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¹ Children's Cancer Institute Australia for Medical Research; ² Centenary Institute of Cancer Medicine and Cell Biology; ³ School of Pharmacology, and ⁴ Faculty of Medicine, University of Sydney, Sydney, Australia; ⁵ Department of Pathology, Free University Medical Centre; ⁶ Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands; ⁷ Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; and ⁸ Department of Statistics, University of Florida and Children's Oncology Group Statistical Department, Gainesville, Florida

Requests for reprints: John D. Allen, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag 6, Newtown, New South Wales 2042, Australia. Phone: 61-2-9565-6156; Fax: 61-2-9565-6101. E-mail: j.allen{at}centenary.usyd.edu.au

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.

Key Words: neuroblastoma • MRP4 • Irinotecan • prognostic marker • drug resistance • Pediatric cancers • Drug transport and metabolism • Molecular pharmacology • Molecular diagnosis and prognosis • Drug Resistance

Grant support: National Health and Medical Research Council, Australia (M.D. Norris, G.M. Marshall, J. Allen, and M. Haber), Cancer Council New South Wales, Australia (M.D. Norris, G.M. Marshall, and M. Haber), and Ronald Geoffrey Arnott Foundation (J.D. Allen).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital.

⁹ G.L. Scheffer, manuscript in preparation

Received 7/ 1/04; revised 2/ 6/05; accepted 2/21/05.