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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1758-1766
NEOPLASIA
From the Department of Experimental Oncology, Istituto Nazionale
Tumori, Milan; Cancer Center, University of Colorado Health Sciences
Center, Denver, CO; Mario Negri Institute, Milan; and Section of
Hematology, University of Milano Bicocca, S. Gerardo Hospital, Monza,
Italy.
The 2-phenylaminopyrimidine derivative STI571 has been shown to
selectively inhibit the tyrosine kinase domain of the oncogenic bcr/abl fusion protein. The activity of this inhibitor has been demonstrated so far both in vitro with bcr/abl expressing cells derived from leukemic patients, and in vivo on nude mice inoculated with bcr/abl positive cells. Yet, no information is available on whether leukemic cells can develop resistance to bcr/abl
inhibition. The human bcr/abl expressing cell line LAMA84 was
cultured with increasing concentrations of STI571. After approximately
6 months of culture, a new cell line was obtained and named LAMA84R.
This newly selected cell line showed an IC50 for the STI571 (1.0 µM) 10-fold higher than the IC50 (0.1 µM) of the parental sensitive cell
line. Treatment with STI571 was shown to increase both the early and
late apoptotic fraction in LAMA84 but not in LAMA84R. The induction of
apoptosis in LAMA84 was associated with the activation of caspase
3-like activity, which did not develop in the resistant LAMA84R cell
line. LAMA84R cells showed increased levels of bcr/abl protein and mRNA
when compared to LAMA84 cells. FISH analysis with BCR- and ABL-specific
probes in LAMA84R cells revealed the presence of a marker chromosome
containing approximately 13 to 14 copies of the BCR/ABL gene.
Thus, overexpression of the Bcr/Abl protein mediated through gene
amplification is associated with and probably determines resistance of
human leukemic cells to STI571 in vitro.
(Blood. 2000;95:1758-1766)
The blockade of Bcr/Abl kinase activity
represents a rational strategy to treat leukemias caused by this
oncogenic fusion protein. Expression of the bcr/abl oncogenic
product has been found in virtually all patients with chronic
myelogenous leukemia (CML) and in 30% to 50% of adult patients with
acute lymphoblastic leukemia (ALL). bcr/abl bears a causal
relationship with both CML and ALL1,2; in addition,
increased bcr/abl levels have been associated with disease
progression.3 The 2-phenylaminopyrimidine derivative STI571
is a recently designed tyrosine kinase inhibitor4 that
inhibits the ATP binding in the kinase domain of both abl and
bcr/abl in a competitive fashion.5 This compound is
active both in vitro and in vivo against a variety of bcr/abl
or v-abl transformed cells. In previous studies, we and others
have demonstrated the selectivity of STI571 to inhibit the
proliferative activity and the clonogenic potential of cell lines and
fresh leukemic cells expressing the Bcr/Abl fusion
protein.6,7 In addition we showed that the inhibition of
Bcr/Abl kinase activity led to the development of apoptosis in leukemic
cells. In particular, LAMA84, a human bcr/abl expressing cell
line derived from a leukemic patient in blast crisis,8
underwent apoptosis as early as 28 hours after treatment with STI571,
while an incubation time of about 100 hours was needed in
fresh samples obtained from CML patients in chronic phase.6
In vivo treatment of nude mice injected with human leukemic cells can
achieve tumor eradication in 70% to 100% of treated mice, when
schedules able to obtain continuous bcr/abl inhibition were
used.9 These data constitute a significant promise for better treatments in patients with leukemias caused by
bcr/abl,10 and initial clinical studies are already
in progress.
While in vivo data indicate that the continuous presence of the STI571
drug in effective concentrations is needed to eradicate tumors in nude
mice derived from bcr/abl expressing cells, some leukemia relapse can
occur, depending on the initial tumor load.9 In this study,
we selectively generated a bcr/abl positive cell line derived
from LAMA84 and resistant to the effects of STI571, designated as
LAMA84R. Furthermore, the molecular and cellular mechanisms that lead
to such a resistance were investigated. We present evidence that the
resistant, newly generated cell line contained a higher level of
bcr/abl expression and phosphorylation, when compared to the
parental, sensitive cell line. Finally, the observed bcr/abl
overexpression was found to be mediated through gene amplification.
STI571
Cell lines
Induction of resistance in LAMA84 LAMA84 cells were initially cultured in the presence of 0.05 µM STI571. The concentration of the STI571 in the culture medium was subsequently increased by 0.1 µM every 3 to 4 weeks. After 4 months of culture, a LAMA84 subline growing at 0.6 µM STI571 was isolated and designated LAMA84R. Further culture showed that this cell line can grow in the presence of STI571 concentrations up to 1 µM (data not shown), whereas higher concentrations proved to be toxic for the cells.Proliferation assay The assay was performed using a standard 3H-thymidine (3HTdR) incorporation assay as described.9 Briefly, 104 cells, from LAMA84 and LAMA84R, were seeded in 6 replicates in the presence of various concentrations of STI571 ranging from 0.1 to 10 µM, in round-bottomed 96-microtiter well plates (Costar, Cambridge, MA). After 60 hours at 37°C, 20 µL of RPMI/10% FCS containing 3HTdR (1 µCi/well) were added to each well. After an additional 18 hours, the cells were harvested and transferred to a filter (spot-on filtermat, Wallac, Turku, Finland). 3HTdR uptake was determined by a 1205 betaplate liquid scintillation counter (Wallac).Determination of apoptosis by FACS analysis Quantitative determination and differentiation of viable, early, and late apoptotic cells were carried out using the Annexin V/Propidium iodide binding technique, as previously described.11 Briefly, 0.5 × 106 cells were incubated in the presence of 0.6 µM STI571. Controls were cultured in the absence of the drug. After 28 hours, samples were washed in phosphate-buffered saline (PBS) and kept for 15 minutes in an Annexin V/Propidium Iodide mixture prior to the analysis at the FACScan. Compensation for double fluorescence was performed by staining the samples either with Annexin V or with Propidium Iodide only.6Caspase 3-like activity Acetyl-Asp-Glu-Val-Asp-(amino-4-methylcoumarin) (DEVD-amc) hydrolytic activity was analyzed as previously described.12 106 LAMA84 and LAMA84R cells were treated with 0.6 µM STI571 at various time points (7, 17, and 23 hours). Controls for each cell line were incubated in the absence of STI571. Cells were washed in PBS and lysed in 100 µL of lysis buffer, containing 10 mmol/L Hepes pH 7.4, 0.1% CHAPS, 2 mmol/L EDTA, and 2 mmol/L Dithiothreytol (DTT). Protein content was determined by the Bradford method and volumes equivalent to 3 µg of protein were incubated in 500 µL reaction buffer containing 20 mmol/L Hepes buffer pH 7.4, 10% glycerol, 2 mmol/L Dithiothreytol, and 20 µM DEVD-amc (Peptide Co, Kyoto, Japan) at 37°C for 2 hours. The reaction was stopped by the addition of 500 µL of reaction buffer without DEVD-amc. Samples were read immediately on a spectrophotofluorimeter, at an excitation wavelength of 380 nm and an emission wavelength of 460 nm.12Western blot analysis Immunoblotting was performed as described before.6 In general 106 LAMA84 and LAMA84R cells, the latter deprived overnight of STI571, were respectively incubated in a 24-well plate (Costar) at 37°C with various concentrations of STI571, ranging from 0.6 to 10 µM. Controls were incubated in the absence of the inhibitor. After 2 hours, cells were washed twice with cold PBS and subsequently lysed in 200 µL of 1× Laemmli's buffer (50 mmol/L Tris-HCl pH 6.8, 2% SDS, 0.1% bromophenol blue, 10% glycerol, 5% -mercaptoethanol). Cell lysates, corresponding to 150,000 cells,
were boiled at 95°C for 10 minutes, sonicated for 1 minute, and
analyzed by SDS Electrophoresis on 7.5% polyacrylamide gels.
Endogenous bcr-abl, tyrosine-phosphorylated bcr-abl,
and the endogenous actin were detected with the corresponding mouse
monoclonal antibody or rabbit antiserum and then visualized by enhanced
chemioluminescence detection (ECL) (Amersham Corp Cleveland, OH), using
horseradish peroxidase-linked goat anti-mouse or anti-rabbit
immunoglobulin G as the secondary antibody (Amersham Corp.). The
monoclonal anti-abl antibody (clone Ab-3) was purchased from
Calbiochem. The monoclonal anti-phospho tyrosine antibody (clone 4G10)
was purchased from Upstate Biotechnology. Rabbit polyclonal anti-actin
was purchased from Sigma.
Bacterial expression of GST fusion proteins The BL 21 Lys strain of Escherichia coli was transformed by electroporation with the vector PGEX-4T3 alone or encoding the CH1 domain of Shc.13 The transformed bacteria were cultured overnight at 37°C and then diluted 1:20 in 500 mL of Luria-Bertani medium. When the optical density reached 0.5, bacteria were incubated with 1 mmol/L isopropyl-[beta]-thiogalactopyranoside (IPTG) for 3 hours at 37°C. Cells were collected by centrifugation at 3000g for 30 minutes and resuspended in a lysis buffer containing 10 mL PBS, 1% Triton X-100, 1 mmol/L EDTA, 2 µg/mL aprotinin, 2 µg/mL leupeptin, and 1 mmol/L phenylmethylsulfonyl fluoride (PMSF). The cell suspension was sonicated and cellular debris removed by centrifugation at 10 000g for 10 minutes. The supernatant was mixed with 300 µL of glutathione-agarose beads (Pharmacia Biotech) and incubated for 1 hour at 4°C with constant rotation. The glutathione-bound protein was recovered by centrifugation at 3000g for 5 minutes and the pellet washed 3 times in a buffer containing 1× of PBS, 1% Triton X-100, 1 mmol/L EDTA, 2 µg/mL aprotinin, 2 µg/mL leupeptin, and 1 mmol/L PMSF; and 2 times in a solution containing 1× PBS, 2 µg/mL aprotinin, 2 µg/mL leupeptin, and 1 mmol/L PMSF. Finally, purified fusion proteins were eluted in a buffer containing 50 mmol/L Tris, 10 mmol/L glutathione, 2 µg/mL aprotinin, 2 µ/mL leupeptin, and 1 mmol/L PMSF.Kinase assay LAMA84 and LAMA84R cells were washed with cold PBS and lysed at 4°C in a buffer containing 25 mmol/L HEPES (pH 7.5), 0.3 mol/L NaCl, 1.5 mmol/L MgCl2, 0.2 mmol/L EDTA, 0.1% SDS, 0.5 mmol/L DTT, 20 mmol/L-glycerophosphate, 0.1 mmol/L Vanadate, 1% Triton X-100, 1 mmol/L phenylmethylsulfonyl fluoride (PMSF), 0.5% sodium dehoxycholate, 2 µg/mL leupeptin, 2 µg/mL aprotinin. Cleared
lysates were immunoprecipitated at 4°C for 2 hours with the
polyclonal anti-abl, clone 24-11 (Santa Cruz Biotechnology).
Immunocomplexes were recovered with the aid of Gamma-Bind Sepharose
beads (Pharmacia) and washed 3 times with PBS containing 1% Nonidet
P-40 and 1 mmol/L sodium orthovanadate, once with 100 mmol/L Tris (pH
7.5), 0.5 mol/L LiCl, and once with kinase reaction buffer (25 mmol/L
Hepes [pH 7.5], 10 mmol/L MgCl2, 10 mmol/L
MnCl2). bcr/abl activity was determined by
resuspension in 30 µl of kinase reaction buffer containing 10 µCi
(4500 Ci/mmol) of  -32P] ATP per reaction,
20 µM of cold ATP, 2 mM of Dithiothreytol and 4 µg of GST (control)
or GST-CH1-Shc as substrate, and 0 and 3 µM of STI571. After
incubation at 30°C for 30 minutes, reactions were terminated by the
addition of 15 µL of 5× Laemmli's buffer. Samples were heated at
95°C for 5 minutes, analyzed by SDS electrophoresis on 10%
polyacrylamide gels, and visualized by autoradiography.
Sequencing of the bcr/abl ATP-binding domain amplified from LAMA84 and LAMA84R cell lines The LAMA84 and LAMA84R total RNA was extracted using the Ultraspec-II RNA isolation system (Biotecx). Of the total RNA, 5 µg was subjected to RT-PCR using Oligo dT primers. Two primers, corresponding to the nucleotides 2638-2659 of the bcr coding sequence and to the nucleotides 1033-1053 of the Abl coding sequence, were synthesized for the polymerase chain reaction (PCR).Northern blot analysis Northern blotting was carried out as described elsewhere.14 Total RNAs from LAMA84 and LAMA84R were extracted using the Ultraspec-II RNA isolation system (Biotecx). For each sample, 25 µg of RNA were separated on a 2% agarose gel. Transfer to a nylon filter (Biotrans, ICN, Costa Mesa, CA) was achieved by standard capillary transfer. A variety of breakpoints both in the ABL and in the BCR genes have been described.15 In LAMA84, the b3a2 junction is present involving breakpoints between BCR exons 3 and 4 and between ABL exons 1 and 2.15 A 40-mer oligonucleotide covering the BCR/ABL b3a2 junction was synthesized (5'TGG ATT TAA GCA GAG TTC AAA AGC CCT TCA CGC GCC AGT A 3') with an 8-mer as primer (5'TACTGGCC3'). Synthesis of 32P-labeled probes was achieved by extension of the 8-mer hybridized to the 40-mer in 10 µL of a primer extension mixture, containing 6 mmol/L Tris-HCl (pH 7.5); 6 mmol/L MgCl2; 6 mmol/L-mercaptoethanol; 50 mmol/L NaCl; 30 µCi
( -32P) dATP; 100 mmol/L each of dGTP, dCTP, and dTTP;
and 5 U of Klenow polymerase.
FISH analysis Harvested cell suspensions were dropped onto slides according to standard laboratory techniques and slides were submitted to dual-color, dual target FISH. Cells were washed 1 minute with 70% acetic acid, dehydrated, and denatured in 70% formamide/2× SSC (300 mmol/L NaCl, 30 mmol/L sodium citrate) at 72°C for 2.5 minutes. The LSI bcr/abl translocation probe (Vysis Inc, Downers Grove, IL) was used. The probe was denatured and applied to selected areas of each slide. These areas were covered with glass coverslips and sealed with rubber cement. Hybridization was allowed to occur for 20 hours at 37°C. Posthybridization washes were performed at 46°C with 50% formamide/2× SSC (3 washes of 6 minutes), 2× SSC, and 2× SSC/0.1% NP40 (1 wash of 6 minutes). After rinsing in PBS, slides were stained with DAPI/DABCO. Analyses were performed on an Olympus B × 60 fluorescence microscope using single interference filter sets for red (Texas red), green (FITC), and blue (DAPI), and a dual-color (red/green) filter. The LSI bcr/abl translocation probe was built in that particular configuration so that the bcr DNA (DNA segment proximal to the 22q11.2 breakpoint) was labeled with SpectrumGreen and identified by a green fluorescent signal, and the abl DNA (DNA segment distal to the 9q34 breakpoint) was labeled with SpectrumOrange and identified as a red signal. In a cell without the t9;22 (q34;q11), 2 red and 2 green signals will be observed. In a cell carrying the t9;22 (q34;q11), 1 red signal (representing the abl gene), 1 green signal (representing the bcr gene), and 1 fused red/green signal (representing the chimeric BCR/ABL expected in the derivative chromosome 22, the Ph chromosome) will be observed. Samples were analyzed using QUIPS XL Genetics System (Vysis Inc) and IPLab (Signal Analytics Corporation, Vienna, VA) softwares, to obtain a quantitative analysis of fluorescence intensity.MDR1 gene expression Highly purified total RNA from approximately 107 cells was obtained with the Ultraspec-II RNA isolation system (Biotecx). Reverse transcription was carried out using 5 µM of Random Hexamers (Boehringer-Mannheim, Germany) in a 20 µL mixture containing 1 µg of RNA and 200 U of reverse transcriptase (GIBCO BRL). PCR was performed using 2 primers (sense: 5'-ATG TTG AGC CGG GCA GTG TGC-3'; antisense: 5'-CTG AAG AGC TGT CTG GGC TGT-3') that amplified a 220-bp (base pair) fragment within the Multi Drug Resistant 1 (MDR1) gene and, as internal control, 2 specific primers for the-actin
gene (sense: 5'-ARG GAT GAT GAT ATC GCC GCG-3'; antisense: 5'-AAA GAA
CAC GGC TAA GTG TGC-3'), which amplified a 500-bp fragment. The
-actin primers were added after the 14th cycle of the PCR.
Cell survival after exposure to doxorubicin Proliferative cellular resistance to the doxorubicin was detected by cell count. LAMA84 and LAMA84R cells (107) and HL-60 cells (5 × 106) were seeded at various concentrations of doxorubicin ranging from 8 × 10 3 to 0.5 µg/mL. After
72 hours, the cells were collected and counted by an automatic cell
counter (ZBI, Coulter Contron, Milan, Italy).
Proliferative activity The proliferative activity of LAMA84 and LAMA84R cells, incubated with increasing concentration of STI571 for 60 hours, was determined.
Induction of apoptosis
Caspase 3 like activity
Expression and phosphorylation of the bcr/abl protein
Determination of the enzymatic activity of bcr/abl isolated
from LAMA84 and LAMA84R
Sequencing of the LAMA84 and LAMA84R bcr/abl ATP binding domain To determine whether a point mutation in the bcr/abl ATP-binding domain was responsible for the resistance of the LAMA84R cells to the inhibitory effect of STI571 on the phosphorylation of the high endogenously expressed bcr/abl, sequencing of the cDNA portion corresponding to the ATP-binding region of the fusion protein was performed (Figure 5). Briefly, oligonucleotides, corresponding to the BCR2 exon (nucleotides 2638-2659 of the bcr coding sequence) and to an ABL region situated carboxyl-terminal to the ATP-binding domain (nucleotides 1033-1053 of the c-abl coding sequence), were synthesized and used to amplify by RT-PCR, a 1,200-bp fragment within the bcr/abl cDNA from LAMA84 and LAMA84R. After purification, the fragment was subjected to automated sequencing in both strands, and the sequences encompassing the ATP-binding domain of the fusion product were analyzed. As shown in Figure 5, both sequences obtained from LAMA84 and LAMA84R were aligned and compared to the c-abl predicted sequence (Gene Bank accession number: M14752). No mutations in the nucleotidic sequence of the bcr/abl ATP-interaction domain from LAMA84R were detected. These data led us to conclude that the LAMA84R-resistant phenotype might not be explained by a decrease of the STI571 binding affinity to the bcr/abl ATP-interaction domain.
Analysis of the BCR/ABL gene transcription in LAMA84 and LAMA84R The increased level of the bcr/abl protein in the LAMA84R cells could be explained by an increased transcription of the fusion gene or a reduced degradation of the protein (posttranslational control). Therefore, to examine the expression of BCR/ABL at the mRNA level in the LAMA84 and LAMA84R cells, a specific oligonucleotide complementary to the b3-a2 sequence of BCR/ABL14 was used as a probe to hybridize the total RNA extracted from the 2 cell lines. As shown in Figure 6, the b3-a2 probe specifically detected a 8.5-kb transcript in both cell lines. LAMA84R cells clearly expressed higher amounts of bcr/abl mRNA. Densitometric analysis indicated that the resistant cell line contained a 4.6-fold higher level of transcript, compared to the parental, sensitive cell line. To further confirm that the same amount of RNAs was analyzed, the blot was rehybridized with a murine-actin probe. Since similar bands were
obtained, these results, taken together, supported the contention that
BCR/ABL was overtranscribed in the resistant LAMA84 cell line.
Genomic analysis of the BCR/ABL gene in LAMA84 and LAMA84R cells To further study whether the overtranscription of the BCR/ABL gene in the LAMA84R cells was due to the presence of increased number of the fusion gene at the genomic level (gene amplification), the 2 cell lines were subjected to fluorescent in situ hybridization (FISH) analysis using 2 bcr- and abl-specific probes. The presence of more than 1 copy of the Philadelphia chromosome in LAMA84 was previously described8 and was confirmed by our observations. Figure 7 shows both interphase (7A, C) and metaphase (7B, D) images of LAMA84 and LAMA84R. The modal number in LAMA84 was 4 fused signals per cell (7B). The average number of fused signals in 216 interphase nuclei was 3.7 ± 1.3 and in 100 metaphase spreads was 4.1 ± 0.6. In LAMA84R, in addition to the above-mentioned single BCR/ABL signals, a cluster of fusion signals was observed in 98% of cells. This cluster appears in a single copy in 95% of nuclei, and in 2 copies in 3% of nuclei. When performing a comprehensive evaluation of the slides, we were able to detect a few metaphases in the specimen, and the amplified fused signal was assigned to a marker metacentric chromosome. This element seems to exclusively contain BCR/ABL sequences, since it appeared totally painted in red and green (Figure 7D, E). The single fused signals were mapped to a small acrocentric chromosome resembling the standard Philadelphia chromosome. The fluorescence intensity of bcr/abl signals was evaluated using IPLab Spectrum software. Forty-eight individual signals and 22 marker elements were segmented and quantitatively analyzed. The sum of the pixel values within the segmented targets (total intensity) was obtained for each target and averaged for the individual fusion and for the marker. These procedures were performed separately for the red and the green signals. The mean intensity of the marker was then compared to the mean intensity of the individual fusions. For the green signals, the fluorescence in the marker was found to be 14 times more intense than in the individual fusion; for the red signals, the marker intensity was found to be 13.2 times higher than the individual fusion.
Cross resistance to doxorubicin and expression of the MDR1 gene Since increased bcr/abl expression was shown to be associated with resistance to various cytotoxic drugs,19,20 the in vitro sensitivity of LAMA84 and LAMA84R to doxorubicin was studied. Cell survival of LAMA84 and LAMA84R cells after exposure to various doses of doxorubicin is presented in Figure 8. LAMA84R cells showed a relative resistance to doxorubicin with an IC50 of 100 ± 9 (SE) ng/ml, while LAMA84 showed an IC50 of 20 ± 1 (SE) ng/ml. Remarkably, these data suggest that the resistant cell line presented 5-fold less sensitivity to the cytotoxic effect exerted by doxorubicin, when compared to the parental sensitive cell line.
The generation of drug resistance represents an important point in the development of new compounds. STI571 represents an innovative new drug for leukemia treatment. This molecule is in fact operationally specific for neoplasias caused by the oncogenic tyrosine kinase bcr/abl, and holds promise for minimal toxicity to normal cells when compared to now available cytotoxic drugs.5 Study of the possible development of resistance to this and similar compounds is rare at present. To the best of our knowledge, the data reported here represent the first example of a successful generation and selection of bcr/abl positive cells (LAMA84) that show a significant and specific resistance to STI571 effects. Here, we show that this newly selected resistant cell line, designated LAMA84R, shows about 4-fold increased expression of bcr/abl at the protein level.
We thank Enrico Garatini, MD, for helpful discussion and support.
Submitted May 14, 1999; accepted October 28, 1999.
This work was supported in part by the Italian Association for Cancer Research (AIRC 420.198.662); the Italian Research Council (95.00842,9600225.CT04); Istituto Superiore di Sanità (881A/10); BIOMED-2 grant BMH4-CT96-0848; EU-TMR grant BMH4-CT96-5006; and NCI P30 CA 46934.
P.L.C. and E.T. are equally contributing authors.
Reprints: Carlo Gambacorti, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy; e-mail: gambacorti{at}istitutotumori.mi.it.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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C. L. Sawyers, A. Hochhaus, E. Feldman, J. M. Goldman, C. B. Miller, O. G. Ottmann, C. A. Schiffer, M. Talpaz, F. Guilhot, M. W. N. Deininger, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study Blood, May 15, 2002; 99(10): 3530 - 3539. [Abstract] [Full Text] [PDF]
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S. Branford, Z. Rudzki, S. Walsh, A. Grigg, C. Arthur, K. Taylor, R. Herrmann, K. P. Lynch, and T. P. Hughes High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance Blood, May 1, 2002; 99(9): 3472 - 3475. [Abstract] [Full Text] [PDF]
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M. O'Dwyer Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias Oncologist, April 1, 2002; 7(90001): 30 - 38. [Abstract] [Full Text] [PDF]
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M. Talpaz, R. T. Silver, B. J. Druker, J. M. Goldman, C. Gambacorti-Passerini, F. Guilhot, C. A. Schiffer, T. Fischer, M. W. N. Deininger, A. L. Lennard, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study Blood, March 15, 2002; 99(6): 1928 - 1937. [Abstract] [Full Text] [PDF]
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W.-K. Hofmann, L. C. Jones, N. A. Lemp, S. de Vos, H. Gschaidmeier, D. Hoelzer, O. G. Ottmann, and H. P. Koeffler Ph+ acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation Blood, March 1, 2002; 99(5): 1860 - 1862. [Abstract] [Full Text] [PDF]
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D. G. Savage and K. H. Antman Imatinib Mesylate -- A New Oral Targeted Therapy N. Engl. J. Med., February 28, 2002; 346(9): 683 - 693. [Full Text] [PDF]
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B. M. F. Mow, J. Chandra, P. A. Svingen, C. G. Hallgren, E. Weisberg, T. J. Kottke, V. L. Narayanan, M. R. Litzow, J. D. Griffin, E. A. Sausville, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro Blood, January 15, 2002; 99(2): 664 - 671. [Abstract] [Full Text] [PDF]
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H. G. Jorgensen, M. A. Elliott, E. K. Allan, C. E. Carr, T. L. Holyoake, and K. D. Smith alpha 1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571 Blood, January 15, 2002; 99(2): 713 - 715. [Abstract] [Full Text] [PDF]
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M. J. Mauro, M. O'Dwyer, M. C. Heinrich, and B. J. Druker STI571: A Paradigm of New Agents for Cancer Therapeutics J. Clin. Oncol., January 1, 2002; 20(1): 325 - 334. [Abstract] [Full Text] [PDF]
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C. Yu, G. Krystal, L. Varticovksi, R. McKinstry, M. Rahmani, P. Dent, and S. Grant Pharmacologic Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase/Mitogen-activated Protein Kinase Inhibitors Interact Synergistically with STI571 to Induce Apoptosis in Bcr/Abl-expressing Human Leukemia Cells Cancer Res., January 1, 2002; 62(1): 188 - 199. [Abstract] [Full Text] [PDF]
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G. Klement, P. Huang, B. Mayer, S. K. Green, S. Man, P. Bohlen, D. Hicklin, and R. S. Kerbel Differences in Therapeutic Indexes of Combination Metronomic Chemotherapy and an Anti-VEGFR-2 Antibody in Multidrug-resistant Human Breast Cancer Xenografts Clin. Cancer Res., January 1, 2002; 8(1): 221 - 232. [Abstract] [Full Text] [PDF]
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S. M. Graham, H. G. Jorgensen, E. Allan, C. Pearson, M. J. Alcorn, L. Richmond, and T. L. Holyoake Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro Blood, January 1, 2002; 99(1): 319 - 325. [Abstract] [Full Text] [PDF]
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N. C. Wolff and R. L. Ilaria Jr Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571 Blood, November 1, 2001; 98(9): 2808 - 2816. [Abstract] [Full Text] [PDF]
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 C. Barthe, P. Cony-Makhoul, J. V. Melo, J. R. F.-X. Mahon, A. Hochhaus, S. Kreil, A. Corbin, P. La Rosee, T. Lahaye, U. Berger, et al. Roots of Clinical Resistance to STI-571 Cancer Therapy Science, September 21, 2001; 293(5538): 2163a - 2163. [Full Text] [PDF]
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A. Viloria-Petit, T. Crombet, S. Jothy, D. Hicklin, P. Bohlen, J. M. Schlaeppi, J. Rak, and R. S. Kerbel Acquired Resistance to the Antitumor Effect of Epidermal Growth Factor Receptor-blocking Antibodies in Vivo: A Role for Altered Tumor Angiogenesis Cancer Res., July 1, 2001; 61(13): 5090 - 5101. [Abstract] [Full Text] [PDF]
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M. J. Mauro and B. J. Druker STI571: Targeting BCR-ABL as Therapy for CML Oncologist, June 1, 2001; 6(3): 233 - 238. [Abstract] [Full Text] [PDF]
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B. J. Druker, C. L. Sawyers, H. Kantarjian, D. J. Resta, S. F. Reese, J. M. Ford, R. Capdeville, and M. Talpaz Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome N. Engl. J. Med., April 5, 2001; 344(14): 1038 - 1042. [Abstract] [Full Text] [PDF]
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J. M. Goldman and J. V. Melo Targeting the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia N. Engl. J. Med., April 5, 2001; 344(14): 1084 - 1086. [Full Text] [PDF]
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X. Sun, J. E. Layton, A. Elefanty, and G. J. Lieschke Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571 Blood, April 1, 2001; 97(7): 2008 - 2015. [Abstract] [Full Text] [PDF]
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A. Reichert, N. Heisterkamp, G. Q. Daley, and J. Groffen Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336 Blood, March 1, 2001; 97(5): 1399 - 1403. [Abstract] [Full Text] [PDF]
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R. Nimmanapalli, M. Porosnicu, D. Nguyen, E. Worthington, E. O’Bryan, C. Perkins, and K. Bhalla Cotreatment with STI-571 Enhances Tumor Necrosis Factor {{alpha}}-related Apoptosis-inducing Ligand (TRAIL or Apo-2L)- induced Apoptosis of Bcr-Abl-positive Human Acute Leukemia Cells Clin. Cancer Res., February 1, 2001; 7(2): 350 - 357. [Abstract] [Full Text]
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B. J. Druker, C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman Chronic Myelogenous Leukemia Hematology, January 1, 2001; 2001(1): 87 - 112. [Abstract] [Full Text] [PDF]
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Z. A. Knight;, C. Gambacorti-Passerini, P. le Coutre, E. Tassi, and H. Ruchatz Another possible mechanism of resistance to STI571 Blood, December 1, 2000; 96(12): 4003 - 4005. [Full Text] [PDF]
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 C. Gambacorti-Passerini, R. Barni, P. le Coutre, M. Zucchetti, G. Cabrita, L. Cleris, F. Rossi, E. Gianazza, J. Brueggen, R. Cozens, et al. Role of {alpha}1 Acid Glycoprotein in the In Vivo Resistance of Human BCR-ABL+ Leukemic Cells to the Abl Inhibitor STI571 J Natl Cancer Inst, October 18, 2000; 92(20): 1641 - 1650. [Abstract] [Full Text] [PDF]
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H. Kantarjian, J. V. Melo, S. Tura, S. Giralt, and M. Talpaz Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies Hematology, January 1, 2000; 2000(1): 90 - 109. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
20°C.
