RELATIONSHIP BETWEEN CYTOTOXIC DRUG RESPONSE PATTERNS AND ACTIVITY OFDRUG EFFLUX TRANSPORTERS MEDIATING MULTIDRUG-RESISTANCE

Drug activity patterns in 10 human tumor cell lines representing defin ed mechanisms of drug resistance, including cell lines with high expre ssion of P-glycoprotein and multidrug resistance associated protein (M RP), have previously been used for prediction of mechanism of drug act ion. In the present study, this cell line panel was analyzed for cellu lar accumulation of the fluorescent probe calcein/AM [4'5'-bis(N,N-bis (carboxymethyl) aminomethyl) fluorescein acetoxymethyl ester] and com pared with drug response patterns of 20 standard chemotherapeutic drug s. According to degree of correlation with the ability to exclude calc ein/AM, topoisomerase II inhibitors and tubulin actives were at the to p of the list although the correlations were of lower magnitude than t hose obtained from the drug response patterns of mechanistically simil ar drugs. There was a significant relationship between the rank-order of drugs based on correlation with calcein/AM accumulation and Pgp/MRP mediated drug resistance suggesting that compounds being substrates f or these pumps were identified. In simulated drug response profiles, t he impact of Pgp and MRP expressing cell lines on the mechanistic pred iction was found to be marginal. The results indicate that the differe ntial molecular function/expression in the cell line panel may identif y drugs interacting with specific biochemical pathways. Furthermore, t he presence of cell lines overexpressing drug efflux mechanisms in the panel do not significantly influence the mechanistic predictions. (C) 1998 Elsevier Science B.V.