© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 2, 163-168,
January 20, 1999
© 1999 Oxford University Press
REPORTS |
In Vivo Eradication of Human BCR/ABL-Positive Leukemia Cells With an ABL Kinase Inhibitor
Affiliations of authors: P. le Coutre, L. Mologni, L.Cleris, E. Marchesi, F. Formelli (Department of Experimental Oncology), R. Giardini (Department of Pathology), Istituto Nazionale Tumori, Milan, Italy; E. Buchdunger, Oncology Research Department, Novartis International Inc., Basel, Switzerland; C. Gambacorti-Passerini, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, and Section of Hematology, University of Milan, S. Gerardo Hospital, Monza, Italy.
Correspondence to: Carlo Gambacorti-Passerini, M.D.,Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy (e-mail: gambacorti{at}istitutotumori.mi.it).
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ABSTRACT |
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BACKGROUND: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. METHODS: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule. RESULTS: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice. CONCLUSION: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chronic myeloid leukemia (CML) is caused by the acquisition of the reciprocal (9:22) (q34;q11) chromosomal translocation (Philadelphia chromosome) in hematopoietic stem cells. In the resulting fusion protein, part of the ABL gene product (Abl), including the tyrosine kinase (TK) domain, is fused to the amino-terminal end of the BCR gene product (Bcr) (1). The Bcr domain probably interferes with an intramolecular Abl inhibitory loop and unveils a constitutive kinase activity that is absent in the normal Abl protein (2). This chromosomal defect is seen in about 95% of all patients with CML as well as in 30%-50% of adult patients with acute lymphoblastic leukemia (ALL). The only curative treatment available at present is allogeneic bone marrow transplantation, a toxic and costly procedure, available for only 30% of patients. While the precise mechanism employed by the Bcr/Abl fusion protein to transform cells is still unknown, it is well accepted that the enhanced TK activity is crucial to its transforming ability (3). Thus, the inhibition of the TK activity of this protein represents a specific therapeutic strategy for Bcr/Abl-expressing leukemias. A 2-phenylaminopyrimidine derivative named CGP57148B (4) has been reported to selectively inhibit the kinase activity of both Abl and Bcr/Abl (5). CGP57148B is a competitive inhibitor of the adenosine triphosphate (ATP)-binding cleft of Abl. We and others (6,7) have previously reported the selective block of proliferation in BCR/ABL-positive cells (either cell lines or fresh tumor samples) and showed that this compound can commit these cells to apoptosis without inducing differentiation. So far, no data are available on the in vivo activity of CGP57148B on human Bcr/Abl-positive leukemia cells; results obtained in murine cells transfected with v-abl or bcr/abl indicate the presence of a limited activity, with retardation of tumor growth but no cure of treated animals (4,5).
We describe here the in vivo effects of this compound in nude mice given an injection of human leukemia cell lines. The nude mouse model was selected because the tumor grows as a solid mass; this fact permits us to obtain purified tumor cells from animals and to assess the in vivo kinetics of Bcr/Abl inhibition following the treatment of tumor-bearing mice. Other models, like the severe combined immunodeficient (SCID) and SCID/non-obese diabetic (NOD) mice, permit transplantation of fresh, chronic-phase CML cells (8). In this case, however, no solid tumor growth or massive outgrowth of leukemia cells in the bone marrow usually occurs, thus preventing the possibility of performing the above-mentioned experiments.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CGP57148B
A 2-phenylaminopyrimidine derivative with a molecular weight of 590, CGP57148B was developed and provided by Novartis Inc. (Basel, Switzerland). The stock solutions of this compound were prepared at 1 and at 10 mM with distilled water, filtered, and stored at -20 °C. For in vitro experiments, CGP57148B was thawed before the experiment was started and used at a concentration of 0.1-10 µM. Preparations used for animal experiments were made in concentrations as indicated below and were kept at 4 °C for a maximum of 4 days.
Cell Lines
Three human leukemia lines were used: KU812, MC3, and U937. KU812 and MC3 expressed p210Bcr/Abl, whereas U937, a BCR/ABL-negative human leukemia cell line, served as a negative control (9,10). Both Bcr/Abl-positive cell lines were derived from CML patients in blast crisis, who previously had been treated with busulfan. All cells were cultured in RPMI-1640 medium (BioWhittaker, Inc., Walkersville, MD; Boerhinger Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) containing 10% fetal calf serum (FCS) (HyClone Laboratories, Inc., Logan, UT) under standard cell culture conditions. Four additional Bcr/Abl-positive cell lines [KCL22, BV173, K562, and LAMA84 (6)] were tested in preliminary experiments, but they failed to produce reproducible growth in nude mice and were not studied further.
Determination of In Vitro Proliferative Activity (Tritiated Thymidine Uptake Assay)
Two hundred microliters of each cell line (KU812, MC3, and U937), containing 4 x 104 cells, was seeded at various concentrations of CGP57148B, ranging from 0.1 to 10 µM in 96-well microtiter plates (Corning Costar Corp., Cambridge, MA) in six replicates. After 54 hours at 37 °C, 20 µL of RPMI-1640 medium/10% FCS containing tritiated thymidine (1 µCi/well) was added to each well. After an additional 18 hours, cells were harvested and transferred to a filter (Spot-on filtermat; Pharmacia Biotech Europe, Brussels, Belgium). Tritiated thymidine uptake was determined by a 1205 betaplate liquid scintillation counter (Wallac Inc., Turku, Finland). IC50 was defined as the concentration of compound producing a 50% decrease in proliferation in comparison with untreated controls.
In Vitro Wash-Out Experiments
To determine the minimal duration of drug exposure, 0.5 x 106 cells were incubated in medium containing 1 µM of CGP57148B. Cells were first seeded in 24-well plates (Corning Costar Corp.). At various time points, the wells were washed twice in RPMI-1640/10% FCS and reseeded in a new 24-well plate. Each sample was seeded in six replicates. After a total culture time of 54 hours, the samples were washed again, 200 µL containing 4 x 104 cells was transferred to a 96-microtiter plate (Corning Costar Corp.), and proliferative activity was determined over a period of 18 hours (see above).
Western Blot Analysis
Tumor-bearing mice were treated either orally (160 mg/kg) or intraperitoneally (50 mg/kg) with CGP57148B as described below. At various time points, ranging between 2 hours and 24 hours after treatment, mice were killed and non-necrotic tumor tissue was extracted and homogenized in a fivefold volume of sodium dodecyl sulfate (SDS)-loading buffer (50 mM Tris-HCl [pH 6.8], 2% SDS, and 5% ß-mercaptoethanol). After sonication for 2 minutes, samples were centrifuged at 15 000g for 15 minutes, heated at 95 °C for 10 minutes, and stored at -80 °C. Polyacrylamide gel electrophoresis was carried out on a 7.5% SDS gel (Mini-Protean II electrophoresis cell; Bio-Rad Laboratories, Hercules, CA). Equal amounts of protein were loaded as determined by BCA Protein Assay (Pierce Chemical Co., Rockford, IL). Before loading, 0.05% of bromophenol blue was added to each sample. Samples were subsequently transferred to a nitrocellulose membrane (Hybond Super-C; Amersham Life Science Inc., Arlington Heights, IL). Transfer was carried out overnight at 4 °C in a Mini Trans-Blot electrophoretic transfer cell (Bio-Rad Laboratories) in 25 mM Tris, 192 mM glycine, and 20% methanol. After protein transfer, the membrane was blocked with TBST (0.01 M Tris, 0.15 M NaCl, and 0.05% Tween 20 [pH 7.4]) containing 5% milk, and a monoclonal anti-phosphotyrosine antibody (05-321; Upstate Biotechnology, Lake Placid, NY) was used in a 1 : 500 dilution (TBST/5% milk) to detect phosphorylated proteins. After stripping (2% SDS, 62.5 mM Tris-HCl [pH 6.8], and 0.7% ß-mercaptoethanol for 1 hour), the filter was blotted with an anti-Abl antibody (clone Ab-3; Calbiochem Corp., La Jolla, CA; 1 : 100 in TBST/5% milk) that also recognized Bcr/Abl. An anti-mouse horseradish peroxidase-conjugated antibody (Bio-Rad Laboratories) was used as a secondary antibody and identified both primary antibodies after addition of a supersignal chemiluminescent substrate (Pierce Chemical Co.). Densitometric analysis of films was carried out on an Eagle Eye II Photodensitometer (Stratagene, La Jolla, CA). Band intensities were calculated as areas; nonspecific changes caused by differences in Bcr/Abl content (as evidenced by the anti-Abl antibody) were subtracted.
In Vivo Administration of CGP57148B
Seven to 9-week-old female CD-1 nu/nu mice purchased at Charles River Breeding Laboratories (Calco, Italy) were kept under standard laboratory conditions according to the guidelines of the National Cancer Institute, Milan, Italy. This study was approved by the institutional ethics committee for laboratory animals used in experimental research. Both Bcr/Abl-positive and -negative cell lines were injected (50 x 106 cells per animal) subcutaneously in the left flank. Treatment was started 1-8 days after leukemia cell injection. Oral treatment was administered through a syringe connected to a soft plastic tube introduced into the mouse esophagus (gavage). CGP57148B was prepared at concentrations of 16 mg/mL (oral) and 5 mg/mL (intraperitoneal) in distilled water. Control animals were given equal volumes of water. Tumor weight (TW) and total weight were monitored every 3-4 days. TW was calculated by the formula TW (mg) = (d2 x D)/2, where d and D are the shortest and longest diameters of the tumor, respectively, measured in millimeters.
When mice were treated twice per day, six mice per treatment or control group were used (total of 12 mice). For treatment of mice 24 hours after KU812 leukemia cell injection, eight mice per treatment or control group (total of 24 mice) were used, whereas the U937 group consisted of 10 mice per treatment or control group (total of 30 mice). In experiments with measurable tumor-bearing mice, 12 mice per treatment or control group (total of 24 mice) were used.
Statistical Analysis
Statistical analysis of tumor weights was performed with one-way variance analysis using the Statpac analysis program (version 3.1; Walonick Assoc., Minneapolis, MN). For survival analysis, data were compared by the logrank test (11). P values <.05 were considered statistically significant and were derived from two-sided statistical tests.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In Vitro Sensitivity to CGP57148B
The in vitro IC50 for CGP57148B was determined by a proliferation assay. It was found to be between 0.1 and 0.3 µM in the two BCR/ABL-positive cell lines KU812 and MC3, whereas the BCR/ABL-negative cell line U937 was unaffected by CGP57148B concentrations 30 times higher (10 µM) (not shown). These data are in accordance with previously published results (6).
In Vitro Wash-Out Experiments
CGP57148B is a competitive (reversible) inhibitor of Abl kinase
activity. To determine the minimum time of exposure to this compound
necessary to inhibit proliferation, experiments were performed in
vitro on KU812 cells. Cells were cultured in the presence of 1
µM CGP57148B for the various times indicated in Fig.
1.
The results clearly indicate that 20-21 hours
were sufficient to block cell proliferation, whereas 6-7 hours
produced little change. These data are in agreement with the kinetics
of early apoptosis induction in these cell lines, which occurred
between 16 and 24 hours (6). Therefore, the duration of
Bcr/Abl inhibition following treatment with CGP57148B could be critical
in determining biologic results in vivo.
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In Vivo Molecular Pharmacokinetic Experiments
In our previous in vitro experiments (6),
inhibition of proliferation and apoptosis induction was observed in
leukemia lines when the Bcr/Abl TK activity was inhibited by 50% or
more. To investigate the degree and duration of Bcr/Abl inhibition
in vivo, we acutely treated tumor-bearing mice and killed them
at various time points after treatment. The levels of Bcr/Abl kinase
activity (measured as autophosphorylation) obtained at different times
in a representative experiment are presented in Fig.
2. CGP57148B was administered both intraperitoneally
(50 mg/kg) and orally (160 mg/kg). At 2 hours after injection, Bcr/Abl
inhibition of 64.7% (intraperitoneal) and 66.4% (oral) was
present in both groups. At 5 hours, the level of inhibition was still
46.7% in orally treated mice and 53.4% in intraperitoneally
treated animals; by 8 hours, more than 70% of the initial kinase
activity was restored in both groups. Therefore, Bcr/Abl was blocked
in vivo, but this inhibition was short-lived, and a single
CGP57148B dose was clearly insufficient to maintain a substantial
Bcr/Abl inactivation for the time necessary to block proliferation and
to commit cells to apoptosis.
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In Vivo Activity of CGP57148B
Since a dose of 50 mg/kg (one intraperitoneal injection/day) was
used in vivo with murine cells (4,5), this schedule
was selected initially for our study and was administered for 25 days.
This dosage achieves maximum concentrations (Cmax) greater than 3
µM (data not shown). No statistically significant
retardation in tumor growth was observed in animals treated once per
day. For this reason, the treatment schedule was modified, and the same
dose was administered two times daily, at 8 AM and 4
PM. The results obtained in mice given an injection of KU812
or MC3 cells and treated twice per day are reported in Fig.
3. Tumor growth inhibition was present and reached
statistical significance on days 17 (P<.01 for both cell
lines), 21 (P<.01 for KU812 and P<.05 for MC3),
and 25 (P<.05 for both cell lines); growth inhibition was
present during the treatment period (days 1-25), while growth curves
tended to run in a parallel way when the treatment was discontinued. No
growth inhibition was noted in mice given an injection of the myeloid
Bcr/Abl-negative cell line U937 (data not shown). The twice-per-day
treatment schedule appeared necessary to inhibit tumor growth, since
the administration of the same total dose (100 mg/kg intraperitoneal)
in a single daily injection did not produce a statistically significant
delay in tumor growth (data not shown).
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These data indicate that the treatment administered at 50 mg/kg by intraperitoneal injection twice per day caused a specific and statistically significant inhibition in the growth of Bcr/Abl-positive human leukemia cell lines. However, no differences in the number of animals developing tumors or in the leukemia-free survival of treated mice were observed. Therefore, the treatment schedule was modified further, on the basis of the results from the in vitro wash-out and in vivo kinetics experiments, with the aim of producing a continuous inhibition of the Bcr/Abl kinase activity. Experiments were focused on KU812, which produced a higher in vivo growth rate (80%-90% of inoculated animals) than MC3 (60%-70%). Tumor-bearing mice received CGP57148B at a dose of 50 mg/kg intraperitoneally or 160 mg/kg orally every 8 hours for 11 consecutive days. Fig. 4,
A, shows the tumor-free
survival in animals given an injection of KU812 cells; two independent
experiments were performed with similar results. Each group contained
eight animals. Seven mice (87.5%) in the control group developed
tumors within 9 days, while one (12.5%) of eight mice in the
intraperitoneally treated group developed a tumor (87.5% were
cured). All mice in the group treated orally remained tumor free.
Differences in tumor-free survival between control and treated groups
were highly significant (P<.0001), whereas the comparison
between the two treated groups did not reveal statistical significance.
No evidence of tumor growth was noted during the follow-up of
tumor-free animals (up to 240 days). In contrast, no differences were
noted between control mice and treated mice receiving an injection of
U937 cells, confirming the specificity of the results obtained (not shown).
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Treatment of Mice With Measurable Tumors
To study the effect of this treatment schedule on animals with more
advanced disease, already bearing measurable tumors, we administered
CGP57148B (oral schedule) to a group of 12 animals, 8 days after
leukemia cell injection, with tumors already weighing 286 mg (95%
confidence interval [CI] = 201-371 mg) in the controls and 289 mg
(95% CI = 209-369 mg) in the treatment group. Fig. 4
, B,
presents
the results of this experiment. Nodules started to regress 48 hours
after treatment; the reduction, compared with the control group,
averaged 68% at day 3 and 98% by day 7 after the beginning of
CGP57148B treatment. No treated animal had a measurable tumor by day 8,
while 12 of 12 control mice had growing nodules (P<.0001).
The same schedule was also tested in U937-bearing mice; the treatment
did not cause any statistically significant change in tumor growth or
leukemia-free survival in animals given an injection of this
Bcr/Abl-negative leukemia cell line (data not shown). Tumor-free
animals were also followed up in this group: Four (33%) of 12
animals developed a relapse between day 48 and day 60, while the
remaining eight animals (67%) have remained tumor free up to the
present day (+210 days). A longer treatment schedule (18 days)
apparently failed to reduce the risk of relapse (data not shown).
These data indicate that the continuous inhibition of Bcr/Abl was needed to produce major biologic effects and converted an apparently ineffective molecule (when administered once per day) to a highly active compound. However, the tumor load present at the time of treatment represented an important variable, and the treatment of mice with a measurable tumor mass, although highly effective, did not eradicate the disease in 100% of cases, as it consistently did in the group of animals treated 24 hours after the injection of leukemia cells.
Toxicity of Treatment
The weight of the animals in the treated groups increased at a reduced pace during treatment compared with the weight of the controls. This difference in weight never exceeded 8% and disappeared after treatment. No statistically significant differences in white blood cell and platelet counts or in hemoglobin levels were noted during treatment. Treated animals were also subjected to histopathologic analysis. No major finding was noted at autopsy; in particular, no changes or altered myeloid/erythroid ratios were observed in bone marrow (skull + femurs) specimens. The only abnormality observed in some, but not all, treated animals was represented by a modest periportal lymphocyte infiltrate, with no sign of hepatocellular necrosis (data not shown).
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CGP57148B is a potent inhibitor of the Bcr/Abl kinase and acts by blocking the ATP-binding site of this protein. In this report, we investigated the in vivo effects of CGP57148B in a nude mouse model. This model was chosen since the availability of solid nodules permits us to study the Bcr/Abl activity in tumor tissues and to assess the kinetics of Bcr/Abl inhibition following CGP57148B administration. This need would render some important experiments described here impossible to perform in the SCID/NOD model.
Our results suggest that a too short in vivo inhibition of Bcr/Abl is responsible for the initial negative data. The development of a treatment schedule designed to maintain a prolonged in vivo Bcr/Abl inactivation produced a statistically significant increase in the activity of this compound, and long-term remissions in tumor-bearing animals were achieved. The number of neoplastic cells present at the beginning of treatment seems to play an important role; in fact, when treatment was started at day 8 (in the presence of approximately 300 millions cells), one third of the animals had a relapse, while the same regimen eradicated the disease in 100% of treated animals when the treatment was started 24 hours after the injection of 50 million cells. It will be interesting to study the possible emergence of resistance to this new class of specific antineoplastic compounds. Progressive resistance to CGP57148B treatment can theoretically develop over time as a result of different mechanisms, such as cellular modifications inside leukemic cells and in vivo induction of drug metabolism or of proteins able to bind CGP57148B and to decrease its bioavailability. The investigation of this phenomenon bears clinical relevance, since chronic treatment with CGP57148B will probably be needed over extended periods of time.
The toxicity of the treatment was rather limited in our experience, even if the normal Abl protein was certainly inhibited [in addition to the known cross-activity with kit and pdgfrß (i.e., platelet-derived growth factor receptor-ß) (4)]. These results indicate that, while Bcr/Abl clearly identifies a critical "bottleneck" for Bcr/Abl leukemia cells, the normal Abl protein appears to be less critical for the survival of normal cells. Longer and more exhaustive toxicologic studies are, however, needed to better assess the possible long-term side effects of this molecule.
An additional point that deserves discussion is the apparent activity of the "once-per-day" schedule when cytokine-dependent murine cell lines transfected with v-ABL or BCR/ABL were used, as previously described (4,5). In these reports, the growth of transfectants was inhibited (although no animal was cured) by a schedule that was completely ineffective in our model. However, we observed that, in these transfectants, the in vitro IC50 for CGP57148B was lower than that in the human leukemia cell lines used in our study (0.001 µM versus 0.1-0.3 µM [data not shown]), suggesting that the murine transfectants could be inhibited at CGP57148B concentrations lower than those active on KU812 or MC3. Therefore, in the experiments performed by Buchdunger et al. (4) and Druker et al. (5), a single administration of the compound could result in longer lasting inhibitory concentrations than in our model.
These data indicate that CGP57148B exerts a specific activity against human Bcr/Abl-positive leukemia cells in vivo; given the competitive (reversible) nature of this compound, continuous exposure is necessary to produce major antileukemia effects.
The information contained in this report might help to establish therapeutic regimens in patients with Bcr/Abl-positive leukemias. Our results suggest, for example, that a single daily administration of CGP57148B (or of other molecules with a similar mechanism of action and in vivo half-life) could result in limited biologic and therapeutic effects. Although we do not yet know the in vivo kinetics of CGP57148B in humans, the data presented here indicate the importance of developing treatment regimens able to achieve continuous inhibition of the targeted kinase in vivo.
It has to be remembered, however, that nude mice given an injection of Bcr/Abl-positive cells present a hematopoietic system that is not affected by the leukemia, in contrast to CML patients, in whom most of the mature granulocytes derive from the leukemic clone; it is possible that CGP57148B might cause cytopenia in treated patients because of the low frequency of BCR/ABL-negative precursors in untreated CML patients. In addition, leukemia cells grow in nude mice as solid tumors, and even if they can spread and form distant metastases, they do not grow diffusely as in patients; attempts at injecting KU812 or MC3 intravenously were unsuccessful. Therefore, although this model was needed to carry out the in vivo kinetics experiments, it is less clinically relevant than other systems, like SCID/NOD mice given an injection of uncultured chronic phase CML cells (8).
Finally, these data could also become relevant for other neoplasias in which competitive TK inhibitors are presently being investigated in vivo.
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, and EU-TMR grant BMH4-CT96-5006.
E. Buchdunger is an employee and stockholder of Novartis AG, Inc., manufacturer of compound CGP57148B investigated in this study.
We thank Dr. Giorgio Parmiani, Gian Marco Corneo, Pietro Pioltelli, and Enrico Pogliani for their helpful discussion.
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Manuscript received June 16, 1998; revised November 4, 1998; accepted November 18, 1998.
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S. Mishra, B. Zhang, J. M. Cunnick, N. Heisterkamp, and J. Groffen Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. Cancer Res., May 15, 2006; 66(10): 5387 - 5393. [Abstract] [Full Text] [PDF]
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Y. Yamada, M. E. Rothenberg, A. W. Lee, H. S. Akei, E. B. Brandt, D. A. Williams, and J. A. Cancelas The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease Blood, May 15, 2006; 107(10): 4071 - 4079. [Abstract] [Full Text] [PDF]
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O. J. Becher, E. C. Holland, E. A. Sausville, and A. M. Burger Genetically Engineered Models Have Advantages over Xenografts for Preclinical Studies. Cancer Res., April 1, 2006; 66(7): 3355 - 3359. [Abstract] [Full Text] [PDF]
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A. S. Corbin, S. Demehri, I. J. Griswold, Y. Wang, C. A. Metcalf III, R. Sundaramoorthi, W. C. Shakespeare, J. Snodgrass, S. Wardwell, D. Dalgarno, et al. In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit Blood, July 1, 2005; 106(1): 227 - 234. [Abstract] [Full Text] [PDF]
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N. C. Wolff, D. R. Veach, W. P. Tong, W. G. Bornmann, B. Clarkson, and R. L. Ilaria Jr PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia Blood, May 15, 2005; 105(10): 3995 - 4003. [Abstract] [Full Text] [PDF]
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P.-H. Tseng, H.-P. Lin, J. Zhu, K.-F. Chen, E. M. Hade, D. C. Young, J. C. Byrd, M. Grever, K. Johnson, B. J. Druker, et al. Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance Blood, May 15, 2005; 105(10): 4021 - 4027. [Abstract] [Full Text] [PDF]
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M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF]
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J. Thomas, L. Wang, R. E. Clark, and M. Pirmohamed Active transport of imatinib into and out of cells: implications for drug resistance Blood, December 1, 2004; 104(12): 3739 - 3745. [Abstract] [Full Text] [PDF]
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S. Trudel, S. Ely, Y. Farooqi, M. Affer, D. F. Robbiani, M. Chesi, and P. L. Bergsagel Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma Blood, May 1, 2004; 103(9): 3521 - 3528. [Abstract] [Full Text] [PDF]
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G. Rosti, G. Martinelli, S. Bassi, M. Amabile, E. Trabacchi, B. Giannini, D. Cilloni, B. Izzo, A. De Vivo, N. Testoni, et al. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia Blood, March 15, 2004; 103(6): 2284 - 2290. [Abstract] [Full Text] [PDF]
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S. Appel, A. M. Boehmler, F. Grunebach, M. R. Muller, A. Rupf, M. M. Weck, U. Hartmann, V. L. Reichardt, L. Kanz, T. H. Brummendorf, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells Blood, January 15, 2004; 103(2): 538 - 544. [Abstract] [Full Text] [PDF]
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N. von Bubnoff, D. R. Veach, W. T. Miller, W. Li, J. Sanger, C. Peschel, W. G. Bornmann, B. Clarkson, and J. Duyster Inhibition of Wild-Type and Mutant Bcr-Abl by Pyrido-Pyrimidine-Type Small Molecule Kinase Inhibitors Cancer Res., October 1, 2003; 63(19): 6395 - 6404. [Abstract] [Full Text] [PDF]
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R. Nimmanapalli, L. Fuino, P. Bali, M. Gasparetto, M. Glozak, J. Tao, L. Moscinski, C. Smith, J. Wu, R. Jove, et al. Histone Deacetylase Inhibitor LAQ824 Both Lowers Expression and Promotes Proteasomal Degradation of Bcr-Abl and Induces Apoptosis of Imatinib Mesylate-sensitive or -refractory Chronic Myelogenous Leukemia-Blast Crisis Cells Cancer Res., August 15, 2003; 63(16): 5126 - 5135. [Abstract] [Full Text] [PDF]
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A. N. Mohamed, P. Pemberton, J. Zonder, and C. A. Schiffer The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations Clin. Cancer Res., April 1, 2003; 9(4): 1333 - 1337. [Abstract] [Full Text] [PDF]
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C. Gambacorti-Passerini, M. Zucchetti, D. Russo, R. Frapolli, M. Verga, S. Bungaro, L. Tornaghi, F. Rossi, P. Pioltelli, E. Pogliani, et al. {alpha}1 Acid Glycoprotein Binds to Imatinib (STI571) and Substantially Alters Its Pharmacokinetics in Chronic Myeloid Leukemia Patients Clin. Cancer Res., February 1, 2003; 9(2): 625 - 632. [Abstract] [Full Text] [PDF]
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J. M. Golas, K. Arndt, C. Etienne, J. Lucas, D. Nardin, J. Gibbons, P. Frost, F. Ye, D. H. Boschelli, and F. Boschelli SKI-606, a 4-Anilino-3-quinolinecarbonitrile Dual Inhibitor of Src and Abl Kinases, Is a Potent Antiproliferative Agent against Chronic Myelogenous Leukemia Cells in Culture and Causes Regression of K562 Xenografts in Nude Mice Cancer Res., January 15, 2003; 63(2): 375 - 381. [Abstract] [Full Text] [PDF]
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H. M. Kantarjian, M. Talpaz, S. O'Brien, T. L. Smith, F. J. Giles, S. Faderl, D. A. Thomas, G. Garcia-Manero, J.-P. J. Issa, M. Andreeff, et al. Imatinib Mesylate for Philadelphia Chromosome-positive, Chronic-Phase Myeloid Leukemia after Failure of Interferon-{alpha}: Follow-Up Results Clin. Cancer Res., July 1, 2002; 8(7): 2177 - 2187. [Abstract] [Full Text] [PDF]
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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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M. S. Holtz, M. L. Slovak, F. Zhang, C. L. Sawyers, S. J. Forman, and R. Bhatia Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation Blood, May 15, 2002; 99(10): 3792 - 3800. [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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J. Albanell, F. Rojo, S. Averbuch, A. Feyereislova, J. M. Mascaro, R. Herbst, P. LoRusso, D. Rischin, S. Sauleda, J. Gee, et al. Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition J. Clin. Oncol., January 1, 2002; 20(1): 110 - 124. [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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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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L. Mologni, E. Marchesi, P. E. Nielsen, and C. Gambacorti-Passerini Inhibition of Promyelocytic Leukemia (PML)/Retinoic Acid Receptor-{alpha} and PML Expression in Acute Promyelocytic Leukemia Cells by Anti-PML Peptide Nucleic Acid Cancer Res., July 1, 2001; 61(14): 5468 - 5473. [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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J. I. Koontz, A. L. Soreng, M. Nucci, F. C. Kuo, P. Pauwels, H. van den Berghe, P. D. Cin, J. A. Fletcher, and J. Sklar Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors PNAS, May 22, 2001; 98(11): 6348 - 6353. [Abstract] [Full Text] [PDF]
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M. Gianni', Y. Kalac, I. Ponzanelli, A. Rambaldi, M. Terao, and E. Garattini Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RAR{alpha} and PML-RAR{alpha} Blood, May 15, 2001; 97(10): 3234 - 3243. [Abstract] [Full Text] [PDF]
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Y. Kano, M. Akutsu, S. Tsunoda, H. Mano, Y. Sato, Y. Honma, and Y. Furukawa In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents Blood, April 1, 2001; 97(7): 1999 - 2007. [Abstract] [Full Text] [PDF]
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R. Nimmanapalli, E. O’Bryan, and K. Bhalla Geldanamycin and Its Analogue 17-Allylamino-17-demethoxygeldanamycin Lowers Bcr-Abl Levels and Induces Apoptosis and Differentiation of Bcr-Abl-positive Human Leukemic Blasts Cancer Res., March 1, 2001; 61(5): 1799 - 1804. [Abstract] [Full Text]
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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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M. W. N. Deininger, J. M. Goldman, and J. V. Melo The molecular biology of chronic myeloid leukemia Blood, November 15, 2000; 96(10): 3343 - 3356. [Full Text] [PDF]
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J. L. Hecht and J. C. Aster Molecular Biology of Burkitt's Lymphoma J. Clin. Oncol., November 1, 2000; 18(21): 3707 - 3721. [Abstract] [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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G. Fang, C. N. Kim, C. L. Perkins, N. Ramadevi, E. Winton, S. Wittmann, and K. N. Bhalla CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs Blood, September 15, 2000; 96(6): 2246 - 2253. [Abstract] [Full Text] [PDF]
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N. J. Donato and M. Talpaz Clinical Use of Tyrosine Kinase Inhibitors: Therapy for Chronic Myelogenous Leukemia and Other Cancers Clin. Cancer Res., August 1, 2000; 6(8): 2965 - 2966. [Full Text]
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G. W. Krystal, S. Honsawek, J. Litz, and E. Buchdunger The Selective Tyrosine Kinase Inhibitor STI571 Inhibits Small Cell Lung Cancer Growth Clin. Cancer Res., August 1, 2000; 6(8): 3319 - 3326. [Abstract] [Full Text]
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F. X. Mahon, M. W. N. Deininger, B. Schultheis, J. Chabrol, J. Reiffers, J. M. Goldman, and J. V. Melo Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance Blood, August 1, 2000; 96(3): 1070 - 1079. [Abstract] [Full Text] [PDF]
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E. Weisberg and J. D. Griffin Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines Blood, June 1, 2000; 95(11): 3498 - 3505. [Abstract] [Full Text] [PDF]
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C. Bertazzoli, E. Marchesi, L. Passoni, R. Barni, F. Ravagnani, C. Lombardo, G. M. Corneo, P. Pioltelli, E. Pogliani, and C. Gambacorti-Passerini Differential Recognition of a BCR/ABL Peptide by Lymphocytes from Normal Donors and Chronic Myeloid Leukemia Patients Clin. Cancer Res., May 1, 2000; 6(5): 1931 - 1935. [Abstract] [Full Text] [PDF]
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P. le Coutre, E. Tassi, M. Varella-Garcia, R. Barni, L. Mologni, G. Cabrita, E. Marchesi, R. Supino, and C. Gambacorti-Passerini Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification Blood, March 1, 2000; 95(5): 1758 - 1766. [Abstract] [Full Text] [PDF]
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C. Perkins, C. N. Kim, G. Fang, and K. N. Bhalla Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL Blood, February 1, 2000; 95(3): 1014 - 1022. [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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E. A. Sausville A Bcr/Abl Kinase Antagonist for Chronic Myelogenous Leukemia: a Promising Path for Progress Emerges J Natl Cancer Inst, January 20, 1999; 91(2): 102 - 103. [Full Text] [PDF]
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