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Molecular Oncology, Markers, Clinical Correlates |
Departments of Hematology [D. M. v. d. K., E. V.] and Medical Oncology [D. M. v. d. K., E. G. E. d. V.] and Dutch-Belgian Hemato-Oncology Cooperative Group (Hovon) [E. V.], University Hospital Groningen, Groningen, the Netherlands; Department of Biostatistics, Daniel den Hoed Cancer Center, University Hospital Rotterdam, Rotterdam, the Netherlands [W. L. J. v. P.]; Department of Hematology, University Hospital Utrecht, Utrecht, the Netherlands [L. F. V.]; Free University Hospital Amsterdam, Amsterdam, the Netherlands [G. J. O.]; and Department of Hematology, University Hospital Leuven, Leuven, Belgium [G. E. G. V.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have recently presented a functional assay for MRP activity in which the fluorescent MRP substrate CF was used in combination with the leukotriene D4 receptor antagonist and MRP inhibitor MK-571 (22) in a flow cytometric assay (23) . MRP activity, expressed as CF efflux blocking by MK-571, correlated with the MRP1 protein expression in AML blasts.
The data about the importance of the expression and functional role of MRP1 in clinical drug resistance in AML are diverse. Some studies suggest that MRP1 mRNA expression is a prognostic factor for the achievement of CR in AML (24 , 25) and demonstrate increased expression of MRP1 mRNA at relapse (25) . Other studies describe no effect of MRP1 mRNA and protein expression on the treatment outcome of de novo AML patients (26, 27, 28) . An additional study by Legrand et al. (29) of 56 AML patients reported that MRP functional activity, as determined in a flow cytometric assay with calcein and the MRP inhibitor probenecid, but not MRP1 protein expression, is an unfavorable prognostic factor for the achievement of CR. The same group recently presented a study in which a correlation is described between simultaneous activity of MRP and P-gp and in vivo resistance in AML (30) .
In the present study, the clinical significance of the functional activity of MRP and P-gp and the relationship between both transporters in 104 de novo AML patients were studied. MRP and P-gp activities were determined in protocol-treated patients with a flow cytometric assay using CF with the MRP inhibitor MK-571 and Rh123 with the P-gp inhibitor PSC833. MRP1, MRP2, and MDR1 mRNA levels were determined by RT-PCR. GSH level was measured in a flow cytometric assay with the GSH substrate MCB. Univariate and multivariate analyses were performed, and the results were compared with known prognostic factors and with clinical outcome.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20 x
106) were collected. Several clinical
characteristics were determined, such as biological characteristics
(WBC count, FAB classification, and karyotype) and the response to
treatment. Cytogenetic analysis was performed using standard binding
techniques according to the International System for Human Cytogenetic
Nomenclature ISCN 1995. The patients were treated according to the
standard protocol of the Dutch-Belgian Hemato-Oncology Cooperative
Hovon Group (31)
for AML Hovon 4/4A or Hovon 29
(32)
. Protocol Hovon 4/4A consisted of daunorubicin (45
mg/m2
, i.v., days 1–3) plus Ara-C (200
mg/m2
, i.v., days 1–7), followed by a second
induction cycle of amsacrine (120 mg/m2
, i.v.,
days 4–6) plus Ara-C (2 g/m2
, i.v., days 1–6).
The AML Hovon 29 protocol consisted of the same regimen as the Hovon
4/4A protocol, except that idarubicin (12 mg/m2
,
i.v., days 5–7) was used instead of daunorubicin in induction cycle 1.
Hovon 4/4A patients were randomized to treatment with or without
granulocyte macrophage colony-stimulating factor (5 µg/kg, s.c.)
after each cycle of chemotherapy. Hovon 29 patients were randomized
between treatment with or without granulocyte colony-stimulating factor
(150 µg/m2
/day, s.c.) during chemotherapy.
Hovon 29 patients with FAB classification M3 received
all-trans-retinoic acid. After the two induction cycles,
patients were to receive a third cycle consisting of mitoxantrone (10
mg/m2
, i.v., days 1–5) plus etoposide (100
mg/m2
, i.v., days 1–5), an autograft, or a
HLA-matched allograft, depending on the risk estimates according to
protocol and the availability of a HLA-matched donor. CR status was
determined after each cycle of chemotherapy and after transplantation
and was defined as normocellular peripheral blood and <5%
blasts in a bone marrow smear.
Cell Lines.
The human small cell lung cancer cell line GLC4 (33)
and
the in vitro doxorubicin-selected MRP1-overexpressing
sublines GLC4/ADR2x, GLC4/ADR25x, and GLC4/ADR150x (the numbers
indicate the resistance factor for doxorubicin; Ref. 34
)
were cultured in RPMI 1640 (BioWhittaker, Brussels, Belgium)
supplemented with 10% FCS (Hyclone, Logan, UT). The
doxorubicin-selected cell lines were cultured in the presence of
doxorubicin (2 µM; Pharmacia and UpJohn,
Woerden, the Netherlands).
The MDR1-transfected cell line GLC4/P-gp (35 , 36) was cultured in RPMI 1640 with 10% FCS in the presence of 50 nM vincristine (Teva Pharma BV, Mijdrecht, the Netherlands).
Sample Preparation.
Mononuclear cells from bone marrow or peripheral blood were enriched by
Ficoll-Isopaque (Nycomed, Oslo, Norway) density gradient
centrifugation. The cells were cryopreserved in RPMI 1640 supplemented
with 10% FCS and 10% DMSO (Merck, Amsterdam, the Netherlands) and
stored at -196°C. On analysis, cells were thawed, centrifuged in
normal calf serum (Life Technologies, Inc., Breda, the Netherlands),
treated with DNase (Boehringer Mannheim, Mannheim, Germany), and washed
with RPMI 1640. Subsequently, the AML cells were incubated for
1 h in RPMI 1640 supplemented with 10% FCS at 37°C in 5%
CO2. Viability of the cells was determined by
trypan blue exclusion, and cases with a viability of <90% were
excluded from this study.
Flow Cytometric Detection of Functional Drug Efflux.
Functional activity of the MRP and P-gp transporters was demonstrated
as described previously (22)
. To determine MRP activity,
the CFDA compound (Sigma Chemical Co., Bornem, Belgium) was used, which
permeates the plasma membrane and is transformed into the fluorescent
anion CF on cleavage of the ester bonds. CFDA was used in combination
with the leukotriene D4 receptor antagonist and MRP inhibitor MK-571
[provided by Dr. A. W. Ford-Hutchinson; Merck Sharp, Kirkland,
Quebec, Canada (37)
]. For the detection of P-gp activity,
Rh123 (Sigma Chemical Co.) was used together with the P-gp inhibitor
PSC833 (provided by Novartis Pharma Inc., Basel, Switzerland).
Cells (0.5 x 106) were loaded for 20 min at 37°C in 5% CO2 with 0.1 µM CFDA or 200 ng/ml Rh123 with or without inhibitor (20 µM MK-571 or 2 µg/ml PSC833) in RPMI 1640. Thereafter, cells were washed in ice-cold medium and incubated for 1 h in drug-free medium with or without inhibitor at 37°C in 5% CO2 to allow efflux to occur. Efflux was stopped by pelleting the cells and adding ice-cold medium. Fluorescence of CF and Rh123 was analyzed with a FACStar flow cytometer (Becton Dickinson Immune Cytometry Systems, Mountain View, CA) equipped with an argon laser. The blast population was gated by forward- and side-scatter characteristics. CF and Rh123 fluorescence of 10,000 events was measured logarithmically through a 530 nm bandpass filter at an excitation wavelength of 488 nm. Each time the assay was performed, a mixture of beads with several different, known numbers of molecules of FITC fluorescent dye (Flow Cytometry Standards Europe, Leiden, the Netherlands) was measured under the same conditions. The logarithmically acquired signals were converted geometrically into linear values and expressed as MESF units using the programs Quick Call for Winlist and Winlist 32 (Verity Software House, Inc., Topsham, ME). CF and Rh123 accumulation after 1 h of efflux, as a measure for MRP and P-gp activity, respectively, was expressed in MESF units. The efflux-blocking factors of the inhibitors were expressed as the median MESF value in inhibitor-blocked cells divided by the median MESF value in unblocked cells after 1 h of efflux. Each time the assay was performed, GLC4 cells served as a control.
Flow Cytometric Detection of GSH.
GSH-bimane conjugates were detected in a flow cytometric assay as
described by Lorico et al. (38)
, with some
modifications. Cells (0.5 x 106) were
incubated with 10 µM MCB (Calbiochem-Behring,
La Jolla, CA) for 1 h at 4°C. At this concentration and
incubation time, a plateau of intracellular fluorescence was reached.
The cellular fluorescence of GSH-bimane conjugates was measured with an
Epics-Elite flow cytometer (Coulter Electronics, Hialeah, FL). Emission
was collected with a 525 nm bandpass filter with an argon laser tuned
at 350 nm. To standardize the assay, the fluorescence of MCB-treated
GLC4 cells from a frozen stock was measured each time the assay was
performed. GSH content of the patient samples was expressed as the
median fluorescence percentage of the GLC4 cells, and a
correction for cell size, as measured by forward-scatter
characteristics, was applied.
RNA Extraction and RT-PCR Analysis for MRP1, MRP2, and MDR1.
Total cellular RNA was isolated from 5–10 x
106 AML blasts or cell line cells using
Trizol reagent (Life Technologies, Inc.). RNA was extracted,
precipitated, and washed according to the manufacturer’s protocol.
Five µg of RNA were reverse-transcribed and supplemented with
H2O up to a final volume of 50 µl. The PCR
reactions were performed under the following conditions. For MRP1, 29
cycles of denaturation (95°C, 30 s), annealing (56°C, 30 s), and extension (72°C, 30 s) were performed. For the cell line
samples, 27 PCR cycles were performed. For MRP2, 31 cycles (95°C,
58°C, and 72°C, 30 s) were performed; for MDR1, 31 cycles
(95°C, 55°C, and 72°C, 30 s) were performed; and for ß-2
microglobulin, 20 cycles (95°C, 55°C, and 72°C, 30 s) were
performed. The amplified products contain 990 bp for MRP1, 1067
bp for MRP2, 161 bp for MDR1, and 268 bp for ß-2 microglobulin.
Reaction products were separated on a 1.5% agarose gel and visualized
by ethidium bromide staining. The absorbance of the visualized bands
was expressed as absorbance x mm2
using
the program Diversity One 1D (PDI, New York, NY). The mRNA
expression the MDR genes was expressed as the absorbance x
mm2
of the MRP1, MRP2, or MDR1 PCR product
divided by the absorbance x mm2
of the
ß-2 microglobulin PCR product.
Statistical Analysis.
The analysis presented here must be considered primarily exploratory.
The implicit hypothesis or expectation at the initiation of the study
was that low accumulation or high efflux blocking would go together
with a low CR rate and a high overall death rate. However, because it
was unknown whether such a relation would be more or less continuous or
whether a cutpoint would exist depending on the parameter considered,
the following explorative approach was followed. CR after cycle 1 was
chosen as the primary end point for measuring response on treatment,
whereas OS was used for measuring overall outcome. Logistic regression
analysis was used to test for association between a factor and the
probability of CR after cycle 1. Cox regression analysis was used to
test for an association with death rate. Tests for trend in such an
analysis with a continuous parameter were done by using a logarithmic
transform of the parameter as a covariate in the analysis. Due
to the lack of a priori cutpoints, the range of each
continuous variable was arbitrarily subdivided into three subgroups of
equal size to determine CR rates in these subgroups with low, medium,
and high values. When a significant association was observed, isotonic
regression (39)
analysis was performed to search for an
optimal cutpoint to subdivide low and high values. The method of Kaplan
and Meier was used to calculate survival curves and probabilities
(40)
. Tests for trend in regression analyses were
performed with and without adjustment for risk group. Spearman rank
correlation was used as a measure for the association between
continuous variables. The Kruskal-Wallis test was used to test for
differences between subgroups in the distribution of ordinal variables.
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RESULTS |
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. Considering the FAB classifications and cytogenetics, the patients
were subdivided into three groups, i.e., favorable karyotype
[t(8;21); FAB classification M3 with t(15;17), inv(16)
, del(16)
, or
t(16)
; WBC count < 20 x 109/l], very
poor (-5/5q, -7/7q), or poor [other karyotypes (Table 1)
]. Twenty-four patients (23%) achieved no CR at any moment, and 49
patients (47%) relapsed or died in CR; thus, 31 patients (30%) were
in CR at the time of evaluation (Table 1)
. The median follow-up time of
the patients still alive (n = 38) was 15 months (range,
2–109 months). The last patient was entered in March 1998, and the
time of evaluation was November 1998.
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. In normal bone marrow control cells, these values are 1.8 ± 0.4
(mean ± SD) for Rh123 efflux blocking by PSC833 and 2.8 ±
0.5 for CF efflux blocking by MK-571 (41)
. A strong
negative correlation was observed between Rh123 efflux-blocking factor
PSC833 and Rh123 accumulation measured after 60 min of efflux
(rs = -0.69; P < 0.001) and
between CF efflux-blocking factor of MK-571 and CF accumulation after
60 min of efflux (rs = -0.59; P < 0.001). No correlation was observed between Rh123 efflux blocking by
PSC833 and CF efflux blocking by MK-571 (P = 0.08).
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The distributions of CF accumulation and CF efflux-blocking factors of MK-571 were similar in all three risk groups (Kruskal-Wallis test, P > 0.20). However, Rh123 accumulation was lower in the very poor risk patients [-5/5q and -7/7q (median, 66,478 versus 162,334; P = 0.05)], and Rh123 efflux-blocking factor of PSC833 was higher in this subgroup of patients (median, 3.2 versus 1.3; P = 0.005).
No correlation was observed between the five MDR parameters (Rh123 efflux blocking by PSC833, Rh123 accumulation, CF efflux blocking by MK-571, CF accumulation, and GSH level) and age. A weak correlation was found between WBC count and Rh123 accumulation (rs =0.25; P = 0.01) and Rh123 efflux blocking of PSC833 (rs = -0.23; P = 0.02).
Considering the FAB classifications, AML patients with FAB classifications M1 or M2 showed a lower Rh123 accumulation than patients with FAB classifications of M4 or M5 (P = 0.02). However, Rh123 efflux-blocking factors of PSC833 did not differ between these groups (P = 0.39). With respect to CF accumulation or CF efflux blocking by MK-571 or GSH level, no differences were observed between patients with FAB classifications of M1 or M2 and patients with FAB classifications of M4 or M5.
MRP1, MRP2, and MDR1 mRNA Expression in Cell Lines and AML
Patients.
Total cellular RNA was obtained from 18 patient samples and from GLC4,
GLC4/ADR2x, GLC4/ADR25x, GLC4/ADR150x, and GLC4/P-gp cell lines. mRNA
expression of ß-2 microglobulin and MRP1 of the cell lines is shown
in Fig. 1
A (MDR1 data not shown) and correlated well with the MRP and
P-gp functions. The MRP1-overexpressing cell lines showed CF
efflux-blocking factors of MK-571 between 4.4 ± 1.1 and 21.3 ± 6.0 (n = 3; Fig. 1
B). The GLC4 cell line
and its MDR1-transfected counterpart GLC4/P-gp demonstrated Rh123
efflux-blocking factors by PSC833 of 0.8 ± 0.3 (n = 3) and 3.0 ± 0.8 (n = 5), respectively (Fig. 1
B).
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A) and between MDR1 mRNA expression and Rh123 efflux-blocking
factors of PSC833 (r = 0.63; P < 0.01;
n = 18; Fig. 2
B). No correlation was
observed between MRP2 mRNA expression and CF efflux-blocking factors of
MK-571 in the AML patient samples (data not shown).
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Eighty patients reached CR; of these patients, 49 achieved CR1. Table 3
shows the probabilities of reaching CR1 in subgroups of almost equal
size defined by risk, age, and the MDR parameters considered. Risk
group was the most important factor for reaching CR1; 100% of good
risk patients versus 14% of very poor risk patients
achieved CR1 (P < 0.001). No correlation was found
between age and the achievement of CR. A low Rh123 accumulation and a
high Rh123 efflux blocking of PSC833 were associated with a low CR1
rate (P = 0.008 and P = 0.01,
respectively). It was observed that the CR1 rate in the subgroup with
the lowest Rh123 accumulation was 25% versus 58% in the
subgroup with the highest Rh123 accumulation. Isotonic regression
analysis suggested 90,000 MESF units as an optimal cutpoint for a
subdivision of low and high Rh123 accumulation. A low CF accumulation
was also associated with a lower CR1 rate (P = 0.04);
the subgroup with the lowest CF accumulation had a CR1 rate of 34%
versus 48% in the group with the highest accumulation,
but the differences were minor as compared with the Rh123 accumulation,
and a test for trends based on the logarithmic transform showed
no statistical significance. Of special interest is the fact that the
subgroup of patients with high efflux-blocking factors of both Rh123
and CF had a CR1 rate of 0% (n = 14), and the
subgroup of patients with both low efflux-blocking factors of Rh123 and
CF showed a CR1 rate of 56% (n = 57; Table 3
). The
patients with low accumulation of both Rh123 (<90,000 MESF units) and
CF (<157,900 MESF units) had the lowest CR1 rate (6%;
n = 16), whereas the subgroup of patients with both
high Rh123 (>90,000 MESF units) and CF (>350,000 MESF units)
accumulation had a CR1 rate of 73% (n = 11; Table 3
).
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; Table 3
), although it is interesting to note that the lowest 5-year
survival rates were observed for the patients with a low Rh123 and CF
accumulation or a high Rh123 and CF efflux blocking (Table 3)
. Risk
group was the only predictive parameter for OS (P =
0.003).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These discrepancies
might reflect the presence of MRP1 homologues, additional unknown
efflux pumps, or the existence of a dysfunctional P-gp or MRP1 protein.
With regard to the GSH level, GSH content in AML cells correlated well
with MRP function, as measured by CF efflux blocking of MK-571. In some
other studies, chemotherapeutic drugs, such as vincristine and
daunorubicin, are described as being transported by MRP in a
GSH-dependent way (16
, 21
, 45)
. However, CF is transported
by MRP in a GSH-independent manner. A coordinated induction of MRP and
GSH-related enzymes is reported in drug-resistant human leukemia cells
and colon cancer cells (46
, 47)
, which might also be the
case in the present study. This study demonstrates that MRP activity is not an independent prognostic factor for the achievement of CR after chemotherapy cycle 1, although patients with both high P-gp and MRP activity show a lower CR rate after cycle 1 than patients with low P-gp and MRP activity. CR rate after cycle 1 was chosen as an end point for this study because all patients received the MDR drugs daunorubicin or idarubicin only in induction cycle 1, whereas only a subgroup of patients (33 of 104 patients) was treated with the MDR drug mitoxantrone in the third cycle of chemotherapy. Legrand et al. (30) recently reported that not only P-gp but also MRP activity was a prognostic factor for achieving CR in AML. In addition, their study described a correlation between the simultaneous activity of P-gp and MRP and the OS of the patients. The discrepancy between both studies with regard to OS is not clear because in both studies, MDR drugs were applied in the first course of chemotherapy.
When the subgroup of patients who received mitoxantrone in the third cycle of chemotherapy (33 of 104 patients) was analyzed separately, a trend was observed between MRP function and EFS after 24 months, but not between P-gp function and EFS, which suggests that mitoxantrone is effluxed by MRP and is not effluxed or is effluxed to a lesser extent by P-gp. Thus far, results of the studies on mitoxantrone as a substrate for P-gp or MRP are conflicting. Mitoxantrone has been described to be a substrate for P-gp (48 , 49) , whereas in certain P-gp-positive cell lines, no effect of a P-gp inhibitor on mitoxantrone sensitivity was observed (50) . With regard to MRP, it has been reported that MRP does not play a role in effluxing mitoxantrone (51 , 52) , although a cross-resistance has been described for mitoxantrone in a MRP1-positive cell line selected for resistance to etoposide (53) .
P-gp activity was higher in the very poor risk group as compared with the other risk groups, which was also observed in the study of Legrand et al. (30) . However, when adjusted for risk group, P-gp activity was not an independent predictive factor for OS. The only predictive parameter for OS appeared to be the defined risk group.
Rh123 accumulation was lower in FAB classifications M1 and M2 than in FAB classifications M4 and M5, demonstrating a higher P-gp activity in myeloblastic cells than in monoblastic AML cells. Because the expression of the CD34 antigen is greater on myeloid cells than on monocytic cells, these findings are in agreement with the results of Te Boekhorst et al. (54) , who reported a predominance of functional P-gp in CD34-positive AML cells.
In view of the results obtained, the possibility of measuring P-gp and MRP activities in newly diagnosed AML patients before the chemotherapy regimen should be considered to construct a risk analysis in which patients with high P-gp and MRP activities can be identified. This would allow us to analyze whether treatment with a limited number of MDR drugs or inhibitors of P-gp as well as MRP function might improve the results.
Thus far, the use of competitive inhibitors of P-gp such as cyclosporin A and PSC833 in Phase II/III clinical studies has shown diverse results. Some studies indicate that the use of inhibitors improves the uptake of drugs in cells of patients with AML and multiple myeloma (55, 56, 57) , whereas other studies report an increased toxicity due to these inhibitors as a result of a change in the pharmacokinetics (58 , 59) . Furthermore, it is conceivable that in cases in which P-gp function is inhibited, additional MDR proteins such as MRP1 or one of its homologues can take over the P-gp function, at least in part. Therefore, for a full understanding of the mechanism of MDR modulation, the evaluation of activity and expression of all known MDR proteins will be required in future studies.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Department of Hematology, Division of Internal Medicine,
University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the
Netherlands. Phone: 31-50-3612354; Fax: 31-50-3614862; E-mail: E.Vellenga{at}int.azg.nl 
2 The abbreviations used are: Ara-C,
1-ß-D-arabinofuranosylcytosine; AML, acute myeloid
leukemia; P-gp, P-glycoprotein; MRP, multidrug resistance protein; CF,
carboxyfluorescein; CFDA, carboxyfluorescein diacetate; Rh123,
rhodamine 123; CR, complete remission; FAB, French-American-British;
MDR, multidrug resistance; OS, overall survival; GSH, glutathione;
RT-PCR, reverse transcription-PCR; MCB, monochlorobimane; MESF,
molecule equivalents of soluble fluorochrome; CR1, complete remission
after induction cycle 1; EFS, event-free survival.
Received 10/21/99; revised 3/16/00; accepted 5/ 9/00.
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D. M. van der Kolk, E. Vellenga, G. L. Scheffer, M. Muller, S. E. Bates, R. J. Scheper, and E. G. E. de Vries Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia Blood, May 15, 2002; 99(10): 3763 - 3770. [Abstract] [Full Text] [PDF]
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