Relationship between cytotoxic drug response patterns and activity of drug efflux transporters mediating multidrug resistance.
Drug activity patterns in 10 human tumor cell lines representing defined mechanisms of drug resistance, including cell lines with high expression of P-glycoprotein and multidrug resistance associated protein (MRP), have previously been used for prediction of mechanism of drug action. In the present study, this cell line panel was analyzed for cellular accumulation of the fluorescent probe calcein/AM [4'5'-bis(N,N-bis (carboxymethyl) aminomethyl) fluorescein acetoxymethyl ester] and compared with drug response patterns of 20 standard chemotherapeutic drugs. According to degree of correlation with the ability to exclude calcein/AM, topoisomerase II inhibitors and tubulin actives were at the top of the list although the correlations were of lower magnitude than those obtained from the drug response patterns of mechanistically similar 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 for these pumps were identified. In simulated drug response profiles, the impact of Pgp and MRP expressing cell lines on the mechanistic prediction was found to be marginal. The results indicate that the differential molecular function/expression in the cell line panel may identify drugs interacting with specific biochemical pathways. Furthermore, the presence of cell lines overexpressing drug efflux mechanisms in the panel do not significantly influence the mechanistic predictions.
Dhar
S
S
Division of Clinical Pharmacology, University Hospital, Uppsala, Sweden. sumeer.dhar@klinfarm.uu.se
Nygren
P
P
Liminga
G
G
Sundström
C
C
de la Torre
M
M
Nilsson
K
K
Larsson
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005452:Fluoresceins / Q000494:pharmacology; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D059005:Topoisomerase II Inhibitors; C085925:calcein AM