title: Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides.
abstract: We have studied the potential contribution of ABCG2 (breast cancer resistance protein) to resistance to nucleoside analogues. In cells transfected with DNA constructs resulting in overexpression of human or mouse ABCG2, we found resistance against cladribine, clofarabine, fludarabine, 6-mercaptopurine, and 6-mercaptopurine riboside in both MDCKII and HEK293 cells and against gemcitabine only in HEK293 cells. With Transwell studies in MDCK cells and transport experiments with vesicles from Sf9 and HEK293 cells, we show that ABCG2 is able to transport not only the nucleotide CdAMP, like several other ATP-binding cassette transporters of the ABCC (multidrug resistance protein) family, but also the nucleoside cladribine itself. Expression of ABCG2 in cells results in a substantial decrease of intracellular CdATP, explaining the resistance against cladribine. The high transport rate of cladribine and clofarabine by ABCG2 deduced from Transwell experiments raises the possibility that this transporter could affect the disposition of nucleoside analogues in patients or cause resistance in tumors.
authors.affiliation: Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX The Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: de Wolf
authors.forename: Robert
authors.initials: R
authors.lastname: Jansen
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Marcel
authors.initials: M
authors.lastname: de Haas
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
authors.forename: Jos
authors.initials: J
authors.lastname: Beijnen
authors.forename: Piet
authors.initials: P
authors.lastname: Borst