Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein

R W Stam, M M van den Heuvel-Eibrink, M L den Boer, M E G Ebus, G E Janka-Schaub, J D Allen, R Pieters

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45 Citations (Scopus)


Infants with acute lymphoblastic leukemia (ALL) are more resistant to chemotherapeutic drugs than older children with ALL, except for Ara-C. Drug resistance mechanisms in infant ALL, however, remain unknown. Possibly, multidrug resistance (MDR) proteins like P-glycoprotein, MDR-associated protein (MRP1), lung resistance-related protein (LRP/MVP) and the breast cancer resistance protein (BCRP) play a role. Accordingly, we measured the mRNA levels of these proteins in infants (n=13) and non-infants (n=13) with ALL, using quantitative RT-PCR. Infants expressed 2.4-fold less BCRP mRNA (P=0.009) than non-infants with ALL. MDR1, MRP1 and LRP/MVP expression did not differ between both groups. MDR gene expression levels did not correlate to prednisolone, vincristine, daunorubicin or Ara-C cytotoxicity, except for BCRP expression, which correlated with resistance to Ara-C (Rs=0.53, P=0.012), suggesting that Ara-C might be a BCRP substrate. However, culturing patients ALL cells in the presence of the BCRP inhibitor Ko143 had no effect on Ara-C sensitivity. Inhibiting Bcrp1 in the Mdr1a-, Mdr1b- and Mrp1-deficient and Bcrp1-overexpressing mouse cell line Mef3.8/T6400, also did not modulate Ara-C cytotoxicity. Therefore, we conclude that Ara-C is not a substrate for BCRP and that MDR proteins do not play a significant role in drug resistance in infant ALL.

Original languageEnglish
Pages (from-to)78-83
Number of pages6
Issue number1
Publication statusPublished - Jan 2004
Externally publishedYes


  • ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters/genetics
  • Animals
  • Antimetabolites, Antineoplastic/metabolism
  • Antineoplastic Agents/pharmacology
  • Cell Survival/drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cytarabine/metabolism
  • Drug Resistance, Multiple/genetics
  • Drug Resistance, Neoplasm/genetics
  • Fibroblasts/metabolism
  • Gene Expression Regulation, Leukemic
  • Humans
  • Infant
  • Mice
  • Neoplasm Proteins/genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • RNA, Messenger/metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Topotecan/pharmacology
  • Vault Ribonucleoprotein Particles/genetics


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