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Experimental Therapeutics |
Oncology Research, Novartis Pharma AG, CH-4002 Basel, Switzerland [J. M. W., G. B., E. B., R. C., S. F., J. F., F. H., J. M., H. M., T. O., E. P., J. R., C. S., D. S., A. T., H. T., F. W., K. W-C.]; Research Laboratories of Schering AG, D-13342 Berlin, Germany [A. M., G. S., M. S., K-H. T., M. R. S.]; and Institute of Molecular Medicine, Tumor Biology Center, D-79106 Freiburg, Germany [J. D., G. M-B., F. T., D. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of
kinase insert domain-containing receptor (KDR), endothelial cell
proliferation, migration, and survival in the nanomolar range in
cell-based assays. In concentrations up to 1 µM,
PTK787/ZK 222584 does not have any cytotoxic or antiproliferative
effect on cells that do not express VEGF receptors. After oral dosing
(50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain
above 1 µM for more than 8 h. PTK787/ZK 222584
induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis
in a growth factor implant model, as well as a tumor cell-driven
angiogenesis model after once-daily oral dosing (25–100 mg/kg). In the
same dose range, it also inhibits the growth of several human
carcinomas, grown s.c. in nude mice, as well as a murine renal
carcinoma and its metastases in a syngeneic, orthotopic model.
Histological examination of tumors revealed inhibition of microvessel
formation in the interior of the tumor. PTK787/ZK 222584 is very well
tolerated and does not impair wound healing. It also does not have any
significant effects on circulating blood cells or bone marrow
leukocytes as a single agent or impair hematopoetic recovery after
concomitant cytotoxic anti-cancer agent challenge. This novel compound
has therapeutic potential for the treatment of solid tumors and other
diseases where angiogenesis plays an important role. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, VEGF2 appears to be a key factor in pathological situations that involve neovascularization as well as enhanced vascular permeability (19 , 20) . The VEGF receptors, Flt-1 (VEGF-R1; Ref. 21 ) and KDR (VEGF-R2; Ref. 22 ), are almost exclusively located on endothelial cells (23) . Expression of these receptors is low in normal tissues and only up-regulated during the development of these pathological states when neovascularization occurs (24 , 25) . Both receptors have seven immunoglobulin-like domains in their extracellular region, a single transmembrane-spanning domain, and an intracellular split tyrosine kinase domain and belong to the same family of receptors as PDGFR, c-Kit ( a receptor for stem cell factor), c-Fms (a receptor for colony-stimulating factor), Flt-3, and Flt-4. Flt-1 binds VEGF-A and VEGF-B (26 , 27) and the related placenta growth factor (28 , 29) , whereas KDR binds VEGF-C and VEGF-D (30 , 31) in addition to VEGF-A. VEGF-C and VEGF-D are both ligands and activators of Flt-4 (VEGF-R3), which is expressed on the endothelial cells of lymphatic vessels (32, 33, 34) . Although activation of Flt-1 was shown to mediate biological responses, such as endothelial and monocyte cell migration and tissue factor induction (27 , 28 , 35, 36, 37, 38) , in cells expressing only Flt-1 or in Flt-1-deficient cells transfected with Flt-1 cDNA, stimulation with VEGF induces only weak receptor phosphorylation and no significant mitogenic response (37 , 38) . In contrast to Flt-1, KDR is strongly autophosphorylated upon VEGF stimulation and mediates a mitogenic response (39 , 40) .
Gene knock-out experiments for VEGF (41 , 42) as well as its receptors (43, 44, 45, 46) have highlighted the pivotal role of the VEGF/VEGF receptor system in the development of the embryonic vascular system. Various different approaches have been used to interfere with the VEGF/VEGF receptor system in adult animals and thereby determine the role of VEGF receptors in the various pathological states. These approaches include VEGF neutralizing antibodies (47, 48, 49) , antibodies against the VEGF receptors (50 , 51) , recombinant soluble VEGF receptor proteins (52 , 53) , a tetracycline-regulated VEGF expression system (54 , 55) , and dominant-negative mutants of the VEGF receptors (56) . Results from these approaches suggest the VEGF/VEGF receptor system is a novel and attractive therapeutic target for suppression of pathological neovascularization and, in particular, for inhibiting tumor growth (57 , 58) .
Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. In this report, we describe the pharmacological profile of a potent inhibitor of the VEGF tyrosine kinases that fulfills this goal. Although other synthetic molecules have been reported that inhibit the VEGF receptor kinases (59 , 60) , to our knowledge this is one of the first low molecular weight inhibitors of the VEGF/VEGF receptor system reported to be active at inhibiting VEGF-mediated processes after oral administration (61) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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VEGF Receptor Tyrosine Kinase Assays.
The in vitro kinase assays were performed in 96-well plates
as a filter binding assay, using the recombinant GST-fused kinase
domains expressed in baculovirus and purified over
glutathione-Sepharose. 
-[33P]ATP was used as
the phosphate donor, and poly-(Glu:Tyr 4:1) peptide was used as the
acceptor. Recombinant GST-fusion proteins were diluted in 20
mM Tris·HCl (pH 7.5) containing 1–3
mM MnCl2, 3–10
mM Mg Cl2, 0.25 mg/ml
polyethylene glycol 20000, and 1 mM DTT,
according to their specific activity. Each GST-fused kinase was
incubated under optimized buffer conditions [20
mM Tris-HCl buffer (pH 7.5), 1–3
mM MnCl2, 3–10
mM MgCl2, 3–8 µg/ml
poly-(Glu:Tyr 4:1), 0.25 mg/ml polyethylene glycol 20000, 8
µM ATP, 10 µM sodium
vanadate, 1 mM DTT, and 0.2 µCi
[-33P]ATP in a total volume of 30 µl in
the presence or absence of a test substance for 10 min at ambient
temperature. The reaction was stopped by adding 10 µl of 250
mM EDTA. Using a 96-well filter system, half the
volume (20 µl) was transferred onto a Immobilon-polyvinylidene
difluoride membrane (Millipore, Bedford, MA). The membrane was then
washed extensively in 0.5%
H3PO4 and then soaked in
ethanol. After drying, Microscint cocktail (Packard, Meriden, CT) was
added, and scintillation counting was performed.
IC50s for PTK787/ZK 222584 or SU5416 in these as
well as all assays described below were calculated by linear regression
analysis of the percentage inhibition.
Kinase Selectivity Assays.
To determine the enzyme selectivity profile of PTK787/ZK 222584, its
effects on the kinase activity of Flt-4, c-Kit, c-Fms, epidermal growth
factor receptor, fibroblast growth factor receptor-1, PDGFR-ß,
c-Met oncogene (receptor for hepatocyte growth
factor), Tie-2, c-Abl, c-Src proto-oncogene,
PKC-, and Cdc2 were measured using kinase assays according to the
procedure described above for VEGF receptor kinases.
Cellular Receptor Phosphorylation Assays.
Because a kinase inhibitor must enter cells to inhibit the kinase
domain of the receptor, the effects of PTK787/ZK 222584 were tested in
cell-based receptor autophosphorylation assays using HUVECs that
naturally express KDR or KDR-transfected CHO cells. The HUVECs or CHO
cells were seeded in six-well plates and grown to 
80% confluency.
PTK787/ZK 222584 was added in serial dilutions, and the cells incubated
for 2 h at 37°C in medium without FCS. VEGF (20 ng/ml) was then
added. After 5 min incubation (37°C), cells were washed twice with
ice-cold PBS and then lysed. Nuclei were removed by full-speed
centrifugation for 10 min at 4°C using an Eppendorf-centrifuge.
Protein concentrations of the lysates were determined using BSA as
standard. For the second part of the assay a monoclonal antibody to KDR
(monoclonal antibody 1495.12.14; Novartis) was coated to microtiter
plates as a capture antibody. Cell lysates (20 µg protein/well) were
added in triplicate together with PY-20(AP), an alkaline
phosphatase-labeled anti-phosphotyrosine antibody (Transduction
Laboratories, Lexington, KY). After overnight incubation at 4°C, the
bound PY-20(AP) was detected with a luminescent alkaline phosphatase
substrate (TROPIX, Bedford MA), and chemiluminescence was then
determined.
Endothelial Cell Proliferation Assays.
As a test of the ability of PTK787/ZK 222584 to inhibit a functional
response to VEGF, an endothelial cell proliferation assay, based on
BrdUrd incorporation was used (Biotrak Cell Proliferation System V.2,
Amersham, England). Subconfluent HUVECs were seeded at a density of
5 x 103 cells/well into 96-well
plates coated with 1.5% gelatin and then incubated at 37°C and 5%
CO2 in growth medium. After 24 h, growth
medium was replaced by basal medium containing 1.5% FCS and a constant
concentration of VEGF (50 ng/ml), bFGF (0.5 ng/ml), or FCS (5%), in
the presence or absence of PTK787/ZK 222584. As a control, wells
without growth factor were also included. After 24 h of
incubation, BrdUrd labeling solution was added, and cells incubated an
additional 24 h before fixation, blocking, and addition of
peroxidase-labeled anti-BrdUrd antibody. Bound antibody was then
detected using 3,3'5,5'-tetramethylbenzidine substrate, which results
in a colored reaction product that is quantified spectrophotometrically
at 450 nm.
Endothelial Cell Survival Assay.
To determine whether PTK787/ZK 222584 could block the endothelial cell
survival properties of VEGF, the effects of this compound on cell
survival in the presence and absence of VEGF was determined under
serum-free conditions. HUVECs (11 x 103 cells/well) were cultured in
fibrinogen-coated wells (eight-well chamber slides) in the absence of
serum with or without VEGF (10–100 ng/ml) and in the presence of
increasing concentrations of PTK787/ZK 222584. After 48 h, slides
were fixed in cold 70% ethanol, and RNase A digested (200 µg/ml)
before the DNA was labeled with saturating concentrations of propidium
iodide (25 µg/ml) in Coplin jars. Slides were coverslipped
with glycerin-PBS containing propidium iodide at the same propidium
iodide concentration. Analysis of the cells was performed using a Laser
Scanning Cytometer (Compucyte Corporation, Cambridge, MA). The argon
ion laser 488-nm excitation (5 mW) and a 570-nm long pass filter using
the x20 objective were used to collect propidium iodide fluorescence.
This was used as the contouring and thresholding parameter for
collecting data on cells remaining in the culture wells at the end of
the experiment. Scan area was set to encompass the available culture
area for each of the chambers. Data acquisition/analysis parameters
were set to include only single cells and to exclude debris and
aggregates.
Endothelial Cell Migration Assay.
As a test of the ability of this compound to inhibit another functional
response to VEGF that is important for angiogenesis, an endothelial
cell migration assay was used. Plates (24-well) were coated with 1.5%
gelatin and fitted with circular fences as a barrier to prevent cells
from growing in the center of the well. Subconfluent HUVECs were seeded
into the outer area (1 x 105
cells/well) and then incubated at 37°C and 5%
CO2 in growth medium. After 24 h, the fences
were removed, and the growth medium was replaced by basal medium
containing human VEGF (10 ng/ml), in the presence or absence of
PTK787/ZK 222584. To inhibit the cell proliferation, 50 µg/ml
5-fluorouracil (Roche, Basel, Switzerland) was added. After 72 h
of incubation, the cells were fixed and stained with Diff-Quik (Dade
Behring AG, Düdingen, Switzerland), and the number of migrated
cells was counted under a binocular microscope, using the software
KS-400 (Carl Zeiss Jena, Jena, Germany). The number of cells in the
wells with VEGF or serum and vehicle alone was taken as 100%
(control), and changes in cell number in wells with different
concentrations of PTK787/ZK 222584 were calculated as a percentage of
the control values.
Assays of Antiproliferative Activity against Cells Not Expressing
the VEGF Receptors.
Potential antiproliferative effects of PTK787/ZK 222584 unrelated to
VEGF inhibition were tested using cells that do not express the VEGF
receptors, the human tumor cell lines A431 (epithelial carcinoma) and
DU145 (prostate carcinoma). Cells were seeded into 96-well microtiter
plates (1.5 x 106 cells/well) and
incubated overnight. PTK787/ZK 222584 was added in serial dilutions on
day 1. The plates were then incubated for 6 days. After incubation, the
cells were fixed with 3.3% glutaraldehyde, washed with water, and
stained with 0.05% methylene blue. After washing, the dye was eluted
with 3% HCl, and the absorbance measured with a SpectraMax 340
microtiter plates reader at 665 nm.
Vessel Sprout Formation Assay.
The ability of PTK787/ZK 222584 to inhibit angiogenesis was tested in
an in vitro model of capillary sprout formation
(64)
. Fragments (1 mm2) of rat aorta
were imbedded in a fibrin gel (500 µl) in 24-well plates and
incubated with medium containing 10% FCS, in the presence or absence
of increasing concentrations of PTK787/ZK 222584. After 6 days,
capillary density was quantified from images viewed under an inverse
microscope using a computerized imaging system (KS-400, Carl Zeiss
Jena, Jena, Germany).
Determination of Plasma Concentrations after Oral Dosing in Mice.
Because our aim was to develop a compound that would inhibit
VEGF-induced angiogenesis after oral administration, we tested whether
PTK787/ZK 222584 is absorbed after oral administration in female mice
(MAG). Plasma concentrations of free base were also measured after
single oral administration of 50 mg/kg (free base) of the
dihydrochloride or succinate salt. Both salts were formulated in 5%
DMSO/1% Tween 80. As a reference, plasma concentrations of SU5416 were
measured after oral administration at the same dose and with the same
vehicle. Oral dosing was done by gavage, and the mice had free access
to food and water during the experiment. At the allotted times, four
mice were sacrificed from each treatment group, and heart blood was
collected into heparinized tubes. Plasma samples were analyzed
immediately for the free base of the compounds by reversed-phase
high-pressure liquid chromatography. The plasma samples were
deproteinated by the addition of an equal volume of acetonitrile,
followed by thorough mixing and centrifugation. The supernatant was
analyzed directly. A standard curve was constructed from plasma spiked
with known concentrations of compound and processed and analyzed as
described above. Concentrations down to 0.1 µM (the
lowest concentration in the standard curve) could be determined.
In Vivo Growth Factor-induced Angiogenesis Model.
To determine whether PTK787/ZK 222584 inhibits VEGF-mediated
angiogenesis in vivo, we tested the effects of PTK787/ZK
222584 on the angiogenic response induced by VEGF in a growth factor
implant model in mice. To test the specificity of the response, the
effects on PDGF-induced angiogenesis were also tested. A porous Teflon
chamber (volume, 0.5 ml) was filled with 0.8% w/v agar containing
heparin (20 units/ml) with or without growth factor (3 µg/ml human
VEGF, 2 µg/ml human PDGF) was implanted s.c. on the dorsal flank of
C57/C6 mice. The mice were treated with PTK787/ZK 222584 (12.5, 25 or
50 mg/kg dihydrochloride p.o. once daily) or vehicle (water) starting 1
day before implantation of the chamber and continuing for 5 days after.
At the end of treatment, the mice were killed, and the chambers were
removed. The vascularized tissue growing around the chamber was
carefully removed and weighed, and the blood content was assessed by
measuring the hemoglobin content of the tissue (Drabkins method; Sigma,
Deisenhofen, Germany). We have shown previously that these growth
factors induce dose-dependent increases in weight and blood content of
the tissue growing (characterized histologically to contain fibroblasts
and small blood vessels) around the chambers and that this response is
blocked by antibodies that specifically neutralize the growth factors
(65)
.
In Vivo Tumor Cell-induced Angiogenesis Model.
To determine whether PTK787/ZK 222584 inhibits an angiogenic response
mediated by tumor cells in vivo, we tested the effects of
PTK787/ZK 222584 on the angiogenic response induced by epithelial
carcinoma A431 (2 x 106)
encapsulated in alginate beads and implanted s.c. on the dorsal flank
of nude mice as described in detail previously (66)
. The
mice were treated with PTK787/ZK 222584 (50 mg/kg dihydrochloride p.o.
once daily) or vehicle starting on the day of implantation of the beads
and continuing for 12 days after. On day 12, the mice were killed 20
min after injection of 0.1 ml of FITC-labeled high molecular weight
dextran solution (Mr 150,000; 100
mg/kg). The blood content of the alginate beads was quantified by
measuring the uptake of fluorescent dextran into the alginate implant,
as described previously (66)
.
Nude Mouse Human Tumor Xenograft Model.
To determine the effects of PTK787/ZK 222584 on tumor growth, its
effects were tested against various human tumors grown s.c. in nude
mice. Tumor growth was initiated by s.c. injection of the human
carcinoma cell lines (106 cells; A431 epithelial
carcinoma, Ls174T colon carcinoma, and HT-29 colon carcinoma) or by
transplantation of tumor fragments (PC-3 prostate carcinoma, DU145
prostate carcinoma, and CWR-22 prostate carcinoma; 25 mg) from
carrier mice. Drug treatments were initiated when tumor volumes of
25–100 mm3 were attained. PTK787/ZK 222584 was
given in doses from 25 to 100 mg/kg p.o., once or twice daily. Tumor
growth was monitored weekly by measuring perpendicular diameters. Tumor
areas were determined as the product of the largest diameter
(a) and its perpendicular (b) according to the
formula [tumor area = a x b], and tumor volumes were calculated from the
determination of the largest diameter (a) and its
perpendicular (b) according to the formula [tumor
volume = a x (b2/2)].
Tumor Histology.
To determine whether tumor grow inhibition by PTK787/ZK 222584 was
associated with inhibition of tumor vessel formation, groups of mice
bearing the A431 epithelial carcinoma produced from tumor fragments
were used for histological examination. The tumor-bearing mice were
treated with either PTK787/ZK 222584 (50 mg/kg dihydrochloride p.o.) or
vehicle. Two animals from each group (n = 6)
were killed each week, i.e., 7, 14, and 22 days after
starting treatment (14, 21, and 29 days after tumor transplantation),
for histological examination of the tumor. The tumor tissue was quickly
frozen in isopentane at -130°C and stored at -70°C. For the
visualization of the blood vessel endothelial cells, cryosections were
stained with anti-CD31 antibody (rat anti mouse; PharMingen, San Diego,
CA; dilution, 1:5000) using diaminobenzidine as the chromagen
(ABC-Vectastain kit; Vector Laboratories, Burlingame, CA). Sections
were counterstained with hematoxylin.
Syngeneic Mouse Model.
To determine whether PTK787/ZK 222584 inhibits tumor growth and
metastasis formation in immune competent mice, its effects were also
tested in the orthotopic murine renal carcinoma model (RENCA). Tumors
were initiated by injection of 1 x 106 cells into the subcapsular space of
the kidney. Drug treatment was initiated 1 day after tumor cell
inoculation. Mice received either PTK787/ZK 222584 (50 mg/kg
dihydrochloride p.o. once daily) or vehicle (distilled water). Three
weeks after starting therapy, mice were killed for determination of
metastasis formation in the lungs and regional lymph nodes in the
abdominal cavity.
Wound Healing Model.
Full-thickness linear incisional wounds (3 cm) were made along the
dorsal midline of young male Sprague Dawley rats (250 g;
n = 10 group) and coapted with
mattress sutures. Rats were administered PTK787/ZK 222584 (5, 20, or 50
mg/kg dihydrochloride i.p., once per day, days -2 to 7) or 1 ml/kg
saline i.p. (once per day, days -2 to 7). PTK787/ZK 222584 was dosed
i.p. rather than p.o. to avoid handling stress to the wound. The
50-mg/kg i.p. dose was estimated to be equivalent to a 100-mg/kg p.o.
dose by pharmacokinetic evaluation. As a control of impaired wound
healing, another group of animals received a daily dose of
dexamethasone (5 mg/kg, i.m.) starting 1 day before the incision was
made. Rats were sacrificed, skin sections (30 x 8-mm
strips) within the wounds were excised, and the tensile strength of the
healed wound (measured by stretching the wound to the breaking point
with a Universal Tensile Strength Machine, model 144501; Zwick, Ulm,
Germany) was measured. The skin sections were fixed (4%
paraformaldehyde in PBS pH 7.2), embedded, sectioned, and stained with
H&E for qualitative histological assessment.
Evaluation of Effects on Circulating and Bone Marrow Leukocytes.
To determine the effects of PTK787/ZK 222584 on hematopoiesis, normal
BALB/c mice (n = 5/group) were treated with
50 mg/kg PTK787/ZK 222584 or vehicle, p.o., once per day for 21 days.
To determine the effect of PTK787/ZK 222584 on hematopoetic recovery
after cytotoxic insult, BALB/c mice (n = 5/group) were treated with 100 mg/kg cyclophosphamide or saline (i.p.,
days 3, 5, and 7) to reduce the total number of bone marrow cells and
circulating blood cells. The mice were also treated with 50 mg/kg
PTK787/ZK 222584 or vehicle (p.o., once per day). After 21 days of
treatment, the mice were sacrificed, and a blood sample was taken by
puncture of the vena cava and using EDTA anticoagulant. The tibofibula
were exposed by dissection and removed by cutting the bone as near to
the malleolus and condyle as possible. The fibula was cut off, and the
bone fragment was weighed. The bone marrow was obtained by inserting a
23-gauge needle into the condyle end of the bone, and the cells were
flushed out with 1 ml of PBS containing 1 unit/ml heparin. The
resulting "plug" of cells could be homogeneously suspended
by gentle vortexing. The leukocytes, erythrocytes, and platelets were
enumerated by use of a Sysmex TOA E-5000 blood cell counter (Digitana
AG, Horen, Switzerland).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. It also inhibited Flt-4 (VEGF-R3) at even higher concentrations
(Table 1)
. PTK787/ZK 222584 was also active against other tyrosine
kinases belonging to the same family of tyrosine kinase receptors as
the VEGF receptors, i.e., the PDGFR-ß, c-Kit, and c-Fms
(Table 1)
. SU5146 was less selective than PTK787/ZK 222584 for KDR;
SU5416 inhibited c-Kit, and KDR was in the same concentration range,
with Flt-1 at even lower concentrations. It inhibited PDGFR-ß with
similar potency to PTK787/ZK 222584.
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, and Cdc2.
Effects of PTK787/ZK 222584 on VEGF-induced Cellular Responses.
To determine whether PTK787/ZK 222584 is taken up by cells to reach its
intracellular target, its effects on receptor phosphorylation were
tested in cell-based assays. Measurement of VEGF-induced
autophosphorylation of KDR in a double antibody chemiluminescence
assay, using either HUVECs or CHO cells transfected with the KDR
receptor, showed that PTK787/ZK 222584 inhibits the VEGF-induced
phosphorylation with an IC50 of 17 ± 2 nM (n = 4) and
34 ± 2 nM (n = 14) for the HUVECs (Fig. 1)
and CHO cells, respectively. SU5416 stimulated autophosphorylation of
KDR in both cell types under these assay conditions.
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Analysis of the HUVECs labeled with propidium iodide by laser scanning
cytometry showed that VEGF prevented death and loss of cells under
serum deprivation (Fig. 2)
. PTK787/ZK 222584 dose dependently inhibited VEGF-induced survival of
endothelial cells in the same dose range as it inhibited endothelial
cell proliferation (Fig. 2)
. When viewed under a fluorescence
microscope, condensed and fragmented nuclei typical of cells undergoing
apoptosis could be clearly seen in the serum-deprived cells in the
absence of VEGF. They were not seen in the samples treated with VEGF
but were induced by increasing concentrations of PTK787/ZK 222584.
Apoptosis was also shown by the leftward shift of the DNA histograms in
Fig. 2
with 1–10 nM PTK787/ZK 222584. With higher
concentrations, most of the cells had died and were lost during
preparation of the slides. In a cell migration assay, PTK787/ZK 222584
also inhibited VEGF-induced HUVEC migration dose dependently
(IC50, 58 ± 10 nM;
n = 8).
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To test is effects on capillary formation, the effects of
PTK787/ZK 222584 were tested on the formation of sprouts from pieces of
rat aorta embedded in a fibrin gel. PTK787/ZK 222584 inhibited sprout
formation dose dependently with an IC50 of
675 ± 64 nM (n = 8; Fig. 3
).
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. After oral administration of SU5416 at the same dose as PTK787/ZK
222584, plasma concentrations were barely detectable (Fig. 4)
and fell
below the level of detection after 2 h.
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. PTK787/ZK 222584 also induced dose-dependent inhibition
of the PDGF response, but at a higher dose range (Fig. 5b)
.
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.
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; Figs. 7
and 8
). The most responsive tumor type of those investigated was prostate.
With the DU145, carcinoma tumor growth was inhibited by up to 70%.
With the CWR-22 (Fig. 8)
, no macroscopically visible tumors were found
when the mice were sacrificed after 80 days in three of seven of the
PTK787/ZK 222584-treated mice. With all other tumors, the maximum
effect was to slow tumor growth (Table 2
; Fig. 7
). The maximum effects
were obtained with daily dosing of about 50–100 mg/kg.
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. With time, tumor size increased with growth of larger
vessels at the interface between the tumor and host tissue but no
change in microvessels in the interior of the tumor (Fig. 9, A, C, and E)
PTK787/ZK 222584 in an oral dose of 50 mg/kg
once daily from day 7 after tumor implantation slowed tumor growth
(Fig. 7)
. This was associated with a reduced occurrence of microvessels
in the interior of the tumor mass with time and the appearance of
necrosis in the tumor center (Fig. 9, B, D, and F).
PTK787/ZK 222584 had no effect on larger established
vessels, particularly those at the edge of the tumor (Fig. 9, B, D, and F).
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PTK787/ZK 222584 was well tolerated in all of the in vivo experiments and had no significant effects on body weight, general well-being of the animals, or macroscopic effects on any body organs at the time of sacrifice.
Effects of PTK787/ZK 222584 on Wound Healing.
Because angiogenesis is a critical part of wound healing, we tested for
the possible impairment of wound healing attributable to inhibition of
VEGF signaling. PTK787/ZK 222584, administered in doses ranges of 5,
20, or 50 mg/kg i.p. once daily did not impair the healing of a
full-thickness incisional wound in rats nor alter its tensile strength
(Fig. 10)
. In contrast, in rats treated with dexamethasone (5 mg/kg i.m. once
daily), the wound was slower to heal than in vehicle-treated rats, and
the tensile strength was significantly reduced by 40%. Furthermore,
the wounds from dexamethasone-treated rats had a lower degree of
cellularity, as evidenced by a marked decrease in the influx of
mononuclear phagocytes and fibroblasts and a subsequent decrease in
newly formed matrix in the wound biopsies (data not shown). This
was not seen in wounds from PTK787/ZK 222584-treated rats.
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, as well as circulating erythrocytes and platelets (not shown), but
the mice were able to recover by 8–14 days after the last dose. When
administered in combination with cyclophosphamide, 50 mg/kg PTK787/ZK
222584 (p.o., once per day) did not enhance the depletion of, nor
impair the recovery of, the blood or bone marrow leukocytes (Fig. 11)
nor erythrocytes or platelets (not shown). A higher dose of 100 mg/kg
p.o. of PTK787/ZK 222584 administered only in the recovery phase after
the cyclophosphamide challenge also had no significant effects on
recovery of any of these parameters.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, and Cdc2, are not
inhibited by PTK787/ZK 222584. It is also inactive against FGF-R1,
c-Met, and Tie-2, other receptors implicated to play a role in
angiogenic processes. We have shown that PTK787/ZK 222584 is active against KDR also in cellular VEGF-induced receptor phosphorylation assays, using endothelial cells that naturally express KDR, or a transfected cell line. In these cellular assays, PTK787/ZK 222584 is active in the 20 nM range, indicating that it penetrates into cells and reaches its intracellular target. We have also demonstrated that PTK787/ZK 222584 selectively inhibits VEGF-mediated cellular responses in the same dose range; PTK787/ZK 222584 inhibits VEGF-mediated cell proliferation, cell survival, and cell migration. In the same concentration range, PTK787/ZK 222584 does not inhibit proliferation of cells that do not express the VEGF receptors.
As evidence that PTK787/ZK 222584 can lead to a disruption of neovascularization, we have shown that it inhibits capillary-like sprout formation in an in vitro angiogenesis assay. In addition, we have shown that PTK787/ZK 222584 inhibits VEGF-induced vascularization in an growth factor implant model and a tumor cell-driven angiogenesis model in vivo. Moreover, histological examination of tumors used in the studies described in this study, as well as additional studies in other tumor models (67) , have shown that treatment of tumors in animal models can significantly reduce tumor vascularization. As well as inhibiting tumor vascularization, PTK787/ZK 222584 inhibits ischemia-induced retinal neovascularization in newborn mice (68) . PTK787/ZK 222584 not only inhibits VEGF-mediated neovascularization but also VEGF- and tumor-induced increases in vessel permeability (67) .
In contrast to all other reported inhibitors of VEGF (antisense, antibodies and the previously reported receptor tyrosine kinase inhibitor, SU 5416) and many other angiogenesis inhibitors with other mechanisms of action, PTK787/ZK 222584 is well absorbed after oral administration, with plasma concentrations remaining well above concentrations required to inhibit VEGF-induce receptor phosphorylation for >8 h in mice. This pharmacokinetic profile indicates that PTK787/ZK 222584 can be given p.o. Indeed, we were able to demonstrate that VEGF-mediated responses can be effectively blocked after once daily oral dosing with PTK787/ZK 222584. In a growth factor implant angiogenesis model in which VEGF induces concentration-dependent growth of vascularized tissue, PTK787/ZK 222584 dose dependently blocked the increase in vascularized tissue. It also blocked a similar but weaker response to PDGF, in a higher dose range, consistent with its weaker activity against the PDGFR-ß tyrosine kinase in the in vitro assays. After oral dosing, PTK787/ZK 222584 also inhibited the angiogenic response induced by the human epithelial tumor cell (A431) in a s.c. implant in mice. The growth of s.c. tumors arising from this tumor cell line was also inhibited after oral dosing in nude mice, and this was associated with a reduction in the number of microvessels in the interior of the tumor.
PTK787/ZK 222584 inhibited tumor growth in several different tumor
models. The best effects were seen against the prostate tumors. All of
these tumors are very slow growing. The growth of the CWR-22, a very
slow growing tumor, was completely inhibited in some mice. The growth
of all of the other tumors investigated in the nude mouse was only
inhibited or slowed, and there was no tumor regression observed. The
effective dose range of PTK787/ZK 222584 in the various in
vivo models was between 50 and 100 mg/kg daily. It has to be
considered that PTK787/ZK 222584 is 7-fold less potent against the
mouse receptor tyrosine kinase Flk than the equivalent human kinase,
KDR. Therefore, the doses needed in patients may be lower than can be
directly extrapolated from the mouse models.
Histological studies with the A431 tumor as well as the RENCA tumor after 1–3 weeks of treatment showed decreases in microvessels in the tumor. Further studies in other tumor models have also revealed that PTK787/ZK 222584 significantly reduces the number of microvessels in the tumor (67) . The disappearance of the capillaries under treatment is consistent with our observation that PTK787/ZK 222584 inhibits VEGF-induced survival of endothelial cells in vitro. Not all vessels in the tumors were affected by treatment with PTK787/ZK 222584, particularly larger vessels at the periphery of the tumor. This indicates that only newly forming capillaries are inhibited, and more stable and mature vessels formed before treatment is initiated, or induced by other angiogenic factors, are not sensitive to VEGF inhibition. More mature, larger vessels consisting of more than a single layer of endothelial cells may be resistant to treatment with VEGF inhibitors. The residual tumor growth seen with many of the s.c. tumors in nude mice models appears to be driven by the remaining the larger vessels, particularly at the periphery of the tumor, that are not reduced by treatment with PTK787/ZK 222584.
Our findings that PTK787/ZK 222584 is less effective against some tumors than others is consistent with studies reported using the tyrosine kinase inhibitor, SU 5416 (60) , and neutralizing antibodies against VEGF (47, 48, 49) . Although we and others have shown that almost all tumor cell lines in vitro and tumors grown in vivo produce VEGF, cytokines or growth factors other than VEGF may also contribute to endothelial cell survival and tumor angiogenesis and may even be up-regulated when the effects of VEGF are inhibited. In vitro we have observed that PTK787/ZK 222584 does not induce apoptosis of endothelial cells if any serum is present in the medium. This suggests that there are several different factors supporting endothelial survival and tumor vascularization. Anti-VEGF therapy may be more effective against some types of tumors than others, and future therapy may necessitate a combination of antiangiogenic agents with different mechanisms of action, as well as conventional therapies targeting the tumor cell.
Inhibition of tumor growth was not just confined to tumors growing s.c.; PTK787/ZK 222584 also inhibited primary tumor growth and the growth of metastases in an orthotopic tumor models in immune competent mice. The effect on the metastasis was even greater than the effects on the primary tumor. Inhibition of metastasis formation might be attributable to both the decreased vascularization of a primary tumor, leading to reduced escape routes for metastatic cells, as well as the decreased vascularization of metastasis restricting their growth. PTK787/ZK 222584 also inhibits VEGFR-3, the receptor expressed in the lymphatic system, and this activity might also contribute to its antimetastatic effects.
Because both VEGF and PDGF have been implicated to play a role in wound healing, a surprising finding was that there was no impairment of wound healing in any of the tumor models requiring surgery or impairment in healing or the strength of an incisional wound in a rat wound healing model. Either there is a redundancy of angiogenic factors, or VEGF and PDGF do not play a vital role in the wound healing process. This study suggests that PTK787/ZK 222584 may not impair the normal wound healing process and may be safe to give to patients after surgery. It can be speculated that the larger vessels forming at the periphery of the implanted tumors in nude mice may actually represent a wound healing response, rather than tumor-induced angiogenesis. This may explain why these vessels are not inhibited by PTK787/ZK 222584 in the nude mice and warrants further investigation.
PTK787/ZK 222584 as a single agent had no significant effects on circulating blood cells or bone marrow leukocytes and did not impair hematopoetic recovery after a cytotoxic anticancer agent challenge. This is also quite surprising considering the inhibitory effects of PTK787/ZK 222584 on KDR and c-Kit, class III kinases that are expressed on hematopoetic cells. This suggests a redundancy of hematopoetic growth factors and also indicates that PTK787/ZK 222584 will not enhance the hematopoetic toxicity of cytotoxic agents.
In all of the in vivo experiments described in this report and in further studies that have been performed (67 , 68) as well as in 4-week Good Laboratory Practice toxicology studies in rats and dogs, PTK787/ZK 222584 was extremely well tolerated with no effects on body weight or animal behavior, and no target organ toxicity was observed. Taken together, all of these observations indicate that PTK787/ZK 222584 is well tolerated after at least 1 month of chronic therapy and is much better tolerated than conventional antitumor therapies. It remains to be explored whether chronic therapy as a single agent or cyclic therapy in combination with conventional antitumor therapies will be the best approach for the treatment of cancer.
PTK787/ZK 222584, a synthetic, low molecular weight, p.o. bioavailable, and well-tolerated molecule, offers many advantages over angiogenesis inhibitors reported previously. Several molecules with different mechanisms of action have been reported, some of which have entered clinical trials. We have shown that PTK787/ZK 222584 is as active and much better tolerated than TNP-470 (69 , 70) in several of our tumor models as well as having the advantage of oral dosing. Although angiostatin (71) and endostatin (72) were reported originally to be more effective inhibitors of tumor growth than we report here for PTK787/ZK 222584, not all laboratories have been able to reproduce the same degree of in vitro and in vivo efficacy that was reported originally. Moreover, both molecules are difficult to manufacture in large quantities and are not p.o. active. An additional attractive feature of compounds that inhibit the effects of VEGF is that VEGF is not only an angiogenic factor but also a potent vascular permeability factor. This may give VEGF inhibitors additional therapeutic applications over antiangiogenic agents with other mechanisms of action. Soluble VEGF receptors (52 , 53) and antibodies against VEGF (47, 48, 49) or its receptors (50 , 51) have also been proposed as agents to block VEGF, but compared with PTK787/ZK 222584, have the disadvantages of large proteins (difficult to manufacture, cost, immunogenic potential, and need for parental administration). Other VEGF receptor tyrosine kinase inhibitors, such SU5416, have also been reported (59 , 60) , but we have shown that this compound has poor oral bioavailability and is even less specific for the VEGF receptor tyrosine kinases than PTK787/ZK 222584. More recently, another VEGF receptor tyrosine kinase inhibitor, SU 6668, has been reported that is p.o. active, but it is even less specific, inhibiting bFGF as well as the class III kinases. This might lead to greater antitumor efficacy but also to more side effects.
Our data show that PTK787/ZK 222584 is a potent, p.o. active, and well-tolerated inhibitor of VEGF-mediated responses. The excellent oral activity and tolerability of this compound favor its use for prolonged treatment, not only for cancers dependent on VEGF for their vascularization, but also for other diseases where VEGF-mediated angiogenesis plays a key role in the pathogenesis.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Oncology Research, K-125 2.10, Novartis AG, CH 4002
Basel, Switzerland. 
2 The abbreviations used are: VEGF, vascular
endothelial growth factor; Flt, fms-like tyrosine kinase; KDR, kinase
insert domain-containing receptor; PDGF, platelet-derived growth
factor; PDGFR, PDGF receptor; PTK787/ZK 222584,
1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate;
HUVEC, human umbilical cord endothelial cell; CHO, Chinese hamster
ovarian cells; GST, glutathione S-transferase; PKC,
protein kinase C; BrdUrd, 5-bromo-2-deoxyuridine; bFGF, basic
fibroblast growth factor; Cdc2, cell cycle-dependent kinase 2; Flk,
fetal liver kinase; Fms, feline myelosarcoma; mAb, monoclonal antibody;
Tie, tyrosine kinase with immunoglobulin.
Received 5/14/99. Accepted 2/18/00.
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O. Riesterer, M. Honer, W. Jochum, C. Oehler, S. Ametamey, and M. Pruschy Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment. Clin. Cancer Res., June 1, 2006; 12(11): 3518 - 3524. [Abstract] [Full Text] [PDF]
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D. H. Albert, P. Tapang, T. J. Magoc, L. J. Pease, D. R. Reuter, R.-Q. Wei, J. Li, J. Guo, P. F. Bousquet, N. S. Ghoreishi-Haack, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther., April 1, 2006; 5(4): 995 - 1006. [Abstract] [Full Text] [PDF]
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N. Amino, Y. Ideyama, M. Yamano, S. Kuromitsu, K. Tajinda, K. Samizu, H. Hisamichi, A. Matsuhisa, K. Shirasuna, M. Kudoh, et al. YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors Clin. Cancer Res., March 1, 2006; 12(5): 1630 - 1638. [Abstract] [Full Text] [PDF]
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 A. P. Hall, F. R. Westwood, and P. F. Wadsworth Review of the Effects of Anti-Angiogenic Compounds on the Epiphyseal Growth Plate Toxicol Pathol, February 1, 2006; 34(2): 131 - 147. [Abstract] [Full Text] [PDF]
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A. J. Garton, A. P.A. Crew, M. Franklin, A. R. Cooke, G. M. Wynne, L. Castaldo, J. Kahler, S. L. Winski, A. Franks, E. N. Brown, et al. OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models Cancer Res., January 15, 2006; 66(2): 1015 - 1024. [Abstract] [Full Text] [PDF]
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K. LaMontagne, A. Littlewood-Evans, C. Schnell, T. O'Reilly, L. Wyder, T. Sanchez, B. Probst, J. Butler, A. Wood, G. Liau, et al. Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization Cancer Res., January 1, 2006; 66(1): 221 - 231. [Abstract] [Full Text] [PDF]
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N. Matsunaga, K. Nakamura, A. Yamamoto, E. Taguchi, H. Tsunoda, and K. Takahashi Improvement by solid dispersion of the bioavailability of KRN633, a selective inhibitor of VEGF receptor-2 tyrosine kinase, and identification of its potential therapeutic window Mol. Cancer Ther., January 1, 2006; 5(1): 80 - 88. [Abstract] [Full Text] [PDF]
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Y. Kitagawa, J. Dai, J. Zhang, J. M. Keller, J. Nor, Z. Yao, and E. T. Keller Vascular Endothelial Growth Factor Contributes to Prostate Cancer-Mediated Osteoblastic Activity Cancer Res., December 1, 2005; 65(23): 10921 - 10929. [Abstract] [Full Text] [PDF]
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 G. Thurston, Q. Wang, F. Baffert, J. Rudge, N. Papadopoulos, D. Jean-Guillaume, S. Wiegand, G. D. Yancopoulos, and D. M. McDonald Angiopoietin 1 causes vessel enlargement, without angiogenic sprouting, during a critical developmental period Development, July 15, 2005; 132(14): 3317 - 3326. [Abstract] [Full Text] [PDF]
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 W. Rottbauer, S. Just, G. Wessels, N. Trano, P. Most, H. A. Katus, and M. C. Fishman VEGF-PLC{gamma}1 pathway controls cardiac contractility in the embryonic heart Genes & Dev., July 1, 2005; 19(13): 1624 - 1634. [Abstract] [Full Text] [PDF]
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A. L. Thomas, B. Morgan, M. A. Horsfield, A. Higginson, A. Kay, L. Lee, E. Masson, M. Puccio-Pick, D. Laurent, and W. P. Steward Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTK787/ZK 222584 Administered Twice Daily in Patients With Advanced Cancer J. Clin. Oncol., June 20, 2005; 23(18): 4162 - 4171. [Abstract] [Full Text] [PDF]
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D. Zips, W. Eicheler, P. Geyer, F. Hessel, A. Dorfler, H. D. Thames, M. Haberey, and M. Baumann Enhanced Susceptibility of Irradiated Tumor Vessels to Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibition Cancer Res., June 15, 2005; 65(12): 5374 - 5379. [Abstract] [Full Text] [PDF]
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P. Sini, L. Wyder, C. Schnell, T. O'Reilly, A. Littlewood, R. Brandt, N. E. Hynes, and J. Wood The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition Is Potentiated by ErbB1 Blockade Clin. Cancer Res., June 15, 2005; 11(12): 4521 - 4532. [Abstract] [Full Text] [PDF]
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S. Wada, T. Tsunoda, T. Baba, F. J. Primus, H. Kuwano, M. Shibuya, and H. Tahara Rationale for Antiangiogenic Cancer Therapy with Vaccination Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 2 Cancer Res., June 1, 2005; 65(11): 4939 - 4946. [Abstract] [Full Text] [PDF]
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G. Li, L. Tian, J.-m. Hou, Z.-y. Ding, Q.-m. He, P. Feng, Y.-j. Wen, F. Xiao, B. Yao, R. Zhang, et al. Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4217 - 4224. [Abstract] [Full Text] [PDF]
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S. R. Wedge, J. Kendrew, L. F. Hennequin, P. J. Valentine, S. T. Barry, S. R. Brave, N. R. Smith, N. H. James, M. Dukes, J. O. Curwen, et al. AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer Cancer Res., May 15, 2005; 65(10): 4389 - 4400. [Abstract] [Full Text] [PDF]
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R. S. Herbst, A. Onn, and A. Sandler Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256. [Abstract] [Full Text] [PDF]
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Y. Liu, R. T. Poon, Q. Li, T. W. Kok, C. Lau, and S. T. Fan Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine Kinase Inhibitor PTK787/ZK222584 Cancer Res., May 1, 2005; 65(9): 3691 - 3699. [Abstract] [Full Text] [PDF]
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B. P. Schneider and K. D. Miller Angiogenesis of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1782 - 1790. [Full Text] [PDF]
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B. I. Rini VEGF-Targeted Therapy in Metastatic Renal Cell Carcinoma Oncologist, March 1, 2005; 10(3): 191 - 197. [Abstract] [Full Text] [PDF]
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 M. Murga, O. Fernandez-Capetillo, and G. Tosato Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2 Blood, March 1, 2005; 105(5): 1992 - 1999. [Abstract] [Full Text] [PDF]
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G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]
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K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
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B. I. Rini and E. J. Small Biology and Clinical Development of Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma J. Clin. Oncol., February 10, 2005; 23(5): 1028 - 1043. [Abstract] [Full Text] [PDF]
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D. J. Hicklin and L. M. Ellis Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis J. Clin. Oncol., February 10, 2005; 23(5): 1011 - 1027. [Abstract] [Full Text] [PDF]
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M. Hagedorn, S. Javerzat, D. Gilges, A. Meyre, B. de Lafarge, A. Eichmann, and A. Bikfalvi Accessing key steps of human tumor progression in vivo by using an avian embryo model PNAS, February 1, 2005; 102(5): 1643 - 1648. [Abstract] [Full Text] [PDF]
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K. J. Williams, B. A. Telfer, S. Brave, J. Kendrew, L. Whittaker, I. J. Stratford, and S. R. Wedge ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy: Schedule-Dependent Enhancement of Antitumor Activity Clin. Cancer Res., December 15, 2004; 10(24): 8587 - 8593. [Abstract] [Full Text] [PDF]
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R. L. Yauch, E. E. Kadel III, C. Nicholas, S. Tetangco, and D. O. Clary Transcriptional-Based Screens for Pathway-Specific, High-Throughput Target Discovery in Endothelial Cells J Biomol Screen, December 1, 2004; 9(8): 704 - 711. [Abstract] [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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K. Nakamura, A. Yamamoto, M. Kamishohara, K. Takahashi, E. Taguchi, T. Miura, K. Kubo, M. Shibuya, and T. Isoe KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth Mol. Cancer Ther., December 1, 2004; 3(12): 1639 - 1649. [Abstract] [Full Text] [PDF]
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S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis Cancer Res., October 1, 2004; 64(19): 7099 - 7109. [Abstract] [Full Text] [PDF]
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G. Bocci, S. Man, S. K. Green, G. Francia, J. M. L. Ebos, J. M. du Manoir, A. Weinerman, U. Emmenegger, L. Ma, P. Thorpe, et al. Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies Cancer Res., September 15, 2004; 64(18): 6616 - 6625. [Abstract] [Full Text] [PDF]
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D. Z. Qian, X. Wang, S. K. Kachhap, Y. Kato, Y. Wei, L. Zhang, P. Atadja, and R. Pili The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination with the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Cancer Res., September 15, 2004; 64(18): 6626 - 6634. [Abstract] [Full Text] [PDF]
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A. Potti and D. J. George Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Clin. Cancer Res., September 15, 2004; 10(18): 6371S - 6376S. [Abstract] [Full Text] [PDF]
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 S. Emanuel, R. H. Gruninger, A. Fuentes-Pesquera, P. J. Connolly, J. A. Seamon, S. Hazel, R. Tominovich, B. Hollister, C. Napier, M. R. D'Andrea, et al. A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models Mol. Pharmacol., September 1, 2004; 66(3): 635 - 647. [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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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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 M. A. Castilla, F. Neria, G. Renedo, D. S. Pereira, F. R. Gonzalez-Pacheco, S. Jimenez, P. Tramon, J. J. P. Deudero, M. V. A. Arroyo, S. Yague, et al. Tumor-induced endothelial cell activation: role of vascular endothelial growth factor Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1170 - C1176. [Abstract] [Full Text] [PDF]
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S. Langlois, D. Gingras, and R. Beliveau Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation Blood, April 15, 2004; 103(8): 3020 - 3028. [Abstract] [Full Text] [PDF]
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 K. D. Burman A New Paradigm in the Treatment of Carcinoma: Specific Molecular Targeting Endocrinology, March 1, 2004; 145(3): 1027 - 1030. [Full Text] [PDF]
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J. Schoenberger, D. Grimm, P. Kossmehl, M. Infanger, E. Kurth, and C. Eilles Effects of PTK787/ZK222584, a Tyrosine Kinase Inhibitor, on the Growth of a Poorly Differentiated Thyroid Carcinoma: An Animal Study Endocrinology, March 1, 2004; 145(3): 1031 - 1038. [Abstract] [Full Text] [PDF]
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 M. E. Daly, A. Makris, M. Reed, and C. E. Lewis Hemostatic Regulators of Tumor Angiogenesis: A Source of Antiangiogenic Agents for Cancer Treatment? J Natl Cancer Inst, November 19, 2003; 95(22): 1660 - 1673. [Abstract] [Full Text] [PDF]
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J. S. Beebe, J. P. Jani, E. Knauth, P. Goodwin, C. Higdon, A. M. Rossi, E. Emerson, M. Finkelstein, E. Floyd, S. Harriman, et al. Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy Cancer Res., November 1, 2003; 63(21): 7301 - 7309. [Abstract] [Full Text] [PDF]
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L. M. Ellis Antiangiogenic Therapy: More Promise and, Yet Again, More Questions J. Clin. Oncol., November 1, 2003; 21(21): 3897 - 3899. [Full Text] [PDF]
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B. Morgan, A. L. Thomas, J. Drevs, J. Hennig, M. Buchert, A. Jivan, M. A. Horsfield, K. Mross, H. A. Ball, L. Lee, et al. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies J. Clin. Oncol., November 1, 2003; 21(21): 3955 - 3964. [Abstract] [Full Text] [PDF]
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M.-T. Lin, M.-L. Yen, C.-Y. Lin, and M.-L. Kuo Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis by Resveratrol through Interruption of Src-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation Mol. Pharmacol., November 1, 2003; 64(5): 1029 - 1036. [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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and 
) or SU5416 (•) in mouse plasma after single oral
administration of a dose of 50 mg/kg (calculated as free base).
PTK787/ZK 222584 was administered as either the dihydrochloride salt
(
