Flux of teniposide (VM-26) across the plasma membrane of teniposide-resistant sublines of L1210 cells.

The flux of teniposide (VM-26) across the cell membrane was compared for L1210 cells, nine VM-26-resistant L1210 sublines, and three partially revertant lines. The nine resistant sublines were maintained in medium with VM-26. A "zero-time," temperature-independent binding of VM-26 to cells, attributable to adsorption on the cell membrane or to solvation in the membrane, varied independently of the sensitivity of cell lines to the drug as measured by the extracellular concentration of drug required to inhibit growth of a subline by 50% at the end of 24 hr (IC50). The IC50 values varied from 22 nM VM-26 for parental cells to 45 microM VM-26 for the most resistant subline. After subtraction of the zero-time values, the initial rates of influx for VM-26 (extracellular concentration, 20.5 microM) and the apparent equilibrium constants for the flux of drug across the cell membrane correlated inversely with the logarithm of the IC50 values. Cellular steady-state levels of VM-26, initial rates of efflux of the drug, and cellular levels of nondiffusible drug varied independently of the IC50 values but in relation to each other. The efflux of VM-26 from the sublines was faster than from the parental cells at both 4 degrees and at 37 degrees. We conclude that resistance of L1210 cells to VM-26 is associated with changes in the flux of the drug across the cell membrane.