The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.

Background: The synthetic 4'-O-benzylated doxorubicin analog WP744 was designed to abrogate transport by the multidrug resistance (MDR)-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1). We compared its uptake and cytotoxicity with those of doxorubicin and daunorubicin in cell lines overexpressing Pgp, MRP-1 or breast cancer resistance protein (BCRP) and in acute myeloid leukemia (AML) cells.

Methods: Cellular uptake was studied by flow cytometry and cytotoxicity in 96-h 96-well cultures in cell lines overexpressing Pgp, MRP-1 or wild type (BCRP(R482)) or mutant (BCRP(R482T), BCRP(R482G)) BCRP and in pre-treatment AML marrow cells.