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.

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. 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. Uptake and cytotoxicity of WP744 were consistently greater than those of doxorubicin and daunorubicin at equimolar concentrations in all cell lines studied and in AML cells. WP744 overcomes transport by Pgp, MRP-1 and BCRP in cell lines and AML cells and is a promising agent for clinical development in AML and other malignancies with broad-spectrum multidrug resistance.

Citation

Tracy A Brooks, Kieran L O'Loughlin, Hans Minderman, Brian N Bundy, Laurie A Ford, Michael R Vredenburg, Ralph J Bernacki, Waldemar Priebe, Maria R Baer. 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. Investigational new drugs. 2007 Apr;25(2):115-22

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PMID: 17072745

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