PMID- 7769842
OWN - NLM
STAT- MEDLINE
DCOM- 19950706
LR  - 20181130
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 9
IP  - 5
DP  - 1995 May
TI  - Lack of correlation between expression and function of P-glycoprotein in acute 
      myeloid leukemia cell lines.
PG  - 799-807
AB  - In a panel of acute myeloblastic leukemia (AML) cell lines, representative of 
      distinct differentiation stages, we investigated the possible correlation between 
      drug-resistance and both expression and function of the multidrug resistance 
      (MDR)-related P-glycoprotein (P-gp). The AML cell lines were KG1a, KG1, TF1, HEL, 
      ML1, and two non drug-selected P-gp positive subclones originating from HL-60 
      (HL-60JD) and U937 (U937AQ). All these cells overexpressed the mdr1 gene 
      (analyzed by RT-PCR) and displayed variable levels of P-gp expression. Flow 
      cytometric semi-quantitative evaluation of P-gp with two P-gp specific monoclonal 
      antibodies (MRK16 and UIC2) showed the following P-gp expression hierarchy: TF1 < 
      KG1a < HEL < KG1 < HL-60JD < ML1 < U937AQ; the latter expressing 13 times more 
      P-gp than TF1. When P-gp function was assessed by Rhodamine 123 (Rh123) efflux 
      kinetics, we found that only KG1a and KG1 cells, which have an early (immature) 
      CD34+ CD33- CD38- phenotype, and to a lesser extent TF1, with an intermediate 
      (CD34+ CD33+ CD38+) phenotype, displayed significant P-gp activity which could be 
      inhibited by both verapamil and SDZ PSC 833. In contrast, the other more mature 
      CD33+ CD34- AML cell lines presented no Rh123 efflux capacity although they 
      expressed higher P-gp levels. Daunorubicin (DNR) accumulation studies showed that 
      inhibitors of P-gp increased DNR accumulation only in the immature AML cells 
      whereas they had no impact on the mature AML cell lines. MTT drug cytotoxicity 
      assay confirmed that the immature AML cells were 10-15-fold more resistant to DNR 
      than the mature AML cells. Although P-gp inhibitors were able to increase the 
      cytotoxicity of DNR in AML cells which displayed functional P-gp, they could not 
      increase DNR cytotoxicity to levels comparable to that of the CD34- CD33+ cells, 
      suggesting that DNR resistance of immature AML cells may not solely be related to 
      P-gp. With drug-selection, AML subclones displayed higher levels of P-gp 
      expression and higher extruding capacities, and therefore chemoresistance, and 
      this independently of their initial differentiation phenotype. Finally, this 
      study provides evidence for a lack of correlation between expression and function 
      of P-gp in AML cells; this relationship being dependent upon leukemic cell 
      differentiation in unselected myeloid leukemic cells.
FAU - Bailly, J D
AU  - Bailly JD
AD  - Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS, Toulouse, 
      France.
FAU - Muller, C
AU  - Muller C
FAU - Jaffrezou, J P
AU  - Jaffrezou JP
FAU - Demur, C
AU  - Demur C
FAU - Gassar, G
AU  - Gassar G
FAU - Bordier, C
AU  - Bordier C
FAU - Laurent, G
AU  - Laurent G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Coloring Agents)
RN  - 0 (Rhodamines)
RN  - 1N3CZ14C5O (Rhodamine 123)
RN  - 5J49Q6B70F (Vincristine)
RN  - ZS7284E0ZP (Daunorubicin)
SB  - IM
GS  - mdr1
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/*physiology
MH  - Acute Disease
MH  - Cell Differentiation/physiology
MH  - Coloring Agents/pharmacokinetics
MH  - Daunorubicin/pharmacokinetics/pharmacology/toxicity
MH  - Drug Resistance
MH  - Drug Screening Assays, Antitumor
MH  - Flow Cytometry
MH  - Gene Expression
MH  - Humans
MH  - Immunohistochemistry
MH  - Leukemia, Myeloid/drug therapy/metabolism/*physiopathology
MH  - Phenotype
MH  - Polymerase Chain Reaction
MH  - Rhodamine 123
MH  - Rhodamines/pharmacokinetics
MH  - Transcription, Genetic
MH  - Tumor Cells, Cultured
MH  - Vincristine/pharmacology
EDAT- 1995/05/01 00:00
MHDA- 1995/05/01 00:01
CRDT- 1995/05/01 00:00
PHST- 1995/05/01 00:00 [pubmed]
PHST- 1995/05/01 00:01 [medline]
PHST- 1995/05/01 00:00 [entrez]
PST - ppublish
SO  - Leukemia. 1995 May;9(5):799-807.