Cooperative sequestration of m-AMSA in L1210 cells.
The anticancer drug 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) is known to bind to DNA by intercalation and to produce protein-associated DNA strand breaks in cells. Previous work [Zwelling et al., Biochemistry 20, 6553 (1981)] had shown that m-AMSA is in rapid equilibrium between extracellular and intracellular compartments, and that the DNA strand breaks exist in a steady state of rapid formation and resealing. The current work reports an unusual uptake phenomenon of m-AMSA by mouse leukemia L1210 cells that occurs at higher drug concentrations than previously studied. The new uptake phenomenon was characterized by cooperativity, hysteresis, irreversibility, saturability, slowness and temperature dependence. It is concluded that m-AMSA concentrations above a critical value can initiate the irreversible sequestration of m-AMSA into a new phase, probably in an extranuclear compartment of the cell, from which the drug has no access to the nuclear DNA and probably does not contribute to cytotoxicity.
D000494:Allosteric Regulation; D000609:Aminoacridines / Q000378:metabolism*; D000677:Amsacrine; D000818:Animals; D001386:Azides / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007364:Intercalating Agents / Q000494:pharmacology; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice
D000609:Aminoacridines; D001386:Azides; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D000677:Amsacrine