Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein.

Article Details

Citation

Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH

Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein.

Cancer Res. 2003 Mar 15;63(6):1339-44.

PubMed ID
12649196 [ View in PubMed
]
Abstract

The breast cancer resistance protein [BCRP (BCRP/ABCG2)] has not previously been directly identified as a source of resistance to epipodophyllotoxins.However, when P-glycoprotein (P-gp)- and Mrp1-deficient mouse fibroblast and kidney cell lines were selected for resistance to etoposide, amplification and overexpression of Bcrp1 emerged as the dominant resistance mechanism in five of five cases. Resistance was accompanied by reduced intracellular etoposide accumulation. Bcrp1 sequence in all of the resistant lines was wild-type in the region spanning the R482 mutation hot spot known to alter the substrate specificity of mouse Bcrp1 (mouse cognate of BCRP) and human BCRP. Transduced wild-type Bcrp1 cDNA mediated resistance to etoposide and teniposide in fibroblast lines and trans-epithelial etoposide transport in polarized Madin-Darby canine kidney II cells. Bcrp1-mediated etoposide resistance was reversed by two structurally different BCRP/Bcrp1 inhibitors, GF120918 and Ko143. BCRP/Bcrp1 (inhibition) might thus impact on the antitumor activity and pharmacokinetics of epipodophyllotoxins. However, treatment of P-gp-deficient mice with GF120918 did not improve etoposide oral uptake, suggesting that Bcrp1 activity is not a major limiting factor in this process. In contrast, use of GF120918 to inhibit P-gp in wild-type mice increased the plasma levels of etoposide after oral administration 4-5-fold. It may thus be worthwhile to test inhibition of P-gp in humans to improve the oral availability of etoposide.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
DoxorubicinATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details
EtoposideATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details
MitoxantroneATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details
TeniposideATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details
TopotecanATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details
VincristineATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Substrate
Details