Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

Murray D. Norris, Janice Smith, Kara Tanabe, Peter Tobin, Claudia Flemming, George L. Scheffer, Pieter Wielinga, Susan L. Cohn, Wendy B. London, Glenn M. Marshall, John D. Allen, Michelle Haber

Research output: Contribution to journalJournal articleResearchpeer-review

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.
Original languageEnglish
JournalMolecular Cancer Therapeutics
Volume4
Issue number4
Pages (from-to)547-553
ISSN1535-7163
Publication statusPublished - 2005
Externally publishedYes

Keywords

  • neuroblastoma Neuroblastoma (MeSH) nervous system disease, neoplastic disease drug therapy, genetics
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrate) - Hominidae [86215] human common
  • human MRP1 gene [Hominidae] human multidrug resistance protein 1 gene gene expression
  • human MRP4 gene [Hominidae] human multidrug resistance protein 4 gene gene expression
  • human MYCN gene [Hominidae] amplification
  • CPT-11 100286-90-6 antineoplastic-drug
  • irinotecan 97682-44-5 antineoplastic-drug
  • multidrug resistance-associated proteins
  • nucleoside analogs
  • SN-38 86639-52-3 antineoplastic-drug
  • topoisomerase I 143180-75-0
  • 03502, Genetics - General
  • 03508, Genetics - Human
  • 10006, Clinical biochemistry - General methods and applications
  • 10060, Biochemistry studies - General
  • 10802, Enzymes - General and comparative studies: coenzymes
  • 12512, Pathology - Therapy
  • 20504, Nervous system - Physiology and biochemistry
  • 20506, Nervous system - Pathology
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • Allied Medical Sciences
  • Biochemistry and Molecular Biophysics
  • Human Medicine, Medical Sciences
  • nervous system nervous system
  • Clinical Chemistry
  • Molecular Genetics
  • Neurology
  • Oncology
  • Pharmacology

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