Cell-Cycle-Stage Specificity of 4′-(9-Acridinylamino)methanesulfon-m-Anisidide (m-AMSA) and Interaction with Ionizing Radiation in Mammalian Cell Cultures

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Abstract
The acridine derivative 4''-(-9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) is at present being evaluated for antitumor activity in phase II [human] clinical trials. At low concentrations this agent displays cycle-phase-dependent toxicity for Chinese hamster ovary cells in culture, the initial D0 [mean lethal dose] of the survival curve for S-phase cells being approximately 3-fold lower than for late G2/early G1-phase cells. Treatment with m-AMSA immediately prior to irradiation reduces the extrapolation number of the radiation survival curve in air or N without altering the D0. This effect is seen under conditions where m-AMSA itself causes significant toxicity. When analyzed using a Steel and Peckham isobologram, the interaction between the 2 agents can be described as a mode II addition; it is at least in part due to the selective killing of the most radioresistant (S-phase) subpopulation by the drug. Consistent with this interpretation, killing is maximal when cells are exposed simultaneously to m-AMSA and radiation. In synchronized cultures lowering of the radiation survival curve extrapolation number is again observed. Because of interpretive difficulties introduced by the presence of contaminating cells of other cycle phases, the data fail to establish mechanisms of interaction between m-AMSA and radiation other than the above cytokinetic cooperation.