Toxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide in exponential- and plateau-phase Chinese hamster cell cultures.
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 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 of 0.245 +/- 0.019 (S.D.) microM 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, and 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. However, 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.
D000609:Aminoacridines / Q000633:toxicity*; D000677:Amsacrine; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008168:Lung; D010053:Ovary; D010100:Oxygen
D000609:Aminoacridines; D000677:Amsacrine; D010100:Oxygen