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 s tate drug levels as compared to drug-sensitive controls. Recently it h as been pointed out that there appears to be a discrepancy between the amount of drug accumulated at steady state by drug-sensitive and high ly resistant cells and their degree of resistance. These observations could suggest two things: (1) that factors other than drug accumulatio n may be important in MDR, (2) that they reflect a discrepancy between the short-term measurements of drug accumulation at 60 min versus lon g-term (72 hr) growth inhibition. Due to the different experimental co nditions 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 ac cumulation. We have used a spectrofluorometric method which allows the determination of the nuclear drug accumulation directly on living cel ls. Our data clearly establish that, at least for the compounds used i n that study, there is a very good correlation between their ability t o increase drug accumulation, measured at short-term, and their abilit y to reverse MDR, but no correlation with their ability to inhibit pro tein kinase C activity. In addition, their efficiency to reverse MDR c orrelates with their pK(a) values, the efficiency being the highest wh en the pK(a) is the lowest.