TOXICITY OF 4'-(9-ACRIDINYLAMINO)METHANESULFON-META-ANISIDIDE IN EXPONENTIAL-PHASE AND PLATEAU-PHASE CHINESE-HAMSTER CELL-CULTURES

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (7) , 2809-2816
Abstract
The antitumor acridine derivative 4''-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) is at present being evaluated in Phase 2 clinical trials. Exposure of exponential-phase Chinese hamster [lung] V79-171b cells to physiologically attainable concentrations of m-AMSA for 60 min generates survival curves with little or no threshold region and an initial D0 [mean lethal dose] of 0.245 .+-. 0.019 (SD) .mu.M under standard conditions of assay. A minor subpopulation of apparently drug-resistant cells is revealed at low survivals, but these cells on culturing do not display a stable drug-resistant phenotype. m-AMSA survival curves for Chinese hamster ovary cells display features similar to the above. Sensitivity of V79-171b cells to m-AMSA is maximal near pH 7.2 and is markedly reduced by the presence of fetal calf serum. Hypoxia has little effect on the toxicity of m-AMSA; repair of potentially lethal damage has not been observed after treatment with this agent. Noncycling plateau-phase V79-171b or Chinese hamster ovary cells are markedly less sensitive to m-AMSA than are early log-phase cells. This resistance to m-AMSA appears to be related to the slowly cycling or noncycling status of plateau-phase cells, suggesting that the cytokinetic character of cell populations in vivo will be a major determinant of their sensitivity to this drug. The increase in resistance to m-AMSA during growth into plateau-phase appears to commence well before departure from exponential growth can be detected and may thus be a consequence of metabolic changes more subtle than the transition from a cycling to a noncycling state.