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

TY - JOUR

T1 - Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein.

AU - Stam, [Unbekannt]

AU - van Den, Heuvel-Eibrink

AU - Den, Boer

AU - Ebus, [Unbekannt]

AU - Janka-Schaub, Gritta

AU - Allen, [Unbekannt]

AU - Pieters, R

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 18

SP - 78

EP - 83

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 1

M1 - 1

ER -