title: Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro.
abstract: Members of the multidrug resistance-associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.forename: Janice
authors.initials: J
authors.lastname: Smith
authors.forename: Kara
authors.initials: K
authors.lastname: Tanabe
authors.forename: Peter
authors.initials: P
authors.lastname: Tobin
authors.forename: Claudia
authors.initials: C
authors.lastname: Flemming
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Peter
authors.initials: P
authors.lastname: Wielinga
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.forename: John D
authors.initials: JD
authors.lastname: Allen
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D059004:Topoisomerase I Inhibitors; C073492:ABCC4 protein, human