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Vol. 295, Issue 1, 139-145, October 2000
Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland (E.B., N.L., N.B.L.); Novartis Pharma, Summit, New Jersey (C.L.C.); and Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon (S.O.-J., B.J.D.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase
inhibitor that is currently in clinical trials for the treatment of
chronic myelogenous leukemia. STI571 selectively inhibits the
Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases
in vitro and blocks cellular proliferation and tumor growth of
Bcr-abl- or v-abl-expressing cells. We
have further investigated the profile of STI571 against related
receptor tyrosine kinases. STI571 was found to potently inhibit the
kinase activity of the 
- and 
-PDGF receptors and the receptor for
stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and
stem cell factor-mediated cellular signaling, including
ligand-stimulated receptor autophosphorylation, inositol phosphate
formation, and mitogen-activated protein kinase activation and
proliferation. These results expand the profile of STI571 and suggest
that in addition to chronic myelogenous leukemia, STI571 may have
clinical potential in the treatment of diseases that involve abnormal
activation of c-Kit or PDGF receptor tyrosine kinases.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
protein-tyrosine kinase family can be divided into subgroups that have
similar structural organization and sequence similarity within the
kinase domain. The members of the type III group of receptor tyrosine
kinases include the platelet-derived growth factor (PDGF) receptors
(PDGF receptors and ), colony-stimulating factor (CSF)-1
receptor (CSF-1R, c-Fms), Flt-3, and stem cell or steel factor receptor
(c-Kit). These receptor tyrosine kinases are characterized by five
Ig-like domains in the extracellular domain and a cytoplasmic region
containing a hydrophilic kinase insert domain (Heldin, 1995
). PDGF
receptors are normally found in connective tissue and glia but are
lacking in most epithelia. However, recent studies have implicated
paracrine or autocrine PDGF loops in the growth deregulation of gliomas
and sarcomas as well as various human epithelial tumors. Furthermore,
PDGF has been implicated in the pathogenesis of several
nonmalignant proliferative diseases, including atherosclerosis,
restenosis following vascular angioplasty (Ferns et al., 1991), and
fibroproliferative disorders such as obliterative bronchiolitis (Hertz
et al., 1992).
c-kit is the cellular homolog of the v-kit
retroviral oncogene. The c-kit gene product is expressed in
hematopoietic progenitor cells, mast cells, germ cells, interstitial
cell of cajal, and some human tumors (Nocka et al., 1989; Turner et
al., 1992; Ishikawa et al., 1997). Studies with mice with inactivating
mutations of c-kit or its ligand have demonstrated that the
c-kit gene product is essential for maintenance of normal
hematopoiesis, melanogenesis, gametogenesis, and growth and
differentiation of mast cells and interstitial cell of cajal. In
addition to its normal role, deregulation of c-Kit is thought to plan a
role in certain human tumors, including germ cell tumors, mast cell
tumors, gastrointestinal stomal tumors, small-cell lung cancers
(SCLCs), melanoma, breast cancer, and neuroblastoma. In a number of
tumors types, c-Kit-mediated growth has been found to occur via
mutation of c-kit, which results in ligand-independent
activation of the receptor (Hirota et al., 1998; Longley et al., 1999;
Tian et al., 1999).
Recently, we have described a protein-tyrosine kinase inhibitor
(STI571/CGP 57148B) of the 2-phenylaminopyrimidine class that has
selectivity for the Abl and PDGF receptor tyrosine kinases (Druker et
al., 1996; Carroll et al., 1997; Zimmermann et al., 1997). In these
reports, STI571 inhibited the Abl and PDGF receptor kinases at the in
vitro enzyme, cellular, and in vivo levels. Based on its preclinical
activity against Bcr-Abl, STI571 is currently in clinical trials for
the therapy of chronic myelogenous leukemia (CML). In the current
study, we have further extended the preclinical profile of STI571
against additional protein kinases from the type III group of receptor
tyrosine kinases and other related receptor kinases. In addition to its
previously reported inhibition of the Abl and PDGF receptor tyrosine
kinases, STI571 was found to inhibit c-Kit, but did not affect closely
related kinases such as c-Fms, Kdr, Flt-1, Tek, and Flt-3. The
data also demonstrate that the compound is a potent inhibitor of c-Kit
and PDGF-mediated signal transduction events in cells. In addition to
CML, STI571 may have potential clinical utility in cancers and
nonmalignant proliferative diseases involving deregulated c-Kit or PDGF
receptor activation.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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CGP 57148 and STI571 (formerly known as CGP 57148B, the methane
sulfonate salt of CGP 57148) were synthesized by Novartis Pharma AG
(Basel, Switzerland). CGP 57148 is referred to as compound 1 in
Zimmermann et al. (1997). No significant difference in results was seen
between the two forms of the compound in in vitro studies, and both
forms are referred to as STI571 in this study. For in vitro and
cellular assays, a stock concentration of 10 mM STI571 was prepared in
Me2SO4 and stored at
20°C. Dilutions for all assays were freshly made before use. Liquid
media, fetal calf serum (FCS), and media additives were from Life
Technologies Inc. (Basel, Switzerland). PDGF-BB was from Life
Technologies Inc., and PDGF-AA was from Bachem (Bubendorf,
Switzerland). Stem cell factor (SCF) was from Genzyme (Cambridge, MA),
Flt-3 was provided by Immunex (Seattle, WA), anti-c-Kit antibodies were
from Oncogene Science (Cambridge, MA), anti-PDGF receptor antibodies were from Santa Cruz Biotechnology (sc338; Santa Cruz, CA),
and anti-PDGF receptor / antibodies were from Upstate
Biotechnology (06-495; Lake Placid, NY).
Myo-[2-3H]inositol with PT6 polymer (10-20
Ci/mmol) was from Amersham (Arlington Heights, IL), and the CellTiter
96 Aqueous Non-Radioactive Cell Proliferation assay was from Promega
(Madison, WI).
Cell Lines. The 32D cell line is a murine myeloid cell line that is dependent on interleukin-3 (IL-3) for proliferation and was obtained from Joel Greenberger, University of Massachusetts Medical Center, Worcester, MA. Cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) (Upstate Biotechnology) and 15% WEHI-3B-conditioned medium as a source of IL-3. MO7e cells are a human megakaryocytic leukemia cell line that requires either granulocte macrophage-colony-stimulating factor (GM-CSF), IL-3, or stem cell factor (SCF) for proliferation and were obtained from G. Bagby, Oregon Health Sciences University (Portland, OR). Cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 2.5 ng/ml GM-CSF.
Other cell lines that were used for these studies include 32D cells expressing v-src, courtesy of S. Anderson, Department of Pathology, State University of New York (Stony Brook, NY), and NIH 3T3 cells expressing c-fms (Varticovski et al., 1989). A10 rat aorta smooth muscle cells were obtained from the American Type
Culture Collection (Manassas, VA) and were cultured in the suggested media and additives. M1 cells (American Type Culture Collection), a murine myeloid cell line that expresses Flt-3, were in
grown in RPMI 1640 medium containing 10% FCS. Swiss 3T3 cells were
kindly provided by G. Thomas (Friedrich-Miescher Institute, Basel,
Switzerland). Cells were grown in Dulbecco's modified Eagle's medium
(DMEM) containing 10% FCS.
In Vitro Kinase Assays.
The kinase domains of Kdr, Flt-1,
c-Met, and Tek were expressed in High Five cells (Invitrogen, San
Diego, CA) using the Bac-to-Bac expression system (Life
Technologies Inc.). The proteins were then purified to near homogeneity
by standard chromatographic techniques. Kinase inhibition was measured
by detecting the decrease in phosphorylation of poly(Glu, Tyr)
essentially as previously described for the epidermal growth factor
receptor (Buchdunger et al., 1994). The in vitro kinase assays were
carried out under optimized assay conditions (ATP concentration
~Km), which allows a comparison of
IC50 values for the different kinases.
Jak-2 Kinase Assay. To determine whether Jak-2 was inhibited by STI571, 32Dp210 Bcr-Abl-expressing cells were serum starved for 8 h, and then stimulated for 10 min with 10% WEHI-3B-conditioned medium (IL-3 source). Nonidet P-40 lysates were prepared, and 500 µg of lysate was immunoprecipitated with either anti-Jak-2 antibodies (5 µl; Upstate Biotechnology), or anti-Abl antibodies (20 µl K12; Santa Cruz Biotechnology), overnight at 4°C. Immunoprecipitates were bound to protein G Sepharose for 1 h, washed three times with PBS, and then with kinase buffer (20 mM Tris, pH 7.5, 10 mM MgCl2, 10 µM sodium vanadate, 1 mM dithiothreitol). Kinase assays were performed with or without 10 µM STI571, run on a 10% acrylamide gel, and exposed on a phosphorimager.
Cell Extraction. Swiss 3T3 cells were grown to confluency in DMEM containing 10% FCS. Medium was replaced by DMEM containing 0.1% (w/v) BSA, and cells were incubated for 90 min with the indicated concentrations of STI571 before stimulation with PDGF-AA or PDGF-BB for 10 min. MO7e were serum starved (growth in serum-free medium for 16 h) and incubated for 90 min at 37°C with the drug before stimulation with recombinant human SCF (50 ng/ml) for 10 min at 37°C. M1 cells were washed twice with RPMI 1640 and resuspended at 2 × 106 cell/ml of RPMI containing 1% (w/v) BSA for 6 to 8 h. The indicated concentrations of inhibitor were added for the final 2 h of incubation. Cells were stimulated with 1 µg/ml recombinant Flt-3 ligand (Immunex, Seattle, WA) for 5 min. c-Fms-expressing NIH 3T3 cells and v-Src-expressing 32D cells were incubated for 4 h in the presence of STI571 before lysis. To measure IL-3-stimulated tyrosine kinase activity, MO7e cells were washed twice with RPMI 1640 and resuspended at 2 × 106 cells/ml of RPMI 1640 containing 1% BSA. Cells were incubated in this medium for 6 to 8 h. Various concentrations of inhibitor were added for the final 4 h of incubation. At the end of this period, cells were stimulated with 10 ng/ml human recombinant IL-3 (gift of G. Bagby, Oregon Health Sciences University).
Immunoprecipitation.
c-Kit was immunoprecipitated from MO7e
cell extracts containing 500 µg of total protein using 1 µg of
anti-c-Kit antibody. Immunoprecipitation was carried out overnight at
4°C, and immunocomplexes were harvested by the addition of Pansorbin
(Calbiochem, La Jolla, CA). After extensive washing,
precipitates were resuspended in 40 µl of 2× concentrated SDS sample
buffer. Similarly, PDGF receptors were immunoprecipitated from Swiss
3T3 cell extracts using anti-PDGF receptor or anti-PDGF receptor
/ antibodies.
Western Blot Analysis.
Equal amounts of protein from cell
lysates were analyzed by Western blotting with anti-phosphotyrosine
antibodies, anti-c-Kit antibodies, anti-PDGF receptor or anti-PDGF
receptor / antibodies. Bound antibodies were detected by using
the ECL Western blotting system from Amersham (Amersham, UK). All
experiments were performed at least in triplicate, and the effects of
STI571 on cellular tyrosine phosphorylation were analyzed in a
semiquantitative manner.
Mitogen-Activated Kinase (MAP) Kinase Analysis. Serum-starved MO7e cells were incubated in the presence of the indicated concentrations of STI571 for 2 h at 37°C and then stimulated with 50 ng/ml human SCF for 5 min at 37°C. A10 smooth muscle cells were grown to 70% confluency in 6-well plates and starved in DMEM containing 0.1% BSA for 18 h. After washing with PBS, cells were incubated in DMEM with the indicated concentrations of drug 2 h before stimulation with 20 ng/ml PDGF-BB for 5 min. After washing with ice-cold PBS containing vanadate, cells were lysed. Samples were analyzed by using the Phosphoplus MAP kinase antibody kit (New England Biolabs, Beverley, MA). In brief, samples were resolved on 10% SDS-polyacrylamide gel electrophoresis, and immunoblotted with phosphoMAP kinase antibodies. To control for equal loading of MAP kinase, samples were immunoblotted in parallel with anti-MAP kinase antibodies that recognize both phosphorylated and nonphosphorylated MAP kinase.
Measurement of [3H]Inositol Phosphate Release. A10 cells were grown in 24-well plates (30,000 cells/well) and incubated with [3H]inositol (1 µCi/well) for 2 days in DMEM (without inositol) containing 10% FBS. On the day before the experiment, quiescence was induced by serum derivation for 24 h by replacing the medium with serum-free DMEM containing [3H]inositol (1 µCi/well). On the day of the experiment, quiescent cells were washed twice with Dulbecco's phosphate-buffered salt solution and then incubated for 5 min with HEPES physiological salt solution (142 mM NaCl, 5.6 mM KCl, 2.2 mM CaCl2, 3.6 mM NaHCO3, 1.0 mM MgCl2, 5.6 mM D-glucose, 30 mM HEPES, pH 7.4) containing 0.1% BSA and 20 mM LiCl. Cells were preincubated with STI571 (50 µl) for 30 min in a shaking (50 oscillations/min) water bath at 37°C. The reaction was initiated by the addition of 10 ng/ml PDGF (50 µl) for a final volume of 500 µl. After 5 min, the reaction was terminated by the addition of 0.2 ml HClO4 (10% v/v), and the plates were placed on ice for 15 min. The supernatants were transferred to glass test tubes, centrifuged (2000 rpm; 5 min), and neutralized with 1.5 M KOH containing 60 mM HEPES. [3H]Inositol phosphates were separated from the neutralized acid extracts by anion exchange chromatography.
Measurement of Cell Growth. Cells were grown in 96-well culture plates (5000 cells/well) and allowed to adhere overnight. The cells were washed twice with Dulbecco's phosphate-buffered salt solution, and quiescence was induced by replacing the medium 24 h before the start of the experiment with DMEM containing 0.2% FBS. Medium was removed from the wells and replaced with DMEM (without phenol red). Quiescent cells were incubated for 30 min with inhibitors and then stimulated with either 10 ng/ml PDGF or 10% FBS for 24 h. Cell growth was measured by using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation assay that measures the reduction, by living cells only, of the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium compound (MTS). Briefly, 20 µl of MTS is added to each well during the last 3 h of stimulation with mitogen. The absorbance at 490 nm was recorded by using a microplate reader.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Selectivity for Inhibition of Protein Kinases.
STI571 was
tested for inhibition of protein-tyrosine kinases of the PDGF receptor
subfamily. Previous studies have shown that STI571 inhibits the PDGF
receptor; however, these studies used ligand that activated both PDGF
receptor and , so that is was not possible to determine whether
STI571 inhibits each of these receptor subtypes. Because Swiss 3T3
cells possess significant numbers of both - and -PDGF receptors
(Kazlauskas et al., 1988), we investigated the effect of STI571 on the
response of these cells to PDGF-AA and PGDF-BB. PDGF-AA binds to and
activates only the PDGF receptor , whereas PDGF-BB binds to and
activates all PDGF receptors, including PDGF receptor - and
-homodimers and -heterodimers (Heldin et al., 1988). PDGF-AA
induced the tyrosine phosphorylation of a protein with a molecular
mass of ~170 kDa, which was identified as the PDGF receptor
by immunoprecipitation with anti-PDGF receptor antibodies (Fig.
1A). Pretreatment of cells with STI571
caused a concentration-dependent inhibition of PDGF-AA-stimulated PDGF
receptor -phosphorylation with an IC50 value
of approximately 0.1 µM (Fig. 1A). Tyrosine phosphorylation induced
by the PDGF-BB homodimer was inhibited with a similar IC50 value as shown by Western blotting with
total cell lysates (Fig. 1B, lanes 1-7) or PDGF receptor
-immunoprecipitated lysates (Fig. 1B, lanes 8-14). These data
indicate, by inference, that STI571 also inhibits PDGF receptor .
The overall levels of expressed PDGF receptor protein did not change
after exposure to STI571 (Fig. 1, A and B, bottom).
|
). Additionally, STI571 had little effect on the
growth of normal committed blood cell precursors in response to IL-3
and erythropoietin (Epo) or G-CSF and Epo as measured in colony
formation assays (Druker et al., 1996). When tested for inhibition of
isolated enzymes in vitro, the compound showed no or weak inhibition of
Kdr, Flt-1, Tek, and c-Met tyrosine kinases (IC50
values of 11, 25, 26.8, and 101 µM, respectively).
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Effects on SCF- and PDGF-Mediated Signal Transduction.
A
common cellular response to a variety of extracellular signals involves
the activation of MAP kinase pathways. To assay the phosphorylation of
MAP kinases, an antibody that recognizes the tyrosyl phosphorylated
forms of MAP kinases was used for immunoblotting cell lysates.
Stimulation of MO7e cells with SCF resulted in the phosphorylation of
two MAP kinases, known as pp44erk1 and
pp42erk2. STI571 strongly inhibited the
SCF-induced activation of MAP kinases with an
IC50 value between 0.1 and 1 µM (Fig.
7A). Similarly, STI571 treatment
inhibited PDGF-BB-mediated MAP kinase activation in rat A10 smooth
muscle cells (Fig. 7B). The same cell line was used to test the effect
of STI571 on PDGF-mediated [3H]inositol
phosphate release. The compound inhibited
[3H]inositol phosphate release in response to
PDGF-BB treatment with an IC50 value of 0.25 µM
(Fig. 8A). In addition, this compound inhibited PDGF-BB-stimulated A10 cell proliferation with an
IC50 value of 0.2 µM. In contrast,
concentrations of STI571 up to 10 µM had no effect on A10
proliferation induced by serum (Fig. 8B).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this article we extended the in vitro profile of the
protein-tyrosine kinase inhibitor STI571, which is currently in
clinical trials for the treatment of CML. Previous studies have shown
STI571 to be a selective inhibitor of Abl and PDGF receptor tyrosine kinases (Druker et al., 1996; Carroll et al., 1997; Zimmermann et al.,
1997). However, these previous studies did not determine which of the
PDGF receptor subtypes were inhibited by STI571. The current studies
demonstrate that STI571 potently inhibits PDGF-AA-stimulated receptor
phosphorylation. The finding that STI571 inhibits PDGF-AA-stimulated
receptor phosphorylation in Swiss 3T3 cells indicates that the drug is
a potent inhibitor of the PDGF receptor . Because PDGF-BB homodimers
bind and activate all possible PDGF receptor dimers (Heldin et al.,
1988) and the PDGF-BB-stimulated receptor phosphorylation also was
inhibited by STI571, we conclude that STI571 is a potent inhibitor of
both PDGF receptor subtypes.
In this manuscript, we demonstrate that STI571 also inhibits the c-Kit
tyrosine kinase with essentially the same potency. Because c-Kit and
PDGF receptors are members of the type III receptor tyrosine kinase
family, other members of this family and closely related kinases were
evaluated for inhibition by STI571. Interestingly, the related receptor
tyrosine kinases Flt-3, Fms, Kdr, Flt-1, Tek, and c-Met were not
inhibited. Because STI571 acts as an ATP-competitive inhibitor, this
suggests that these tyrosine kinases, although structurally related,
have subtle differences in the structure of their ATP-binding domains.
These data extend our previous findings where STI571 has been shown to
selectively inhibit the Abl tyrosine kinase in vitro
(IC50 = 0.025 µM) without affecting other
tyrosine kinases such as epidermal growth factor receptor, c-Src,
c-Fgr, c-Lyn, tyrosine protein kinase IIB, or serine threonine kinases such as protein kinase A, phosphorylase kinase, casein kinases 1 and 2, and Cdc-2/CycB (Druker et al., 1996). Similarly, a variety of other
kinases involved in cytokine signaling (e.g., intracellular tyrosine
kinases such as Src or Jak kinases) were not inhibited by STI571. The
lack of inhibition of Jak-2 tyrosine kinase activity is in agreement
with previously reported cellular results, demonstrating that STI571
lacks antiproliferation activity in IL-3-dependent proliferation and
colony-forming assays (Druker et al., 1996). Activation of
transmembrane tyrosine kinase receptors is generally associated with a
variety of intracellular signaling events, including SH2- and
SH3-mediated protein-protein interactions, and activation of signaling
enzymes such as phospholipases C, protein kinase C, MAP kinases, and
phosphatidylinositol 3-kinase. We have used the aorta vascular smooth
muscle cell model to examine interference downstream of the PDGF
receptor kinase. Although the exact contribution of these signaling
pathways to vascular function remains to be elucidated, it has been
demonstrated that activation of distinct signal transduction pathways
contributes to the role of PDGF as a potent mitogen and chemotactic
factor for vascular smooth muscle cells (Innui et al., 1994). Moreover,
PDGF has been implicated as an important factor involved in the
vascular response to injury as observed in cardiovascular diseases such
as atherosclerosis (Ross, 1995), restenosis (Pauletto et al., 1994),
and transplant arteriosclerosis (Gordon, 1992). STI571 was shown to
potently inhibit PDGF-induced inositol release, MAP kinase activation, and proliferation of A10 rat aorta smooth muscle cells. This finding suggests that STI571 may have therapeutic use in vascular disease states associated with smooth muscle cell proliferation and migration. In vivo studies also have recently confirmed the activity of STI571 or
a structurally related compound (CGP 53716) in such systems (Kallio et
al., 1999; Myllarniemi et al., 1999).
Several studies have revealed that the majority of gliomas coexpress
both PDGF and PDGF receptors, suggesting an autocrine mechanism of
growth stimulation in this type of malignancy (Hermanson et al., 1992).
High-grade primary gliomas express increased levels of PDGF receptors
and their ligands compared with low-grade gliomas, indicating that in
gliomas the presence of a PDGF autocrine loop correlates with tumor
progression (Hermanson et al., 1992). There are several examples of
malignant epithelial cells that produce PDGF but do not express PDGF
receptors. Expression of PDGF in cultured malignant epithelial cell
lines from human patients with breast (Perez et al., 1987) and prostate
cancer (Sitaras et al., 1988) has been reported. Recent studies of
plasma and tissue PDGF concentration in patients with breast cancer
indicate that PDGF levels predict for shorter survival times and have
an adverse effect on response to chemotherapy (Seymour et al., 1993).
These findings suggest that tumor cell-derived PDGF also plays a role as a paracrine growth factor in tumorigenesis. Because PDGF is a potent
mitogen and chemoattractant for both fibroblasts (Seppä et al.,
1982) and endothelial cells (Smits et al., 1989), PDGF may have a
function in tumor development by stimulating the growth of a supporting
connective tissue stroma and contribute to endothelial cell growth.
Development of a vascular connective tissue stroma in xenotransplanted
human melanoma producing PDGF-BB has been reported (Forsberg et al.,
1993). Thus, STI571 also may have utility against such tumors that
express PDGF receptors.
SCF is thought to play a central role in the proliferation and
differentiation of stem cells (McNiece and Briddell, 1995). Although
SCF itself does not promote colony formation in vitro, it works in
synergy with other growth factors such as GM-CSF, G-CSF, IL-3, IL-6,
IL-7, and Epo to stimulate formation of both differentiated progenitor
cells and more primitive multilineage progenitor cells of the myeloid
and erythroid lineages (McNiece et al., 1991). In addition to its
normal function, deregulation of SCF receptor signaling has been
implicated in a number of human cancers, including SCLC (Hibi et al.,
1991; Sekido et al., 1991; Krystal et al., 1996), breast carcinomas
(Hines et al., 1995), glioblastoma (Berdel et al., 1992), testicular
malignancies (Strohmeyer et al., 1991), gastrointestinal stromal tumors
(Hirota et al., 1998), gynecological cancers (Inoue et al., 1994) and
mastocytomas (Longley et al., 1999). Evidence for the involvement of
inappropriate receptor signaling by c-Kit in SCLC comes from the
finding that most SCLC cell lines and primary tumors overexpress SCF
and c-Kit (Hibi et al., 1991; Sekido et al., 1991; Krystal et al.,
1996). Introduction of a dominant-negative kinase-defective mutant of c-Kit into the SCLC cell line NCI-H209 markedly decreased the cells'
ability to grow in the absence of growth factors (Krystal et al.,
1996), indicating the need for a c-Kit/SCF autocrine loop for growth.
Furthermore, STI571 has been found to inhibit signal transduction and
growth of SCLC cells (Krystal et al., 2000).
Our findings further suggest that STI571 may have clinical activity in tumors and nonmalignant proliferative disorders with deregulated PDGF receptor and c-Kit signaling. Additionally, the encouraging results seen in clinical trials in CML may result from a combination of the activity of STI571 on Bcr-Abl and c-Kit on leukemia cells.
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Acknowledgments |
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We thank M. Garay, P. Hauser, C. Koelbing, and V. Rigo for excellent technical assistance. We also thank S. Anderson for providing the 32D cell line expressing v-Src, G. Bagby for the MO7e cells and IL-3, and G. Thomas for the Swiss 3T3 cells.
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Footnotes |
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Accepted for publication June 16, 2000.
Received for publication February 21, 2000.
1 Present address: Prolifix Ltd., 91 Milton Park, Abington, Oxford Shire, OX 14 4RY, UK.
2 Present address: Kinetix Pharmaceuticals Inc., Suite 3500, 200 Boston Ave., Medford, MA 02155.
Send reprint requests to: Dr. E. Buchdunger, Novartis Pharma AG, Oncology Research, K-125.416, CH-4002 Basel, Switzerland. E-mail: elisabeth.buchdunger{at}pharma.novartis.com
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Abbreviations |
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PDGF, platelet-derived growth factor; SCLC, small-cell lung cancer; CML, chronic myelogenous leukemia; FCS, fetal calf serum; SCF, stem cell factor; IL, interleukin; FBS, fetal bovine serum; GM-CSF, granulocyte macrophage-colony-stimulating factor; DMEM, Dulbecco's modified Eagle's medium; MAP, mitogen-activated protein kinase; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium compound; Epo, erythropoietin.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Evidence for an impaired c-kit kinase in mutant mice.
Genes Dev
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 S. Sanchez-Guerrero, G. Agreda, E. Oviedo, and C. Lome Langerhans Cell Histiocytosis Responding to 2-Cda and Imatinib Mesylate (IM) Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 4649 - 4649. [Abstract]
|
|
|
|
 |
|
 A. R. Alvarez, A. Klein, J. Castro, G. I. Cancino, J. Amigo, M. Mosqueira, L. M. Vargas, L. F. Yevenes, F. C. Bronfman, and S. Zanlungo Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease FASEB J, October 1, 2008; 22(10): 3617 - 3627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Dewaele, B. Wasag, J. Cools, R. Sciot, H. Prenen, P. Vandenberghe, A. Wozniak, P. Schoffski, P. Marynen, and M. Debiec-Rychter Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor-Associated PDGFRAD842V Mutation Clin. Cancer Res., September 15, 2008; 14(18): 5749 - 5758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. I. Cancino, E. M. Toledo, N. R. Leal, D. E. Hernandez, L. F. Yevenes, N. C. Inestrosa, and A. R. Alvarez STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's {beta}-amyloid deposits Brain, September 1, 2008; 131(9): 2425 - 2442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Artinyan, J. Kim, P. Soriano, W. Chow, S. Bhatia, and J. D.I. Ellenhorn Metastatic Gastrointestinal Stromal Tumors in the Era of Imatinib: Improved Survival and Elimination of Socioeconomic Survival Disparities Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2194 - 2201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Lasater, W. K. Bessler, L. E. Mead, W. E. Horn, D. W. Clapp, S. J. Conway, D. A. Ingram, and F. Li Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway Hum. Mol. Genet., August 1, 2008; 17(15): 2336 - 2344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fabarius, M. Giehl, B. Rebacz, A. Kramer, O. Frank, C. Haferlach, P. Duesberg, R. Hehlmann, W. Seifarth, and A. Hochhaus Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib Haematologica, August 1, 2008; 93(8): 1145 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Leipner, K. Grun, A. Muller, E. Buchdunger, L. Borsi, H. Kosmehl, A. Berndt, T. Janik, A. Uecker, M. Kiehntopf, et al. Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis Cardiovasc Res, July 1, 2008; 79(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. O. Rybin, J. Guo, Z. Gertsberg, S. J. Feinmark, and S. F. Steinberg Phorbol 12-Myristate 13-Acetate-dependent Protein Kinase C{delta}-Tyr311 Phosphorylation in Cardiomyocyte Caveolae J. Biol. Chem., June 27, 2008; 283(26): 17777 - 17788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors PNAS, June 17, 2008; 105(24): 8387 - 8392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Verstovsek, A. Tefferi, J. Cortes, S. O'Brien, G. Garcia-Manero, A. Pardanani, C. Akin, S. Faderl, T. Manshouri, D. Thomas, et al. Phase II Study of Dasatinib in Philadelphia Chromosome-Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis Clin. Cancer Res., June 15, 2008; 14(12): 3906 - 3915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Puissant, S. Grosso, A. Jacquel, N. Belhacene, P. Colosetti, J.-P. Cassuto, and P. Auberger Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol FASEB J, June 1, 2008; 22(6): 1894 - 1904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Haroche, Z. Amoura, F. Charlotte, J. Salvatierra, B. Wechsler, C. Graux, N. Brousse, and J.-C. Piette Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis Blood, June 1, 2008; 111(11): 5413 - 5415. [Full Text] [PDF]
|
|
|
|
|
|
M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al. Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases Clin. Cancer Res., May 1, 2008; 14(9): 2717 - 2725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dadlani, M. L. Ballinger, N. Osman, R. Getachew, and P. J. Little Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle J. Biol. Chem., March 21, 2008; 283(12): 7844 - 7852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Boehrer, L. Ades, T. Braun, L. Galluzzi, J. Grosjean, C. Fabre, G. Le Roux, C. Gardin, A. Martin, S. de Botton, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study Blood, February 15, 2008; 111(4): 2170 - 2180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Ramanathan, M. J. Egorin, C. H.M. Takimoto, S. C. Remick, J. H. Doroshow, P. A. LoRusso, D. L. Mulkerin, J. L. Grem, A. Hamilton, A. J. Murgo, et al. Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group J. Clin. Oncol., February 1, 2008; 26(4): 563 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gibbons, M. J. Egorin, R. K. Ramanathan, P. Fu, D. L. Mulkerin, S. Shibata, C. H.M. Takimoto, S. Mani, P. A. LoRusso, J. L. Grem, et al. Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group J. Clin. Oncol., February 1, 2008; 26(4): 570 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al. Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib Cancer Res., January 15, 2008; 68(2): 571 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. McLaughlin, D. Cheng, O. Singer, R. U. Lukacs, C. G. Radu, I. M. Verma, and O. N. Witte Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics PNAS, December 18, 2007; 104(51): 20501 - 20506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. McAuliffe, A. J.F. Lazar, D. Yang, D. M. Steinert, W. Qiao, P. F. Thall, A. K. Raymond, R. S. Benjamin, and J. C. Trent Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate Clin. Cancer Res., November 15, 2007; 13(22): 6727 - 6734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Hoelzinger, T. Demuth, and M. E. Berens Autocrine Factors That Sustain Glioma Invasion and Paracrine Biology in the Brain Microenvironment J Natl Cancer Inst, November 7, 2007; 99(21): 1583 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. McArthur Dermatofibrosarcoma Protuberans: Recent Clinical Progress Ann. Surg. Oncol., October 1, 2007; 14(10): 2876 - 2886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mathew, P. F. Thall, C. D. Bucana, W. K. Oh, M. J. Morris, D. M. Jones, M. M. Johnson, S. Wen, L. C. Pagliaro, N. M. Tannir, et al. Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases Clin. Cancer Res., October 1, 2007; 13(19): 5816 - 5824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Desai, S. Shankar, M. C. Heinrich, J. A. Fletcher, C. D. Fletcher, J. Manola, J. A. Morgan, C. L. Corless, S. George, K. Tuncali, et al. Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors Clin. Cancer Res., September 15, 2007; 13(18): 5398 - 5405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rahmani, T. K. Nguyen, P. Dent, and S. Grant The Multikinase Inhibitor Sorafenib Induces Apoptosis in Highly Imatinib Mesylate-Resistant Bcr/Abl+ Human Leukemia Cells in Association with Signal Transducer and Activator of Transcription 5 Inhibition and Myeloid Cell Leukemia-1 Down-Regulation Mol. Pharmacol., September 1, 2007; 72(3): 788 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Eisele, M. Baumann, B. Klebl, C. Nordhammer, M. Jucker, and E. Kilger Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-beta degrading Enzyme Neprilysin Mol. Biol. Cell, September 1, 2007; 18(9): 3591 - 3600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Atallah, J.-B. Durand, H. Kantarjian, and J. Cortes Congestive heart failure is a rare event in patients receiving imatinib therapy Blood, August 15, 2007; 110(4): 1233 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Montella, G. Palmieri, and M. Lacouture The Era of Targeted Therapies: Increasing Role for Novel Oncologic Drugs in Dermatology Arch Dermatol, June 1, 2007; 143(6): 788 - 789. [Full Text] [PDF]
|
|
|
|
|
|
L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vittal, H. Zhang, M. K. Han, B. B. Moore, J. C. Horowitz, and V. J. Thannickal Effects of the Protein Kinase Inhibitor, Imatinib Mesylate, on Epithelial/Mesenchymal Phenotypes: Implications for Treatment of Fibrotic Diseases J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 35 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Q.M. Chow and S. G. Eckhardt Sunitinib: From Rational Design to Clinical Efficacy J. Clin. Oncol., March 1, 2007; 25(7): 884 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-N. Yeh, T.-W. Chen, H.-L. Lee, Y.-Y. Liu, T.-C. Chao, T.-L. Hwang, Y.-Y. Jan, and M.-F. Chen Kinase Mutations and Imatinib Mesylate Response for 64 Taiwanese with Advanced GIST: Preliminary Experience from Chang Gung Memorial Hospital Ann. Surg. Oncol., March 1, 2007; 14(3): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Kantarjian, F. Giles, A. Quintas-Cardama, and J. Cortes Important Therapeutic Targets in Chronic Myelogenous Leukemia Clin. Cancer Res., February 15, 2007; 13(4): 1089 - 1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Holtz, S. J. Forman, and R. Bhatia Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment Cancer Res., February 1, 2007; 67(3): 1113 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. David, N. C. P. Cross, S. Burgstaller, A. Chase, C. Curtis, R. Dang, M. Gardembas, J. M. Goldman, F. Grand, G. Hughes, et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders Blood, January 1, 2007; 109(1): 61 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kitadai, T. Sasaki, T. Kuwai, T. Nakamura, C. D. Bucana, and I. J. Fidler Targeting the Expression of Platelet-Derived Growth Factor Receptor by Reactive Stroma Inhibits Growth and Metastasis of Human Colon Carcinoma Am. J. Pathol., December 1, 2006; 169(6): 2054 - 2065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. S. Rajkumar, X. Shiwen, M. Bostrom, P. Leoni, J. Muddle, M. Ivarsson, B. Gerdin, C. P. Denton, G. Bou-Gharios, C. M. Black, et al. Platelet-Derived Growth Factor-{beta} Receptor Activation Is Essential for Fibroblast and Pericyte Recruitment during Cutaneous Wound Healing Am. J. Pathol., December 1, 2006; 169(6): 2254 - 2265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Delbaldo, E. Chatelut, M. Re, A. Deroussent, S. Seronie-Vivien, A. Jambu, P. Berthaud, A. Le Cesne, J.-Y. Blay, and G. Vassal Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors. Clin. Cancer Res., October 15, 2006; 12(20): 6073 - 6078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Akin Molecular Diagnosis of Mast Cell Disorders: A Paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2006; 8(4): 412 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Irvine, C. J. Burns, A. F. Wilks, S. Su, D. A. Hume, and M. J. Sweet A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations FASEB J, September 1, 2006; 20(11): 1921 - 1923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Y. Wen, W.K. A. Yung, K. R. Lamborn, P. L. Dahia, Y. Wang, B. Peng, L. E. Abrey, J. Raizer, T. F. Cloughesy, K. Fink, et al. Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08. Clin. Cancer Res., August 15, 2006; 12(16): 4899 - 4907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lin, M. A. Glenn, R. J. Harris, A. D. Duckworth, S. Dennett, J. C. Cawley, M. Zuzel, and J. R. Slupsky c-Abl Expression in Chronic Lymphocytic Leukemia Cells: Clinical and Therapeutic Implications. Cancer Res., August 1, 2006; 66(15): 7801 - 7809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gabillot-Carre, Y. Lepelletier, M. Humbert, P. de Sepuvelda, N. B. Hamouda, J. P. Zappulla, R. Liblau, A. Ribadeau-Dumas, F. Machavoine, S. Letard, et al. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells Blood, August 1, 2006; 108(3): 1065 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Lindskog, E. Athley, E. Larsson, S. Lundin, M. Hellstrom, and P. Lindahl New Insights to Vascular Smooth Muscle Cell and Pericyte Differentiation of Mouse Embryonic Stem Cells In Vitro Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1457 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Sambol, G. Ambrosini, R. C. Geha, P. T. Kennealey, P. DeCarolis, R. O'Connor, Y. V. Wu, M. Motwani, J.-H. Chen, G. K. Schwartz, et al. Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells Cancer Res., June 1, 2006; 66(11): 5858 - 5866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tarn, Y. V. Skorobogatko, T. Taguchi, B. Eisenberg, M. von Mehren, and A. K. Godwin Therapeutic Effect of Imatinib in Gastrointestinal Stromal Tumors: AKT Signaling Dependent and Independent Mechanisms. Cancer Res., May 15, 2006; 66(10): 5477 - 5486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Potapova, A. D. Laird, M. A. Nannini, A. Barone, G. Li, K. G. Moss, J. M. Cherrington, and D. B. Mendel Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248 Mol. Cancer Ther., May 1, 2006; 5(5): 1280 - 1289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhang and K. E. Meier New Assignments for Multitasking Signal Transduction Inhibitors Mol. Pharmacol., May 1, 2006; 69(5): 1510 - 1512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Boissel, D. Rea, V. Tieng, N. Dulphy, M. Brun, J.-M. Cayuela, P. Rousselot, R. Tamouza, P. Le Bouteiller, F.-X. Mahon, et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J. Immunol., April 15, 2006; 176(8): 5108 - 5116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Guo, P. A. Marcotte, J. O. McCall, Y. Dai, L. J. Pease, M. R. Michaelides, S. K. Davidsen, and K. B. Glaser Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol. Cancer Ther., April 1, 2006; 5(4): 1007 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Holtkamp, A. F. Okuducu, J. Mucha, A. Afanasieva, C. Hartmann, I. Atallah, L. Estevez-Schwarz, C. Mawrin, R. E. Friedrich, V.-F. Mautner, et al. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity Carcinogenesis, March 1, 2006; 27(3): 664 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. West, B. P. Rubin, M. A. Miller, S. Subramanian, G. Kaygusuz, K. Montgomery, S. Zhu, R. J. Marinelli, A. De Luca, E. Downs-Kelly, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells PNAS, January 17, 2006; 103(3): 690 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Young, N. P. Shah, L. H. Chao, M. Seeliger, Z. V. Milanov, W. H. Biggs III, D. K. Treiber, H. K. Patel, P. P. Zarrinkar, D. J. Lockhart, et al. Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680 Cancer Res., January 15, 2006; 66(2): 1007 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Schittenhelm, S. Shiraga, A. Schroeder, A. S. Corbin, D. Griffith, F. Y. Lee, C. Bokemeyer, M. W.N. Deininger, B. J. Druker, and M. C. Heinrich Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies Cancer Res., January 1, 2006; 66(1): 473 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Rao, N. Kremenevskaja, R. von Wasielewski, V. Jakubcakova, S. Kant, J. Resch, and G. Brabant Wnt/{beta}-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Benjamin, C. D. Blanke, J.-Y. Blay, S. Bonvalot, and B. Eisenberg Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies Oncologist, January 1, 2006; 11(1): 9 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rossi, A. Cavazza, A. Marchioni, L. Longo, M. Migaldi, G. Sartori, N. Bigiani, L. Schirosi, C. Casali, U. Morandi, et al. Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR{alpha}, PDGFR{beta}, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung J. Clin. Oncol., December 1, 2005; 23(34): 8774 - 8785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yokoi, T. Sasaki, C. D. Bucana, D. Fan, C. H. Baker, Y. Kitadai, T. Kuwai, J. L. Abbruzzese, and I. J. Fidler Simultaneous Inhibition of EGFR, VEGFR, and Platelet-Derived Growth Factor Receptor Signaling Combined with Gemcitabine Produces Therapy of Human Pancreatic Carcinoma and Prolongs Survival in an Orthotopic Nude Mouse Model Cancer Res., November 15, 2005; 65(22): 10371 - 10380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cutcliffe, D. Kersey, C.-C. Huang, Y. Zeng, D. Walterhouse, E. J. Perlman, and for the Renal Tumor Committee of the Children's On Clear Cell Sarcoma of the Kidney: Up-regulation of Neural Markers with Activation of the Sonic Hedgehog and Akt Pathways Clin. Cancer Res., November 15, 2005; 11(22): 7986 - 7994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Dresemann Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series Ann. Onc., October 1, 2005; 16(10): 1702 - 1708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity J. Immunol., September 15, 2005; 175(6): 3674 - 3680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Appel, S. Balabanov, T. H. Brummendorf, and P. Brossart Effects of Imatinib on Normal Hematopoiesis and Immune Activation Stem Cells, September 1, 2005; 23(8): 1082 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Boureux, O. Furstoss, V. Simon, and S. Roche Abl tyrosine kinase regulates a Rac/JNK and a Rac/Nox pathway for DNA synthesis and Myc expression induced by growth factors J. Cell Sci., August 15, 2005; 118(16): 3717 - 3726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Carter, L. M. Wodicka, N. P. Shah, A. M. Velasco, M. A. Fabian, D. K. Treiber, Z. V. Milanov, C. E. Atteridge, W. H. Biggs III, P. T. Edeen, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases PNAS, August 2, 2005; 102(31): 11011 - 11016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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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 M. S. Cohen, C. Zhang, K. M. Shokat, and J. Taunton Structural Bioinformatics-Based Design of Selective, Irreversible Kinase Inhibitors Science, May 27, 2005; 308(5726): 1318 - 1321. [Abstract] [Full Text] [PDF]
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C. Tarn, E. Merkel, A. A. Canutescu, W. Shen, Y. Skorobogatko, M. J. Heslin, B. Eisenberg, R. Birbe, A. Patchefsky, R. Dunbrack, et al. Analysis of KIT Mutations in Sporadic and Familial Gastrointestinal Stromal Tumors: Therapeutic Implications through Protein Modeling Clin. Cancer Res., May 15, 2005; 11(10): 3668 - 3677. [Abstract] [Full Text] [PDF]
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C. Renne, K. Willenbrock, R. Kuppers, M.-L. Hansmann, and A. Brauninger Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma Blood, May 15, 2005; 105(10): 4051 - 4059. [Abstract] [Full Text] [PDF]
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 H. Yoshiji, R. Noguchi, S. Kuriyama, Y. Ikenaka, J. Yoshii, K. Yanase, T. Namisaki, M. Kitade, T. Masaki, and H. Fukui Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G907 - G913. [Abstract] [Full Text] [PDF]
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X.-F. Zhu, B.-F. Xie, J.-M. Zhou, G.-K. Feng, Z.-C. Liu, X.-Y. Wei, F.-X. Zhang, M.-F. Liu, and Y.-X. Zeng Blockade of Vascular Endothelial Growth Factor Receptor Signal Pathway and Antitumor Activity of ON-III (2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone), a Component from Chinese Herbal Medicine Mol. Pharmacol., May 1, 2005; 67(5): 1444 - 1450. [Abstract] [Full Text] [PDF]
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A. L. Dewar, A. C. Cambareri, A. C. W. Zannettino, B. L. Miller, K. V. Doherty, T. P. Hughes, and A. B. Lyons Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib Blood, April 15, 2005; 105(8): 3127 - 3132. [Abstract] [Full Text] [PDF]
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 R. E. Brown Morphoproteomic Analysis of Osteolytic Langerhans Cell Histiocytosis with Therapeutic Implications Ann. Clin. Lab. Sci., April 1, 2005; 35(2): 131 - 136. [Abstract] [Full Text] [PDF]
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 R. A. Mook Jr. The Importance and Complexities of Target Class Selectivity in Drug Discovery Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 223 - 226. [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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S. Appel, A. Rupf, M. M. Weck, O. Schoor, T. H. Brummendorf, T. Weinschenk, F. Grunebach, and P. Brossart Effects of Imatinib on Monocyte-Derived Dendritic Cells Are Mediated by Inhibition of Nuclear Factor-{kappa}B and Akt Signaling Pathways Clin. Cancer Res., March 1, 2005; 11(5): 1928 - 1940. [Abstract] [Full Text] [PDF]
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K. Pietras and D. Hanahan A Multitargeted, Metronomic, and Maximum-Tolerated Dose "Chemo-Switch" Regimen is Antiangiogenic, Producing Objective Responses and Survival Benefit in a Mouse Model of Cancer J. Clin. Oncol., February 10, 2005; 23(5): 939 - 952. [Abstract] [Full Text] [PDF]
|
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Y.-Y. Wang, G.-B. Zhou, T. Yin, B. Chen, J.-Y. Shi, W.-X. Liang, X.-L. Jin, J.-H. You, G. Yang, Z.-X. Shen, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec PNAS, January 25, 2005; 102(4): 1104 - 1109. [Abstract] [Full Text] [PDF]
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S. Wang, M. C. Wilkes, E. B. Leof, and R. Hirschberg Imatinib mesylate blocks a non-Smad TGF-{beta} pathway and reduces renal fibrogenesis in vivo FASEB J, January 1, 2005; 19(1): 1 - 11. [Abstract] [Full Text] [PDF]
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 A. C. Hofer, R. T. Tran, O. Z. Aziz, W. Wright, G. Novelli, J. Shay, and M. Lewis Shared Phenotypes Among Segmental Progeroid Syndromes Suggest Underlying Pathways of Aging J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2005; 60(1): 10 - 20. [Abstract] [Full Text] [PDF]
|
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H. Sihto, M. Sarlomo-Rikala, O. Tynninen, M. Tanner, L. C. Andersson, K. Franssila, N. N. Nupponen, and H. Joensuu KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid Tumors J. Clin. Oncol., January 1, 2005; 23(1): 49 - 57. [Abstract] [Full Text] [PDF]
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K. W. H. Yee, M. Schittenhelm, A.-M. O'Farrell, A. R. Town, L. McGreevey, T. Bainbridge, J. M. Cherrington, and M. C. Heinrich Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells Blood, December 15, 2004; 104(13): 4202 - 4209. [Abstract] [Full Text] [PDF]
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 F. Y. Chow, D. J. Nikolic-Paterson, R. C. Atkins, and G. H. Tesch Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis Nephrol. Dial. Transplant., December 1, 2004; 19(12): 2987 - 2996. [Abstract] [Full Text] [PDF]
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A. S. Corbin, I. J. Griswold, P. La Rosee, K. W. H. Yee, M. C. Heinrich, C. L. Reimer, B. J. Druker, and M. W. N. Deininger Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970 Blood, December 1, 2004; 104(12): 3754 - 3757. [Abstract] [Full Text] [PDF]
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H. Burger, H. van Tol, A. W. M. Boersma, M. Brok, E. A. C. Wiemer, G. Stoter, and K. Nooter Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump Blood, November 1, 2004; 104(9): 2940 - 2942. [Abstract] [Full Text] [PDF]
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A. Pardanani and A. Tefferi Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders Blood, October 1, 2004; 104(7): 1931 - 1939. [Abstract] [Full Text] [PDF]
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 S. B. Jones, H. Y. Lu, and Q. Lu Abl Tyrosine Kinase Promotes Dendrogenesis by Inducing Actin Cytoskeletal Rearrangements in Cooperation with Rho Family Small GTPases in Hippocampal Neurons J. Neurosci., September 29, 2004; 24(39): 8510 - 8521. [Abstract] [Full Text] [PDF]
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