to tissue drug levels during therapy) was concentration-dependent. Therefore, the results indicated a possible therapeutic advantage to be gained by an increase in drug concentrations (within the limits of acceptable host toxicity) at the target cell site.

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