The acridine derivative 4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) is at present being evaluated for antitumor activity in phase II clinical trials. At low concentrations this agent displays cycle-phase-dependent toxicity for Chinese hamster ovary cells in culture, the initial D 0 of the survival curve for S-phase cells being approximately three-fold lower than for late ${\rm G}_{2}/\text{early}$ G 1 -phase cells. Treatment with m-AMSA immediately prior to irradiation reduces the extrapolation number of the radiation survival curve in air or nitrogen without altering the D 0 . This effect is seen under conditions where m-AMSA itself causes significant toxicity. When analyzed using a Steel and Peckham isobologram (G. G. Steel and M. J. Peckham, Int. J. Radiat. Oncol. Biol. Phys. 5, 85-91 (1979)) the interaction between the two agents can be described as a mode II addition, and 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 simultaneoualy to m-AMSA and radiation. In synchronized cultures lowering of the radiation survival curve extrapolation number is again observed. However, because of interpretive difficulties introduced by the presence of contaminating cells of other cycle phases, these data fail to establish mechanisms of interaction between m-AMSA and radiation other than the above cytokinetic cooperation.

In vitro and in vivo studies indicate that while activated NDPP is an efficient sensitizer of hypoxic mammalian cells in vitro, far better than Ro-07-0582 on a molar basis, the situation is reversed in vivo. Determinations of uptake of radioactive drug indicate that activated NDPP is capable of rapidly accumulating in mammalian cells, but no such effect is seen with Ro-07-0582. The uptake of activated NDPP shows a strong dependence on the cell density, whereas the uptake of Ro-07-0582 is little affected by cell density. These results suggest that the high sensitizing efficiency of activated NDPP is due to its ability to be concentrated by cells in a form which is still capable of sensitization and that the cell density effect is largely due to the depletion of the activated form or forms of NDPP. Evidence is also presented that activated NDPP reacts with cellular constituents, notably sulfhydryl compounds, and that the reaction with glutathione produces a compound which is capable of hypoxic cell sensitization. Such reaction products, which are resistant to washing, may explain the pretreatment sensitization produced by activated NDPP.