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- Title
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.
- Authors
Kieran O’Loughlin; Hans Minderman; Brian Bundy; Laurie Ford; Michael Vredenburg; Ralph Bernacki; Waldemar Priebe
- Abstract
<div class="abstract"><a name="abs1"/><span class="abstractheading">Summary??</span>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 (BCRPR482) or mutant (BCRPR482T, BCRPR482G) BCRP and in pre-treatment AML marrow cells.Results: 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.Conclusion: 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.</div>
- Subjects
DOXORUBICIN; ANTHRACYCLINES; GLYCOPROTEINS; GLYCOCONJUGATES
- Publication
Investigational New Drugs, 2007, Vol 25, Issue 2, p115
- ISSN
0167-6997
- Publication type
Article