Correlation between the short-term measurements of drug accumulation in living cells and the long-term growth inhibition.

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance (P-gp-MDR) is a decrease of steady state drug levels as compared to drug-sensitive controls. Recently it has been pointed out that there appears to be a discrepancy between the amount of drug accumulated at steady state by drug-sensitive and highly resistant cells and their degree of resistance. These observations could suggest two things: (1) that factors other than drug accumulation may be important in MDR, (2) that they reflect a discrepancy between the short-term measurements of drug accumulation at 60 min versus long-term (72 hr) growth inhibition. Due to the different experimental conditions and the different type of cells used it is very difficult to compare the literature data. For this reason we have investigated the effect of 12 compounds in overcoming resistance in relation to drug accumulation. We have used a spectrofluorometric method which allows the determination of the nuclear drug accumulation directly on living cells. Our data clearly establish that, at least for the compounds used in that study, there is a very good correlation between their ability to increase drug accumulation, measured at short-term, and their ability to reverse MDR accumulation, measured at short-term, and their ability to reverse MDR, but no correlation with their ability to inhibit protein kinase C activity. In addition, their efficiency to reverse MDR correlates with their pKa values, the efficiency being the highest when the pKa is the lowest.