P-glycoprotein (PGP) and lung resistance-related protein (LRP) expression and function in leukaemic blast cells.
P-glycoprotein (PGP) lung resistance protein (LRP) and multidrug resistance associated protein (MRP) expressions and function were evaluated by flow cytometry in 65 leukaemic patients (38 acute non-lymphocytic leukaemias, eight acute lymphocytic leukaemias, 19 Ph-positive chronic myeloid leukaemias in blastic phase). By using the MRK-16, the LRP-56 and the MRPm6 MoAbs, 34% of the cases did not over-express any proteins (-); 24.5% over-expressed (+) only PGP, 11% only LRP, 1.5% only MRP, 24.5% both PGP and LRP, and 4.5% both PGP and MRP. The mean intracellular daunorubicin accumulation (IDA) and rhodamine 123 (Rh123) retention in the presence or absence of the reversal agent SDZ PSC 833 (PSC) of the PGP-/LRP-/MRP- cases were comparable to the ones observed in normal leucocytes. With respect to the non-over-expressing cases, the PGP-/LRP+/MRP- cases showed only an impaired IDA (mean 204 +/- 29; P < 0.001). The PGP+/ LRP+/MRP- cases had a defect both in IDA (mean 166 +/- 47, P < 0.001) and Rh123 retention (mean 0.42 +/- 0.14: P < 0.001), which were both corrected by PSC. All the PGP+/LRP+/MRP- cases had a defect in IDA (mean daunorubicin (DNR) accumulation 192 +/- 44; P < 0.001). However, only in 8/16 of them an evident defect in Rh123 retention was found. In conclusion, both PGP and LRP over-expression were common in leukaemia. An impaired IDA was found in all cases over-expressing PGP, LRP or both. The study of Rh123 retention could give incorrect information about the blast cells' ability to accumulate cytotoxic drugs in patients over-expressing both PGP and LRP.
Michieli
M
M
Department of Bone Marrow Transplantation, University and General Hospital, Udine, Italy.
Damiani
D
D
Ermacora
A
A
Raspadori
D
D
Michelutti
A
A
Grimaz
S
S
Fanin
R
R
Russo
D
D
Lauria
F
F
Masolini
P
P
Baccarani
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D003630:Daunorubicin / Q000378:metabolism* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism* / Q000627:therapeutic use; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003630:Daunorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D020112:Rhodamine 123; D012235:Rhodamines; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein