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Experimental Therapeutics |
SUGEN, Inc., San Francisco, California 94080 [A. D. L., L. K. S., C. L., R. A. B., T. A. T. F., L. M. S., L. S., C. T., R. H., F. T., N. S., K. P. H., G. M., J. M. C.]; Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, D-68167 Mannheim, Germany [P. V., A. T.]; Department of Pharmacology, New York University Medical Center, New York, New York 10016 [M. M., J. S.]; Department of Molecular Biology, Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany [A. U.]; and Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University Medical Center, New York, New York 10016 [S. R. H.]
| ABSTRACT |
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| INTRODUCTION |
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Evidence for the direct role of VEGF and its receptor, Flk-1/KDR, in angiogenesis has been well documented. The temporal and spatial patterns of expression of VEGF and its receptors, along with the results of targeted mutagenesis, demonstrate that they are required for angiogenesis during development (3) . Similarly, the role of ligand and receptor in tumor angiogenesis has been clearly demonstrated using tumor models in rodents, in which disruption of VEGF signaling using anti-VEGF antibodies, soluble VEGF receptors, and regulatable expression constructs can inhibit neovascularization and compromise existing tumor vasculature, resulting in inhibition of tumor growth (reviewed in Ref. 6 ). Elevated VEGF levels have been correlated with increased microvessel counts and poor prognosis in many human tumor types (reviewed in Ref. 7 ). Due to its central role in angiogenesis and its modest role in normal adults, VEGF signaling is an attractive therapeutic target. Several VEGF receptor-specific kinase inhibitors have entered clinical trials for the treatment of human cancers. To date, these compounds have shown initial indications of good tolerability, and objective responses have been observed in some patients (8) .
FGF and PDGF also play critical roles in angiogenesis, sometimes in concert with VEGF. The prototype FGF family member, FGF2, is a potent mitogen of different cell types including vascular endothelial cells and fibroblasts (9) . Although FGF2 knockout mice have no apparent defects related to impaired angiogenesis, FGF2 is clearly an angiogenic factor in vivo (10) . Additionally, FGF2 has been reported to be synergistic with VEGF and to induce the expression of VEGF (10) . FGF is also a tumor cell mitogen and is expressed, along with its receptors, in a variety of human tumor types (11, 12, 13, 14, 15, 16) .
PDGF and PDGFRs are expressed in microvascular endothelium in vivo when endothelial cell activation and angiogenesis occur. Moreover, PDGF exerts growth-stimulatory effects on pericytes (17) and fibroblast-like cells (18 , 19) that surround endothelial cells. Direct evidence for a role of PDGF-B in vasculogenesis was demonstrated in mice deficient in PDGF-B; these mice lacked microvascular pericytes, which normally form part of the capillary wall and contribute to its stability (20) . PDGF has been reported to up-regulate other angiogenic factors such as VEGF; thus, it has been postulated that it may also play an indirect activating role in angiogenesis (21 , 22) .
PDGF and its receptors have been detected in diverse human cancers (23, 24, 25, 26, 27, 28, 29, 30) , and PDGFRs are expressed on tumor neovasculature and up-regulated during tumor progression (23) . Circulating PDGF has been associated with metastases (31) and higher microvessel counts (32) . Again suggesting its direct and indirect roles in angiogenesis, PDGFR has been shown to be expressed on vascular endothelial cells as well as smooth muscle cells in the stroma of tumors (33) .
The signaling cascades generated by these three ligands and their respective receptors are complex, directly and indirectly affecting tumor angiogenesis and tumor growth. Given the early promise demonstrated by compounds that inhibit VEGF signaling in the clinic and the knowledge that additional players are important in angiogenesis, we developed a multipotent therapeutic agent that augmented favorable anti-Flk-1/KDR properties with efficacy against other angiogenic signaling molecules. Data presented here demonstrate that SU6668, a small molecule synthetic kinase inhibitor, is a potent inhibitor of the tyrosine kinase activity of Flk-1/KDR, PDGFR, and FGFR; inhibits tumor vascularization and growth of tumor xenografts of diverse origin; and induces regression of large established tumors.
| MATERIALS AND METHODS |
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Biochemical Tyrosine Kinase Assays
Recombinant Protein Production.
GST-fusion proteins of FGFR1 (kinase domain) and Flk-1 (cytoplasmic
domain) were produced in the baculovirus expression system. For both
constructs, pFBG2T was used as the transfer vector. This plasmid
contains the GST coding sequence, which was amplified by PCR as a
BamHI/BglII fragment and cloned into the
BamHI site of pFastBac-1 (Life Technologies, Inc.,
Rockville. MD). The portion of the FGFR1 cDNA encoding amino acids
459757 was amplified by PCR as an EcoRI/HindIII
fragment and ligated downstream of and in frame with the GST coding
sequence in pFBG2T. The portion of Flk-1 cDNA encoding amino acids
812-1346 was amplified by PCR as a NotI/SphI
fragment and ligated downstream of and in frame with the GST coding
sequence in pFBG2T. Recombinant viruses containing the different
recombinant transfer vectors were produced following standard protocols
(FastBac manual; Life Technologies, Inc.). For protein production, Sf9
cells were infected following standard procedures (35)
,
and fusion proteins were purified by affinity chromatography on
glutathione-Sepharose (Sigma, St. Louis, MO). GST-fusion preparations
were determined to be of high quality, with no detectable breakdown
products [as determined using Western blot analysis for the GST moiety
followed by Ponceau S staining (data not shown)].
trans-Phosphorylation Reactions.
Biochemical tyrosine kinase assays to quantitate the
trans-phosphorylation activity of Flk-1 and FGFR1 were
performed in 96-well microtiter plates precoated (20 µg/well in PBS;
incubated overnight at 4°C) with the peptide substrate
poly-Glu,Tyr (4:1). Excess protein binding sites were blocked with the
addition of 15% (w/v) BSA in PBS. Purified GST-FGFR1 (kinase domain)
or GST-Flk-1 (cytoplasmic domain) fusion proteins were produced in
baculovirus-infected insect cells. GST-FGFR1 and GST-Flk-1 were then
added to the microtiter wells in 2x concentration kinase dilution
buffer consisting of 100 mM HEPES, 50
mM NaCl, 40 µM
NaVO4, and 0.02% (w/v) BSA. The final enzyme
concentration for GST-Flk-1 and GST-FGFR1 was 50 ng/ml. SU6668 was
dissolved in DMSO at 100x the final required concentration and diluted
1:25 in H2O. Twenty-five µl of diluted SU6668 were
subsequently added to each reaction well to produce a range of
inhibitor concentrations appropriate for each enzyme. The kinase
reaction was initiated by the addition of different concentrations of
ATP in a solution of MnCl2 so that the final ATP
concentrations spanned the Km for the
enzyme, and the final concentration of MnCl2 was
10 mM. The plates were incubated for 515 min at
room temperature before stopping the reaction with the addition of
EDTA. The plates were then washed three times with TBST. Rabbit
polyclonal antiphosphotyrosine antisera were added to the wells at a
1:10,000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v)
nonfat dry milk, and 100 µM
NaVO4 and incubated for 1 h at 37°C. The
plates were then washed three times with TBST, followed by the addition
of goat antirabbit antisera conjugated with horseradish peroxidase
(1:10,000 dilution in TBST). The plates were incubated for 1 h at
37°C and then washed three times with TBST. The amount of
phosphotyrosine in each well was quantitated as described previously
(36)
after the addition of
2,2'-azino-di-[3-ethylbenzthiazoline sulfonate] as substrate.
Autophosphorylation Reactions.
Tyrosine kinase assays to quantitate the autophosphorylation activity
of PDGFR or EGFR were performed in a similar manner, except that the
wells were precoated (0.5 µg/well in 100 µl of PBS) with PDGFRß-
or EGFR-specific monoclonal antibodies (28D4C10 and SUMO1,
respectively) to capture the respective kinase from lysates of NIH-3T3
cells engineered to overexpress PDGFRß or EGFR. The reaction buffer
for the autophosphorylation studies consisted of 25
mM Tris, 100 mM NaCl, 10 mM
MnCl2, 0.1% (v/v) Triton X-100, and 0.5
mM DTT.
The linear phase of each assay was determined, and reaction rates were calculated from the linear phase of a series of reactions whose duration spanned the linear period. Assays were highly linear with respect to substrate concentration and time (data not shown). Data were analyzed using the Lineweaver-Burk inverse-reciprocal plot of 1/rate versus 1/ATP concentration. Ki calculations were made using the assumption that in the case of competitive inhibition, Km is increased by a factor of (1 + [I]/Ki), where [I] is the concentration of inhibitor, and in the case of noncompetitive inhibition, Vmax is decreased by a factor of (1 + [I]/Ki).
| X-ray Crystallography and Molecular Modeling |
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) operating at
50 kV and 100 mA and equipped with double-focusing mirrors and a R-AXIS
IIC image plate detector. Crystals were flash-cooled in a dry nitrogen
stream at -175°C. Data were processed using DENZO and SCALEPACK
(39)
. Difference Fourier electron density maps were
computed using phases calculated from the structure of unliganded FGFR1
(40)
. The crystallography and NMR system (CNS) software
suite (40)
was used for simulated annealing and
positional/B-factor refinement, and O software suite
(41)
was used for model building. Bulk solvent and
anisotropic B-factor corrections were applied during refinement. The
average B-factor is 37.0 Å2 for all atoms, 37.1
Å2 for protein atoms, and 43.0
Å2 for SU6668 atoms. Homology models for the catalytic domains of Flk-1/KDR and PDGFR were generated using the Modeler program (42) , with the FGFR1/SU6668 cocrystal structure as a reference. Sequence alignment was based on that of Hanks and Quinn (43) , with slight modifications. Docking of SU6668 to Flk-1/KDR and PDGFR was performed manually, based on the FGFR1/SU6668 cocrystal structure, followed by simple energy minimization.
| Cellular Assays |
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| In Vivo Tumor Xenograft Experiments |
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A375, Calu-6, A431, C6, and SF763T tumor cells were obtained and cultured as described previously (44) . Colo205 and H460 cells were obtained from American Type Culture Collection (Manassas, VA) and cultured in RPMI 1640 (Life Technologies, Inc.) supplemented with 10% FBS and 2 mM glutamine. SKOV3 cells were obtained from American Type Culture Collection and passaged five times through mice to yield SKOV3TP5 cells. These cells were cultured in DMEM supplemented with 10% FBS and 2 mM glutamine. Tumor cells (310 x 106 cells/animal) were implanted s.c. into the hind flank of mice on day 0 as described previously (45) . Daily treatment with SU6668 or vehicle commenced 1 day after implantation of cells (to test efficacy against newly implanted tumors) or when tumors had reached a predetermined average size (to test efficacy against established tumors). SU6668 was delivered i.p. by bolus injection in DMSO or p.o. by gavage in a cremophor-based vehicle according to the specifics stated in figure and table legends. Tumor growth was measured twice a week using vernier calipers for the duration of treatment. Tumor volumes were calculated as a product of length x width x height. Ps were calculated using the two-tailed Students t test.
| Intravital Multifluorescence Videomicroscopy |
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| RESULTS |
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Effect of SU6668 on Cellular Tyrosine Kinase Activity.
To confirm the measured biochemical activity of SU6668 in a cell
based-assay, tyrosine phosphorylation of receptors after ligand
stimulation was determined. HUVECs stimulated by VEGF exhibit an
increase in tyrosine phosphorylation of KDR. Treatment of cells with
SU6668 inhibited this increase in a dose-dependent manner (Fig. 3A
). SU6668 also inhibited PDGF-stimulated PDGFRß tyrosine
phosphorylation in NIH-3T3 cells overexpressing PDGFRß at a minimum
concentration of 0.030.1 µM (Fig. 3B
). SU6668 inhibited acidic FGF-induced
phosphorylation of the FGFR1 substrate 2 (FRS-2) at concentrations of
10 µM and higher (Fig. 3C
). However,
SU6668 had no detectable effect on epidermal growth factor-stimulated
EGFR tyrosine phosphorylation in NIH-3T3 cells overexpressing EGFR at
concentrations of up to 100 µM (Fig. 3D
). These cellular data demonstrate that SU6668 inhibits
Flk-1/KDR, PDGFR, and FGFR but has no activity against EGFR at the
concentrations tested.
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| DISCUSSION |
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As shown in Table 1
, SU6668 has broad activity in biochemical assays.
SU6668 is a potent inhibitor of PDGFR kinase activity with a
Ki value at least 50x lower than the
Km value of ATP. SU6668 also inhibited
Flk-1/KDR and FGFR1 kinase activity. Cell-based assays including HUVEC
proliferation and inhibition of tyrosine phosphorylation of these
target kinases confirmed the activity of SU6668 against these RTKs
(Figs. 3
4
). However, it is interesting that the low
Ki value of SU6668 for PDGFR relative
to Flk-1 did not result in a significantly greater ability to inhibit
the receptor in cells. It is noteworthy that although the
Ki values of SU6668 versus
Flk-1 and FGFR are very similar, the inhibition of HUVEC mitogenesis is
approximately 20-fold more potent when using VEGF as a ligand as
compared with FGF (Fig. 5
). Similarly, the inhibition of KDR and Flk-1
phosphorylation in cells is achieved at a lower concentration of SU6668
than inhibition of FRS-2, a substrate phosphorylated by FGFR (Fig. 3
).
Although we do not fully understand these results, these data
illustrate that inhibitory constants derived in the context of purified
receptor proteins may not be uniformly translated to receptors replete
with additional associated signaling molecules in living cells.
Analysis of the interactions of SU6668 and RTKs by X-ray
crystallography and modeling has provided some insight into the
differences in SU6668 potency against PDGFR and FGFR. The proprionic
acid moiety of SU6668 is in a perfect position to interact with the
Arg-604 side chain located at the N-lobe of the entrance of the
ATP-binding site on PDGFR. In contrast, the corresponding residue on
FGFR and Flk-1 is a lysine. Because the lysine side chain is shorter
than the arginine side chain, the interaction between SU6668 on FGFR
and Flk-1 would be weaker than that with PDGFR (Fig. 2
).
As would be expected of an inhibitor of Flk-1, FGFR1, and PDGFR kinase
activity, SU6668 demonstrated significant antitumor activity against a
wide range of xenografts (Table 3
; Fig. 5
). Of particular interest are
the tumor types that were poorly inhibited by SU5416, such as the human
glioma cell line SF763T (37)
and the human ovarian cell
line SKOV3TP5. Given its target profile, SU6668 may influence tumor
growth by multiple mechanisms including inhibition of endothelial cell
proliferation and/or survival as well as tumor cell and stromal cell
proliferation. In addition, we cannot preclude the possibility that
activity against kinases (as yet unidentified) other than Flk-1/KDR,
PDGFR, and FGFR contributes to the biological activity of SU6668.
Strikingly, SU6668 has the ability to induce regression of large
established tumors (Fig. 7A
). Whereas the mechanism(s)
underlying this capability is unknown, the anti-Flk-1/KDR activity of
SU6668 is likely to be pertinent, given data implicating VEGF/Flk-1
signaling in the survival of immature blood vessels and cultured
endothelial cells (6
, 50)
. Additionally, SU6668 may also
impact other host-derived tumor-associated cells such as pericytes and
fibroblasts. Pericytes express VEGF and play an indispensable,
PDGF-dependent, mechanical role in stabilizing immature blood vessels
(51
, 52) . Fibroblasts may support tumor growth by
producing VEGF and are a potential target for PDGF- and FGF-mediated
proliferation (53)
. Consistent with this proposed activity
against host-derived cells, SU6668 exhibited potent antiangiogenic
activity in glioma xenografts implanted into dorsal skinfold chambers
(Fig. 6
). In contrast, SU6668 did not potently inhibit the growth of
cancer cells in culture (data not shown).
The activity of SU6668 on multiple members of the split RTK family has provided the opportunity to study some key questions concerning inhibitors that target several tyrosine kinases compared with inhibitors that target one kinase specifically, such as SU5416. The attractive and validated targets of SU6668, coupled with its broad, remarkable, activity in tumor xenograft models, have motivated its entry into clinical development. Accordingly, SU6668 has recently entered Phase I clinical trials, and its safety and efficacy profile in humans will emerge in the near future.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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1 The intravital fluorescence microscopy studies
were supported by the German Research Foundation (DFG VA 151/4-1 and UL
60/4-1). ![]()
2 To whom requests for reprints should be
addressed, at Preclinical Therapeutics, SUGEN, Inc., 230 East Grand
Avenue, San Francisco, CA 94080. ![]()
3 The abbreviations used are: RTK, receptor
tyrosine kinase; VEGF, vascular endothelial growth factor; FGF,
fibroblast growth factor; FGFR, FGF receptor; PDGF, platelet-derived
growth factor; PDGFR, PDGF receptor; EGFR, epidermal growth factor
receptor; HUVEC, human umbilical vein endothelial cell; GST,
glutathione S-transferase; TBST, 10 mM Tris
(pH 7.4), 150 mM NaCl, and 0.05% Tween 20; FBS, fetal
bovine serum. ![]()
Received 8/23/99. Accepted 5/25/00.
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L. Ma, G. Francia, A. Viloria-Petit, D. J. Hicklin, J. du Manoir, J. Rak, and R. S. Kerbel In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy Cancer Res., June 15, 2005; 65(12): 5365 - 5373. [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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L. Labrecque, S. Lamy, A. Chapus, S. Mihoubi, Y. Durocher, B. Cass, M. W. Bojanowski, D. Gingras, and R. Beliveau Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound Carcinogenesis, April 1, 2005; 26(4): 821 - 826. [Abstract] [Full Text] [PDF] |
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S. Dalal, A. M. Berry, C. J. Cullinane, D. C. Mangham, R. Grimer, I. J. Lewis, C. Johnston, V. Laurence, and S. A. Burchill Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of the Ewing's Sarcoma Family Clin. Cancer Res., March 15, 2005; 11(6): 2364 - 2378. [Abstract] [Full Text] [PDF] |
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S. Rehman and G. C. Jayson Molecular Imaging of Antiangiogenic Agents Oncologist, February 1, 2005; 10(2): 92 - 103. [Abstract] [Full Text] [PDF] |
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D. W. Davis, R. Takamori, C. P. Raut, H. Q. Xiong, R. S. Herbst, W. M. Stadler, J. V. Heymach, G. D. Demetri, A. Rashid, Y. Shen, et al. Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668 Clin. Cancer Res., January 15, 2005; 11(2): 678 - 689. [Abstract] [Full Text] [PDF] |
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A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF] |
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U. E. Knies-Bamforth, S. B. Fox, R. Poulsom, G. I. Evan, and A. L. Harris c-Myc Interacts with Hypoxia to Induce Angiogenesis In vivo by a Vascular Endothelial Growth Factor-Dependent Mechanism Cancer Res., September 15, 2004; 64(18): 6563 - 6570. [Abstract] [Full Text] [PDF] |
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D. Zingg, O. Riesterer, D. Fabbro, C. Glanzmann, S. Bodis, and M. Pruschy Differential Activation of the Phosphatidylinositol 3'-Kinase/Akt Survival Pathway by Ionizing Radiation in Tumor and Primary Endothelial Cells Cancer Res., August 1, 2004; 64(15): 5398 - 5406. [Abstract] [Full Text] [PDF] |
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P. Traxler, P. R. Allegrini, R. Brandt, J. Brueggen, R. Cozens, D. Fabbro, K. Grosios, H. A. Lane, P. McSheehy, J. Mestan, et al. AEE788: A Dual Family Epidermal Growth Factor Receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activity Cancer Res., July 15, 2004; 64(14): 4931 - 4941. [Abstract] [Full Text] [PDF] |
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T. Inai, M. Mancuso, H. Hashizume, F. Baffert, A. Haskell, P. Baluk, D. D. Hu-Lowe, D. R. Shalinsky, G. Thurston, G. D. Yancopoulos, et al. Inhibition of Vascular Endothelial Growth Factor (VEGF) Signaling in Cancer Causes Loss of Endothelial Fenestrations, Regression of Tumor Vessels, and Appearance of Basement Membrane Ghosts Am. J. Pathol., July 1, 2004; 165(1): 35 - 52. [Abstract] [Full Text] [PDF] |
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R. S. Herbst and A. B. Sandler Non-Small Cell Lung Cancer and Antiangiogenic Therapy: What Can Be Expected of Bevacizumab? Oncologist, June 1, 2004; 9(suppl_1): 19 - 26. [Abstract] [Full Text] [PDF] |
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J. Sun, M. A. Blaskovich, R. K. Jain, F. Delarue, D. Paris, S. Brem, M. Wotoczek-Obadia, Q. Lin, D. Coppola, K. Choi, et al. Blocking Angiogenesis and Tumorigenesis with GFA-116, a Synthetic Molecule that Inhibits Binding of Vascular Endothelial Growth Factor to its Receptor Cancer Res., May 15, 2004; 64(10): 3586 - 3592. [Abstract] [Full Text] [PDF] |
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T. Goi, M. Fujioka, Y. Satoh, S. Tabata, K. Koneri, H. Nagano, Y. Hirono, K. Katayama, K. Hirose, and A. Yamaguchi Angiogenesis and Tumor Proliferation/Metastasis of Human Colorectal Cancer Cell Line SW620 Transfected with Endocrine Glands-Derived-Vascular Endothelial Growth Factor, As a New Angiogenic Factor Cancer Res., March 15, 2004; 64(6): 1906 - 1910. [Abstract] [Full Text] [PDF] |
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P. Marzola, A. Degrassi, L. Calderan, P. Farace, C. Crescimanno, E. Nicolato, A. Giusti, E. Pesenti, A. Terron, A. Sbarbati, et al. In Vivo Assessment of Antiangiogenic Activity of SU6668 in an Experimental Colon Carcinoma Model Clin. Cancer Res., January 15, 2004; 10(2): 739 - 750. [Abstract] [Full Text] [PDF] |
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A. Girnita, L. Girnita, F. d. Prete, A. Bartolazzi, O. Larsson, and M. Axelson Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell Growth Cancer Res., January 1, 2004; 64(1): 236 - 242. [Abstract] [Full Text] [PDF] |
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J. A. Sosman Targeting of the VHL-Hypoxia-Inducible Factor-Hypoxia-Induced Gene Pathway for Renal Cell Carcinoma Therapy J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2695 - 2702. [Abstract] [Full Text] [PDF] |
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Y. Ueda, T. Yamagishi, K. Samata, H. Ikeya, N. Hirayama, H. Takashima, S. Nakaike, M. Tanaka, and I. Saiki A novel low molecular weight antagonist of vascular endothelial growth factor receptor binding: VGA1155 Mol. Cancer Ther., November 1, 2003; 2(11): 1105 - 1111. [Abstract] [Full Text] [PDF] |
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D. Saha, K. R. Sekhar, C. Cao, J. D. Morrow, H. Choy, and M. L. Freeman The Antiangiogenic Agent SU5416 Down-Regulates Phorbol Ester-Mediated Induction of Cyclooxygenase 2 Expression by Inhibiting Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity Cancer Res., October 15, 2003; 63(20): 6920 - 6927. [Abstract] [Full Text] [PDF] |
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B. R. Stoll, C. Migliorini, A. Kadambi, L. L. Munn, and R. K. Jain A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy Blood, October 1, 2003; 102(7): 2555 - 2561. [Abstract] [Full Text] [PDF] |
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V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF] |
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N. Patel, L. Sun, D. Moshinsky, H. Chen, K. M. Leahy, P. Le, K. G. Moss, X. Wang, A. Rice, D. Tam, et al. A Selective and Oral Small Molecule Inhibitor of Vascular Epithelial Growth Factor Receptor (VEGFR)-2 and VEGFR-1 Inhibits Neovascularization and Vascular Permeability J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 838 - 845. [Abstract] [Full Text] [PDF] |
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A. Garofalo, E. Naumova, L. Manenti, C. Ghilardi, G. Ghisleni, M. Caniatti, T. Colombo, J. M. Cherrington, E. Scanziani, M. I. Nicoletti, et al. The Combination of the Tyrosine Kinase Receptor Inhibitor SU6668 with Paclitaxel Affects Ascites Formation and Tumor Spread in Ovarian Carcinoma Xenografts Growing Orthotopically Clin. Cancer Res., August 1, 2003; 9(9): 3476 - 3485. [Abstract] [Full Text] [PDF] |
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A. Abdollahi, K. E. Lipson, X. Han, R. Krempien, T. Trinh, K. J. Weber, P. Hahnfeldt, L. Hlatky, J. Debus, A. R. Howlett, et al. SU5416 and SU6668 Attenuate the Angiogenic Effects of Radiation-induced Tumor Cell Growth Factor Production and Amplify the Direct Anti-endothelial Action of Radiation in Vitro Cancer Res., July 1, 2003; 63(13): 3755 - 3763. [Abstract] [Full Text] [PDF] |
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C. A. London, A. L. Hannah, R. Zadovoskaya, M. B. Chien, C. Kollias-Baker, M. Rosenberg, S. Downing, G. Post, J. Boucher, N. Shenoy, et al. Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies Clin. Cancer Res., July 1, 2003; 9(7): 2755 - 2768. [Abstract] [Full Text] [PDF] |
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L. M. Cross, M. A. Cook, S. Lin, J.-N. Chen, and A. L. Rubinstein Rapid Analysis of Angiogenesis Drugs in a Live Fluorescent Zebrafish Assay Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 911 - 912. [Full Text] [PDF] |
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N. H. Segal, P. Pavlidis, W. S. Noble, C. R. Antonescu, A. Viale, U. V. Wesley, K. Busam, H. Gallardo, D. DeSantis, M. F. Brennan, et al. Classification of Clear-Cell Sarcoma as a Subtype of Melanoma by Genomic Profiling J. Clin. Oncol., May 1, 2003; 21(9): 1775 - 1781. [Abstract] [Full Text] [PDF] |
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A. D. Laird, G. Li, K. G. Moss, R. A. Blake, M. A. Broome, J. M. Cherrington, and D. B. Mendel Src Family Kinase Activity Is Required for Signal Tranducer and Activator of Transcription 3 and Focal Adhesion Kinase Phosphorylation and Vascular Endothelial Growth Factor Signaling in Vivo and for Anchorage-dependent and -independent Growth of Human Tumor Cells Mol. Cancer Ther., May 1, 2003; 2(5): 461 - 469. [Abstract] [Full Text] [PDF] |
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C. L. Arteaga Molecular Therapeutics: Is One Promiscuous Drug against Multiple Targets Better than Combinations of Molecule-specific Drugs? Clin. Cancer Res., April 1, 2003; 9(4): 1231 - 1232. [Full Text] [PDF] |
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Y. ZHU, K. JIN, X. O. MAO, and D. A. GREENBERG Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression FASEB J, February 1, 2003; 17(2): 186 - 193. [Abstract] [Full Text] [PDF] |
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F. G. El Kamar, M. L. Grossbard, and P. S. Kozuch Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care Oncologist, February 1, 2003; 8(1): 18 - 34. [Abstract] [Full Text] [PDF] |
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D. B. Mendel, A. D. Laird, X. Xin, S. G. Louie, J. G. Christensen, G. Li, R. E. Schreck, T. J. Abrams, T. J. Ngai, L. B. Lee, et al. In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors: Determination of a Pharmacokinetic/Pharmacodynamic Relationship Clin. Cancer Res., January 1, 2003; 9(1): 327 - 337. [Abstract] [Full Text] [PDF] |
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M. M. Belcheva, P. D. Haas, Y. Tan, V. M. Heaton, and C. J. Coscia The Fibroblast Growth Factor Receptor Is at the Site of Convergence between {micro}-Opioid Receptor and Growth Factor Signaling Pathways in Rat C6 Glioma Cells J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 909 - 918. [Abstract] [Full Text] [PDF] |
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X. Huang, M. K. Wong, H. Yi, S. Watkins, A. D. Laird, S. F. Wolf, and E. Gorelik Combined Therapy of Local and Metastatic 4T1 Breast Tumor in Mice Using SU6668, an Inhibitor of Angiogenic Receptor Tyrosine Kinases, and the Immunostimulator B7.2-IgG Fusion Protein Cancer Res., October 15, 2002; 62(20): 5727 - 5735. [Abstract] [Full Text] [PDF] |
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G. C. Jayson, J. Zweit, A. Jackson, C. Mulatero, P. Julyan, M. Ranson, L. Broughton, J. Wagstaff, L. Hakannson, G. Groenewegen, et al. Molecular Imaging and Biological Evaluation of HuMV833 Anti-VEGF Antibody: Implications for Trial Design of Antiangiogenic Antibodies J Natl Cancer Inst, October 2, 2002; 94(19): 1484 - 1493. [Abstract] [Full Text] [PDF] |
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K. W. H. Yee, A. M. O'Farrell, B. D. Smolich, J. M. Cherrington, G. McMahon, C. L. Wait, L. S. McGreevey, D. J. Griffith, and M. C. Heinrich SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase Blood, September 26, 2002; 100(8): 2941 - 2949. [Abstract] [Full Text] [PDF] |
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F. A. Scappaticci Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies J. Clin. Oncol., September 15, 2002; 20(18): 3906 - 3927. [Abstract] [Full Text] [PDF] |
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C. J. Conti Vascular Endothelial Growth Factor: Regulation in the Mouse Skin Carcinogenesis Model and Use in Antiangiogenesis Cancer Therapy Oncologist, August 1, 2002; 7(90003): 4 - 11. [Abstract] [Full Text] [PDF] |
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A. T. Liao, M. B. Chien, N. Shenoy, D. B. Mendel, G. McMahon, J. M. Cherrington, and C. A. London Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors Blood, June 28, 2002; 100(2): 585 - 593. [Abstract] [Full Text] [PDF] |
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A. N. Witmer, J. Dai, H. A. Weich, G. F.J.M. Vrensen, and R. O. Schlingemann Expression of Vascular Endothelial Growth Factor Receptors 1, 2, and 3 in Quiescent Endothelia J. Histochem. Cytochem., June 1, 2002; 50(6): 767 - 778. [Abstract] [Full Text] [PDF] |
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H. Zhang and A. C. Issekutz Down-Modulation of Monocyte Transendothelial Migration and Endothelial Adhesion Molecule Expression by Fibroblast Growth Factor : Reversal by the Anti-Angiogenic Agent SU6668 Am. J. Pathol., June 1, 2002; 160(6): 2219 - 2230. [Abstract] [Full Text] [PDF] |
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T. M. J. Niederman, Z. Ghogawala, B. S. Carter, H. S. Tompkins, M. M. Russell, and R. C. Mulligan Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors PNAS, May 14, 2002; 99(10): 7009 - 7014. [Abstract] [Full Text] [PDF] |
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A. D. LAIRD, J. G. CHRISTENSEN, G. LI, J. CARVER, K. SMITH, X. XIN, K. G. MOSS, S. G. LOUIE, D. B. MENDEL, and J. M. CHERRINGTON SU6668 inhibits Flk-1/KDR and PDGFR{beta} in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice FASEB J, May 1, 2002; 16(7): 681 - 690. [Abstract] [Full Text] [PDF] |
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R. Beliveau, D. Gingras, E. A. Kruger, S. Lamy, P. Sirois, B. Simard, M. G. Sirois, L. Tranqui, F. Baffert, E. Beaulieu, et al. The Antiangiogenic Agent Neovastat (Ae-941) Inhibits Vascular Endothelial Growth Factor-mediated Biological Effects Clin. Cancer Res., April 1, 2002; 8(4): 1242 - 1250. [Abstract] [Full Text] [PDF] |
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M. C. Heinrich, C. D. Blanke, B. J. Druker, and C. L. Corless Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies J. Clin. Oncol., March 15, 2002; 20(6): 1692 - 1703. [Abstract] [Full Text] [PDF] |
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C.S. Brock and S.M. Lee Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer Eur. Respir. J., March 1, 2002; 19(3): 557 - 570. [Abstract] [Full Text] [PDF] |
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R. J. Griffin, B. W. Williams, R. Wild, J. M. Cherrington, H. Park, and C. W. Song Simultaneous Inhibition of the Receptor Kinase Activity of Vascular Endothelial, Fibroblast, and Platelet-derived Growth Factors Suppresses Tumor Growth and Enhances Tumor Radiation Response Cancer Res., March 1, 2002; 62(6): 1702 - 1706. [Abstract] [Full Text] [PDF] |
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T. Itokawa, H. Nokihara, Y. Nishioka, S. Sone, Y. Iwamoto, Y. Yamada, J. Cherrington, G. McMahon, M. Shibuya, M. Kuwano, et al. Antiangiogenic Effect by SU5416 Is Partly Attributable to Inhibition of Flt-1 Receptor Signaling Mol. Cancer Ther., March 1, 2002; 1(5): 295 - 302. [Abstract] [Full Text] [PDF] |
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F. Carlomagno, D. Vitagliano, T. Guida, M. Napolitano, G. Vecchio, A. Fusco, A. Gazit, A. Levitzki, and M. Santoro The Kinase Inhibitor PP1 Blocks Tumorigenesis Induced by RET Oncogenes Cancer Res., February 1, 2002; 62(4): 1077 - 1082. [Abstract] [Full Text] [PDF] |
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M. Ozen, D. Giri, F. Ropiquet, A. Mansukhani, and M. Ittmann Role of Fibroblast Growth Factor Receptor Signaling in Prostate Cancer Cell Survival J Natl Cancer Inst, December 5, 2001; 93(23): 1783 - 1790. [Abstract] [Full Text] [PDF] |
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P. Guo, L. Xu, S. Pan, R. A. Brekken, S.-T. Yang, G. B. Whitaker, M. Nagane, P. E. Thorpe, J. S. Rosenbaum, H.-J. Su Huang, et al. Vascular Endothelial Growth Factor Isoforms Display Distinct Activities in Promoting Tumor Angiogenesis at Different Anatomic Sites Cancer Res., December 1, 2001; 61(23): 8569 - 8577. [Abstract] [Full Text] [PDF] |
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R. S. Kerbel Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial Results J. Clin. Oncol., September 15, 2001; 19(90001): 45s - 51. [Full Text] [PDF] |
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G. W. Krystal, S. Honsawek, D. Kiewlich, C. Liang, S. Vasile, L. Sun, G. McMahon, and K. E. Lipson Indolinone Tyrosine Kinase Inhibitors Block Kit Activation and Growth of Small Cell Lung Cancer Cells Cancer Res., May 1, 2001; 61(9): 3660 - 3668. [Abstract] [Full Text] |
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Y. Yamasaki, K. Miyoshi, N. Oda, M. Watanabe, H. Miyake, J. Chan, X. Wang, L. Sun, C. Tang, G. McMahon, et al. Weekly Dosing With the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor SU9518 Significantly Inhibits Arterial Stenosis Circ. Res., March 30, 2001; 88(6): 630 - 636. [Abstract] [Full Text] [PDF] |
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B. D. Smolich, H. A. Yuen, K. A. West, F. J. Giles, M. Albitar, and J. M. Cherrington The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts Blood, March 1, 2001; 97(5): 1413 - 1421. [Abstract] [Full Text] [PDF] |
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R. M. Shaheen, W. W. Tseng, D. W. Davis, W. Liu, N. Reinmuth, R. Vellagas, A. A. Wieczorek, Y. Ogura, D. J. McConkey, K. E. Drazan, et al. Tyrosine Kinase Inhibition of Multiple Angiogenic Growth Factor Receptors Improves Survival in Mice Bearing Colon Cancer Liver Metastases by Inhibition of Endothelial Cell Survival Mechanisms Cancer Res., February 1, 2001; 61(4): 1464 - 1468. [Abstract] [Full Text] |
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D. B. Mendel, R. E. Schreck, D. C. West, G. Li, L. M. Strawn, S. S. Tanciongco, S. Vasile, L. K. Shawver, and J. M. Cherrington The Angiogenesis Inhibitor SU5416 Has Long-lasting Effects on Vascular Endothelial Growth Factor Receptor Phosphorylation and Function Clin. Cancer Res., December 1, 2000; 6(12): 4848 - 4858. [Abstract] [Full Text] |
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