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Experimental Therapeutics |
Cell Regulation Program [R. A. B., P. E. T.], Hamon Center for Therapeutic Oncology Research [R. A. B., J. P. O., V. A. S., J. D. M., P. E. T.], and the Department of Pharmacology [R. A. B., J. D. M., P. E. T], University of Texas Southwestern Medical Center, Dallas, Texas 75235-8593, and the Department of Internal Medicine II (Cardiology), Ulm University Medical Center, Ulm D-89081 Germany [J. W.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Angiogenesis is regulated in normal and malignant tissues by the balance of angiogenic stimuli and angiogenic inhibitors that are produced in the target tissue and at distant sites (5 , 6) . VEGF4 (also known as vascular permeability factor) is a primary stimulant of angiogenesis. VEGF is a multifunctional cytokine that is induced by hypoxia and oncogenic mutations and can be produced by a wide variety of tissues (7 , 8) . VEGF functions as a potent permeability-inducing agent, an endothelial cell chemotactic agent, an endothelial survival factor, and endothelial cell proliferation factor (9 , 10) . Its activity is required for normal embryonic development because targeted disruption of one or both alleles of VEGF results in embryonic lethality (11 , 12) . There are at least five splice variants of VEGF, encoding proteins of 121, 145, 165, 189, and 206 amino acids. The smaller versions having 121, 145, or 165 amino acids are secreted from cells (13 , 14) . Secreted VEGF is an obligate dimer of between Mr 38,000 and Mr 46,000 in which the monomers are linked by two disulfide bonds. The VEGF dimer binds to one of two well-characterized receptors, VEGFR1 (FLT-1) and VEGFR2 (KDR/Flk-1), that are selectively expressed on endothelial cells. A recently identified third cell surface protein, neuropilin-1, binds VEGF165 with high affinity (15, 16, 17) .
VEGFR1 and VEGFR2 are members of the type III receptor tyrosine kinase
family that is characterized by seven extracellular IgG-like repeats, a
single spanning transmembrane domain, and an intracellular split
tyrosine kinase domain (18)
. VEGF binds to VEGFR1 and
VEGFR2 with high affinities having a
Kd (dissociation constant) of
15–100 pM and 400–800 pM, respectively
(19)
. VEGFR2 appears to be the dominant signaling receptor
in VEGF-induced mitogenesis and permeability (20, 21, 22)
.
Binding of the VEGF dimer to VEGFR2 induces receptor dimerization,
causing autotransphosphorylation of specific tyrosine residues on
the intracellular side of the receptor that leads to a signal
transduction cascade, which includes activation of phospholipase C
,
an increase in intracellular calcium ions, and an increase in nitric
oxide production (23, 24, 25)
. Activation of VEGFR2 by VEGF
has also been shown to activate src and the ras-MAP
kinase cascade (20
, 26
, 27)
. The role of VEGFR1 in
endothelial cell function is much less clear. Whereas Flt-1 tyrosine
kinase-deficient mice are viable and develop normal vessels
(28)
, Flt-1-null mice die in utero because of
increased hemangioblast commitment that results in an overgrowth of
endothelial cells and a disorganized vasculature (29
, 30)
.
This latter observation, together with recent findings by Rahimi
et al. (31)
, suggest that VEGFR1 may negatively
regulate the activity of VEGFR2.
The recognition of VEGF as a primary stimulus of angiogenesis in pathological conditions has led to the generation of many strategies to block VEGF activity. Inhibitory anti-VEGF receptor antibodies, soluble receptor constructs, antisense strategies, RNA aptamers against VEGF, and low molecular weight VEGF receptor tyrosine kinase inhibitors have all been developed to interfere with VEGF signaling (32) . Most work has been done with neutralizing monoclonal anti-VEGF antibodies that block VEGF from binding its receptors. Monoclonal antibodies, A4.6.1 (33) and MV833 (34) , have both been shown to inhibit human tumor xenograft growth and ascites formation in mice (33 , 35, 36, 37, 38, 39) . These efforts underscore the importance of VEGF in solid tumor growth and its potential as a target for tumor therapy.
We previously described the properties of several monoclonal antibodies directed against human VEGF and the VEGF:VEGFR2 complex (40) . One of the antibodies, 2C3, blocked the binding of VEGF to Flk-1, inhibited VEGF-mediated growth of endothelial cells in vitro, and localized strongly to connective tissue and blood vessels in tumors after injection into mice bearing various human tumor xenografts. The antibody recognized human but not mouse VEGF. Another antibody, 3E7, bound to both human VEGF complexed with KDR/Flk-1 and to free VEGF and localized selectively to tumor endothelium after injection into mice bearing human tumors. 3E7 recognized an NH2-terminal sequence on human VEGF and mouse VEGF.
In the present study, we show that 2C3 blocks the binding of human VEGF to VEGFR2 but not to VEGFR1. 2C3 inhibits VEGF-induced phosphorylation of VEGFR2 and inhibits VEGF-induced vascular permeability increases. The antibody has potent antitumor activity, inhibiting the growth of newly injected human tumors in mice and arresting the growth of various established human solid tumors in mice. These results suggest that VEGFR2 has a dominant role in mediating the effects of VEGF on vascular permeability and tumor angiogenesis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ELISA Analysis.
The extracellular domain of VEGFR1 (Flt-1/Fc, R&D Systems, Minneapolis,
MN) or VEGFR2 (sFlk-1-biotin) was coated directly on wells of a
microtiter plate or captured by NeutrAvidin (Pierce, Rockford, IL)
coated wells, respectively. VEGF at a concentration of 1 nM
(40 ng/ml) was incubated in the wells in the presence or absence of
100-1000 nM (15 µg-150 µg/ml) of control or test
antibodies. The wells were then incubated with 1 µg/ml of rabbit
anti-VEGF antibody (A-20, Santa Cruz Biotechnology, Santa Cruz, CA).
The reactions were developed by the addition of peroxidase-labeled goat
antirabbit antibody (Dako, Carpinteria, CA) and visualized by the
addition of 3,3'5,5'-tetramethylbenzidine substrate (Kirkegaard & Perry
Laboratories, Inc). Reactions were stopped after 15 min with 1
M H3PO4 and
read spectrophotometrically at 450 nM. The assay was also
done by coating wells of a microtiter plate with either control or test
IgG. The wells were then incubated with VEGF:Flt-1/Fc or
VEGF:sFlk-1-biotin and developed with either peroxidase-labeled goat
antihuman Fc (Kirkegaard & Perry Laboratories, Inc.) or
peroxidase-labeled streptavidin, respectively, and visualized as above
(data not shown).
Coprecipitation Assay.
Forty ng of VEGF were preincubated with the
F(ab')2 of either of 2C3 (20 µg) or A4.6.1 (10
and 1 µg) for 30 min in binding buffer (DMEM with 1 mM
CaCl2, 0.1 mM
CuSO4, and 0.5% tryptone). Two hundred ng of
soluble forms of VEGFR1 (Flt-1/Fc) or VEGFR2 (KDR/Fc, R&D Systems,
Minneapolis, MN) were added for a total volume of 50 µl and incubated
for 2 h. The receptor/Fc constructs were precipitated using
protein A-Sepharose beads, and the resulting precipitate was washed
four times with binding buffer. The pellet and supernatant of each
reaction were boiled for 2 min in sample buffer that contained 10
mM DTT to reduce the F(ab')2
constructs and release the receptor/Fc constructs from the protein
A-Sepharose beads. These conditions, however, were not harsh enough to
completely reduce all of the VEGF from dimer to monomer. The samples
were separated by 12% SDS-PAGE and transferred to PVDF membranes. The
membranes were then probed with 12D7 (1.0 µg/ml), a mouse anti-VEGF
antibody (40)
, and developed after incubation with
peroxidase-labeled goat antimouse IgG (Kirkegaard & Perry Laboratories,
Inc.) by Super Signal chemiluminescence substrate (Pierce, Rockford,
IL). The soluble receptor/Fc constructs were also detected through the
use of peroxidase-conjugated goat antihuman Fc (Kirkegaard & Perry
Laboratories, Inc.; data not shown).
Immunoprecipitation and Western Blot Analysis.
PAE/KDR, PAE/FLT, and bEND.3 cells were grown to 80–90% confluency in
100-mm tissue dishes in media containing 5% serum. The cells were then
serum starved for 24 h in media containing 0.1% serum. After
pretreatment with 100 nM sodium orthovanadate in PBS for 30
min, the cells were incubated with 5 nM (200 ng/ml)
VEGF165, 5 nM (100 ng/ml) basic fibroblast growth factor
(R&D Systems, Minneapolis, MN), or A673 tumor-conditioned media in the
presence or absence of control or test antibodies for an additional 15
min. The cells were then washed with ice-cold PBS containing 10
mM EDTA, 2 mM sodium fluoride, and 2
mM sodium orthovanadate and lysed in lysis buffer [50
mM Tris, 150 mM NaCl, 1% NP40, 0.25% sodium
deoxycholate, 0.1%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, 5
mM EDTA, 1.5 mM MgCl2, 2 mM sodium
fluoride, 2 mM sodium orthovanadate, 10% glycerol, and
protease inhibitors (Complete Protease Inhibitor Cocktail tablets,
Boehringer Mannheim)]. The lysates were clarified by centrifugation,
and resulting supernatant was used for immunoprecipitation. VEGFR1 and
VEGFR2 were immunoprecipitated with 5 µg of chicken anti-FLT-1
NH2 terminus (Upstate Biotechnology, Lake Placid,
NY) or 5 µg of T014 (affinity purified anti-Flk-1), respectively. The
reactions using the chicken anti-FLT-1 antibody were subsequently
incubated with a bridging goat antichicken antibody (Kirkegaard & Perry
Laboratories, Inc.) for 1 h at 4°C. The immune complex was
precipitated with protein A/G-Sepharose, washed four times with 10%
lysis buffer in PBS-tween (0.2%) and boiled in SDS sample buffer
containing 100 mM ß-mercaptoethanol and 8 M
urea. The samples were separated by SDS-PAGE and transferred to PVDF
membranes, which were blocked for 30–60 min with PP81 (East Coast
Biologicals, Berwick, ME) and probed for phosphotyrosine residues with
0.5 µg/ml of 4G10 (Upstate Biotechnology, Lake Placid, NY). The
membranes were developed after incubation with peroxidase-labeled
rabbit antimouse IgG (Dako, Carpinteria, CA) by Super Signal
chemiluminescence substrate (Pierce, Rockford, IL). The membranes were
then stripped with ImmunoPure Elution buffer (Pierce, Rockford, IL) for
30 min at 55°C and reprobed for receptor levels with either 0.5
µg/ml chicken anti-FLT-1 or 1.0 µg/ml T014 and developed as above
after incubation with the appropriate peroxidase-conjugated secondary
antibody.
Miles Permeability Assay.
The protocol followed was essentially as described by Murohara et
al. (45)
. In brief, 400–450-g male, IAF
hairless guinea pigs (Charles River, Wilmington, MA) were anesthetized
and then injected i.v. with 0.5 ml of 0.5% Evan’s blue dye in sterile
PBS through an ear vein. Twenty min later, 20 ng of VEGF in the
presence or absence of control or test antibodies were injected i.d.
The resultant blue spots in the back of the guinea pig were
photographed 30 min after the i.d. injections.
In Vivo Tumor Growth Inhibition.
Male nu/nu mice weighing 
25 g were injected s.c. with
either 1 x 107 NCI-H358 NSCLC
cells or 5 x 106 A673
rhabdomyosarcoma cells on day 0. On day 1 and twice per week
thereafter, the mice were given i.p. injections of 2C3 at 1, 10, or 100
µg or of control immunoglobulin as indicated. The tumors were
measured twice per week for a period of 6 weeks for the
NCI-H358-bearing mice and 4 weeks for the A673-bearing mice. Tumor
volume was calculated according to the formula: volume = L x W x H, where L = length,
W = width, and H = height.
In Vivo Tumor Therapy.
Male nu/nu mice bearing s.c. NCI-H358 tumors or HT1080
fibrosarcoma 200–400 mm3 in size were injected
i.p. with test or control antibodies. The NCI-H358-bearing mice were
treated at 100 µg/injection three times per week during the first
week and twice per week during the second and third weeks. The mice
were then switched to 50 µg per injection every 5 days. The
HT1080-bearing mice were treated with 100 µg of the indicated
antibody or with saline every other day throughout the experiment. In
both experiments, mice were sacrificed when their tumors reached 2500
mm3 in size or earlier if tumors began to
ulcerate.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In contrast, in the presence of a 100-fold and 1000-fold molar excess
of 2C3, the amount of VEGF that bound to VEGFR1-coated wells was 92%
and 105%, respectively, of the amount that bound in the absence of
2C3. Similarly, the amounts of VEGF that bound to VEGFR1 or VEGFR2 were
unaffected by the presence of a 100- to 1000-fold excess of the
nonblocking monoclonal anti-VEGF antibody 3E7 or of a control
IgG of irrelevant specificity.
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. VEGF mixed with either VEGFR1/Fc or VEGFR2/Fc was coprecipitated by
protein A-Sepharose, showing that VEGF binds to both receptors (Fig. 2
,
Lanes 6 and 7). The addition of 2C3
F(ab')2 blocked the binding of VEGF to VEGFR2/Fc
(Fig. 2
, Lane 3) but not to VEGFR1/Fc (Fig. 2
, Lane
4). In contrast, 4.6.1 F(ab')2 blocked the
binding of VEGF to both VEGFR2/Fc (Fig. 2
, Lanes 9 and
11) and VEGFR1/Fc (Fig. 2
, Lanes 10 and
12). The results affirm that 2C3 inhibits the binding of
VEGF to VEGFR2 but not to VEGFR1.
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shows that 2C3, along with A4.6.1, blocks VEGF-induced phosphorylation
of VEGFR2 in PAE/KDR cells. This is in agreement with previous results
that demonstrate that both 2C3 and A4.6.1 block VEGF-mediated growth of
endothelial cells (40)
. 3E7, which sees an
NH2-terminal epitope of VEGF, did not block
VEGF-induced phosphorylation of VEGFR2, nor did a control IgG of
irrelevant specificity. Also shown in Fig. 3
is a Western blot that
demonstrates the amounts of VEGFR2 protein in each lane. Densitometric
scanning of the gels confirmed that the ratio of
phosphotyrosine:protein was reduced in immunoprecipitates derived from
cells that had been treated with 2C3 and A4.6.1 but not with 3E7 or IgG
of irrelevant specificity. 2C3 also inhibited VEGF-induced
phosphorylation of VEGFR2 in bEND.3 cells (data not shown). We were
unsuccessful in demonstrating convincing VEGF-induced phosphorylation
of VEGFR1 to examine the effect of 2C3 on VEGFR1 activity. As other
investigators have shown, VEGF-induced phosphorylation of VEGFR1 in
PAE/FLT cells is difficult to demonstrate, possibly because of the low
intrinsic kinase activity of VEGFR1 (15
, 20
, 46
, 47)
.
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. This effect was evident with 2C3 at a 10-fold, 100-fold, or 1000-fold
molar excess over VEGF. A4.6.1, which blocks VEGF from activating both
VEGFR1 and VEGFR2, blocked VEGF-induced permeability at 10-fold molar
excess (Fig. 4
and Ref. 42
). 3E7, which does not block the
VEGF:VEGFR2 interaction, also does not block VEGF-induced vascular
permeability increases in the Miles permeability assay. These results
suggest that the enhancing effect of VEGF on endothelial permeability
is mediated mainly or entirely through VEGFR2 activation. These results
accord with those of other investigators who have shown that the
tyrosine kinase activity of VEGFR2 is necessary for VEGF-induced
permeability (45
, 48
, 49)
.
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. One hundred µg of 2C3 given i.p. twice per week to mice that had
been injected with tumor cells s.c. 1 day earlier inhibited the growth
of both human tumor types. The final tumor volume in the 2C3 recipients
was 150 mm3 in both tumor systems, as compared
with 1000 mm3 in controls. Treatment with 10
or 1 µg of 2C3 twice per week was less effective at preventing tumor
growth. The nonblocking anti-VEGF antibody, 3E7, at a dose of 100 µg
twice per week stimulated the growth of A673 tumors (Fig. 5B)
but not of NCI-H358 tumors (not shown). It is possible
that 3E7 increases angiogenesis in A673 tumors by cross-linking VEGF
and increasing receptor dimerization.
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. Doses were 50–100 µg given i.p. every 3–5 days.
A4.6.1 was used as a positive control because it has been shown by
other investigators to block VEGF activity in vivo,
resulting in an inhibition of tumor growth (33
, 35)
.
Treatment with either 2C3 or A4.6.1 led to a slow regression of the
tumors over the course of the experiment. The mean tumor volume at the
end of the experiment was 30% or 35% of the initial mean tumor
volume, respectively. However, these results are complicated by the
fact that tumors stopped growing in the control groups of mice between
40 and 60 days after tumor cell injection. Thereafter, the tumors grew
progressively. This spontaneous retardation in growth may have
contributed to the tumor regressions in the 2C3- and A4.6.1-treated
groups. The results up to 40 days, before the spontaneous retardation
in growth was evident, show that both 2C3 and A4.6.1 treatment prevent
tumor growth.
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shows the tumor growth curves of mice bearing a
human fibrosarcoma, HT1080, that were every treated every 2 days with
100 µg of 2C3, 3E7, a control IgG of irrelevant specificity, or
saline. 2C3 arrested the growth of the tumors for as long as treatment
was continued. Tumors in mice treated with 3E7, control IgG, or saline
grew progressively to a size that led to sacrifice of the mice less
than 4 weeks after tumor cell injection. No signs of toxicity (weight loss, ruffled fur, behavioral changes) were observed with any of the treatments.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In vitro binding experiments using ELISA in various configurations and coprecipitation assays with purified receptor proteins demonstrated that 2C3 blocks the binding of VEGF to VEGFR2 but not to VEGFR1. By contrast, 3E7, a nonblocking monoclonal antibody directed against an epitope in the NH2 terminus of VEGF, did not block VEGF from binding to either VEGFR1 or VEGFR2, and A4.6.1, a blocking anti-VEGF antibody, blocked the binding of VEGF to both VEGF receptors. Crystallographic and mutagenesis studies have shown that the binding epitopes for VEGFR2 and VEGFR1 are concentrated toward the two symmetrical poles of the VEGF dimer (50) . The binding determinants on VEGF that interact with the two receptors overlap partially and are distributed over four different segments that span across the dimer surface (51) . Antibody 4.6.1 binds to a region of VEGF within the receptor binding region of both receptors (51) . Possibly, 2C3 binds to a region that lies close to the VEGFR2 binding site but not to the VEGFR1 binding site.
Using a probe for phosphotyrosine, we demonstrated that 2C3 blocked the VEGF-induced phosphorylation of VEGFR2. However, like other investigators, we were unable to demonstrate consistent VEGF-induced phosphorylation of VEGFR1 (15 , 20 , 46 , 47) and therefore could not reliably judge whether 2C3 inhibits VEGF-induced phosphorylation of VEGFR1. The low activity of VEGF on VEGFR1 phosphorylation has lead others to suggest that VEGFR1 might not be a signaling receptor on endothelial cells (28) . However, tyrosine phosphorylation of VEGFR1 by VEGF binding has been reported by Kupprion et al. (52) using human microvascular endothelial cells and by Sawano et al. (53) using NIH 3T3 cells that overexpress VEGFR1. Additionally, Waltenberger et al. (20) have shown that VEGF-induced VEGFR1 activation can be followed using an in vitro kinase assay. It is possible that the effect of 2C3 on VEGF-induced phosphorylation of VEGFR1 might be determined using one of these cell types or an in vitro kinase assay.
2C3 and 4.6.1 blocked VEGF-induced increases in vascular permeability in the Mile’s permeability assay in guinea pigs. The nonblocking anti-VEGF antibody, 3E7, had no effect. These results demonstrate that VEGFR2 is mainly or entirely responsible for mediating VEGF-induced permeability increases. This finding accords with recent findings that a novel form of VEGF-C and two virus-derived VEGF-E variants bind VEGFR2 but not VEGFR1, yet retain the ability to enhance vascular permeability (48 , 49 , 54) . Probably, the various forms of VEGF transmit signals via VEGFR2 that cause NO production, which, in turn, causes the increase in vascular permeability (23, 24, 25 , 45 , 55 , 56) . However, there is also some evidence to the contrary because Couper et al. (57) found a strong correlation between increased vascular permeability induced by VEGF and VEGFR1 expression in vivo and Stacker et al. (58) found that VEGF could be mutated such that it still activated VEGFR2 but no longer induced an increase in vascular permeability.
Treatment of mice bearing newly transplanted NCI-H358 NSCLC or A673
rhabdomyosarcomas with 2C3 limited the growth of the tumors to small
nodules of 150 mm3 in size. Similar responses
were observed in mice bearing HT29 and LS174T tumors, both human
adenocarcinomas of the colon (data not shown). Tumor growth suppression
has been demonstrated previously by Mesiano et al.
(35)
and Asano et al. (34)
for
other neutralizing anti-VEGF antibodies, and by Skobe et al.
(59)
for an antimouse VEGFR2 antibody. DC101, a monoclonal
anti-Flk-1 antibody, has been shown to prevent the growth of a variety
of tumors in mice (60)
. Additionally, Klement et
al. (61)
have demonstrated that human neuroblastoma
tumors grown s.c. in mice can be effectively treated by continuous low
dose therapy with vinblastine in combination with DC101. In both
studies with DC101, 0.8–1.2 mg of the antibody was given every 3 days,
a dose that is 8–12-fold higher than the dose of 2C3 that gave similar
antitumor effects in the present studies. Perhaps, in addition to
blocking the VEGF:VEGFR2 interaction, 2C3 binds to and cross-links the
VEGF:VEGFR1 complex and enhances its reported negative effect on
R2-mediated angiogenesis.
Treatment of mice bearing established NCI-H358 NSCLC and
HT1080 fibrosarcomas with 2C3 caused significant tumor regressions.
NCI-H358 tumors treated with 2C3 or A4.6.1 regressed to 30 and 35%,
respectively, of their original size after 10 weeks of treatment.
The antitumor effects were attributable to neutralization of
tumor-derived (human) VEGF rather than of stromally derived (mouse)
VEGF because neither 2C3 nor A4.6.1 bind to mouse VEGF. The fact that
regression, rather than tumor stasis, was observed suggests that VEGF
is providing more than just a proliferation signal for tumor
endothelium. Benjamin et al. (62)
recently
reported that tumors contain a large fraction of immature blood vessels
that have yet to establish contact with periendothelial cells and that
these blood vessels are dependent upon VEGF for survival. It is
possible that neutralization of VEGF causes these immature blood
vessels to undergo apoptosis, thereby reducing the existing vascular
network in the tumor (62)
. It is also likely that a
dynamic process of vascular remodeling occurs in tumors, involving both
vessel formation and vessel regression, and that neutralization of VEGF
prevents vessel formation leading to a net shift toward vessel
regression. This is supported by Helmlinger et al.
(63)
who have recently shown that VEGF induces elongation,
network formation, and branching of nonproliferating endothelial cells
under hypoxic conditions. The authors show that inhibition of VEGF
activity prevents vessel network formation (63)
,
supporting the view that 2C3 and other anti-VEGF therapies exert their
antitumor action by preventing vascular remodeling and endothelial cell
survival in addition to preventing endothelial cell proliferation in
tumors.
The finding that 2C3 suppressed tumor growth as completely as did A4.6.1 indicates a dominant role for VEGFR2 in promoting tumor angiogenesis. The multistep process of angiogenesis requires endothelial cell chemotaxis, metalloproteinase production, invasion, proliferation, and differentiation. If VEGFR1 participates at all in these processes, its participation does not appear to limit the overall rate of the angiogenic process. In fact, the opposite may be true: recent evidence indicates that VEGFR1 suppresses VEGFR2 activity (31) . VEGFR1 may, however, play an important role in the recruitment of macrophages and monocytes into the tumor because these cells express VEGFR1 and respond chemotactically to VEGF via VEGFR1 signaling (28 , 64) . 2C3 may therefore have the advantage over A4.6.1 for therapy in which macrophage infiltration is not impaired, enabling these cells to remove tumor cell debris from necrotic tumors and promote tumor shrinkage. Also, it should not interfere with other VEGF-dependent physiological processes that are mediated through VEGFR1, such as the recruitment and differentiation of chondroclasts and other cells involved in cartilage remodeling and bone formation (65).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH Grants 1RO1 CA74951 and 5RO
CA54168, Predoctoral Training Grant T32 GM07062, and University of
Texas Specialized Programs of Research Excellence in Lung Cancer P50
CA70907. 
2 Present address: Department of Vascular Biology,
The Hope Heart Institute, 528 18th Avenue, Seattle, WA 98122-5798.
3 To whom requests for reprints should be
addressed, at Department of Pharmacology, University of Texas
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX
75390-9111. Phone: (214) 648-1268; Fax: (214) 648-1613.
4 The abbreviations used are: VEGF, vascular
endothelial growth factor; VEGFR1, VEGF receptor 1 (Flt-1); VEGFR2,
VEGF receptor 2 (Flk-1/KDR); PAE, porcine aortic endothelial; NSCLC,
non-small cell lung carcinoma; GPS, L-glutamine,
penicillin, and streptomycin; PVDF, polyvinylidene difluoride; i.d.,
intradermal.
Received 2/ 7/00. Accepted 7/18/00.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A. Lyshchik, A. C. Fleischer, J. Huamani, D. E. Hallahan, M. Brissova, and J. C. Gore Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 Expression Using Targeted Contrast-Enhanced High-Frequency Ultrasonography J. Ultrasound Med., November 1, 2007; 26(11): 1575 - 1586. [Abstract] [Full Text] [PDF]
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Y. Liang, C. Besch-Williford, R. A. Brekken, and S. M. Hyder Progestin-Dependent Progression of Human Breast Tumor Xenografts: A Novel Model for Evaluating Antitumor Therapeutics Cancer Res., October 15, 2007; 67(20): 9929 - 9936. [Abstract] [Full Text] [PDF]
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M. Abdelrahim, C. H. Baker, J. L. Abbruzzese, D. Sheikh-Hamad, S. Liu, S. D. Cho, K. Yoon, and S. Safe Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells Cancer Res., April 1, 2007; 67(7): 3286 - 3294. [Abstract] [Full Text] [PDF]
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J. Fang, Q. Zhou, L.-Z. Liu, C. Xia, X. Hu, X. Shi, and B.-H. Jiang Apigenin inhibits tumor angiogenesis through decreasing HIF-1{alpha} and VEGF expression Carcinogenesis, April 1, 2007; 28(4): 858 - 864. [Abstract] [Full Text] [PDF]
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G. Giaccone The Potential of Antiangiogenic Therapy in Non-Small Cell Lung Cancer Clin. Cancer Res., April 1, 2007; 13(7): 1961 - 1970. [Abstract] [Full Text] [PDF]
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 A. R. Hsu, W. Cai, A. Veeravagu, K. A. Mohamedali, K. Chen, S. Kim, H. Vogel, L. C. Hou, V. Tse, M. G. Rosenblum, et al. Multimodality Molecular Imaging of Glioblastoma Growth Inhibition with Vasculature-Targeting Fusion Toxin VEGF121/rGel J. Nucl. Med., March 1, 2007; 48(3): 445 - 454. [Abstract] [Full Text] [PDF]
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 F. H. Rad, H. Le Buanec, S. Paturance, P. Larcier, P. Genne, B. Ryffel, A. Bensussan, B. Bizzini, R. C. Gallo, D. Zagury, et al. VEGF kinoid vaccine, a therapeutic approach against tumor angiogenesis and metastases PNAS, February 20, 2007; 104(8): 2837 - 2842. [Abstract] [Full Text] [PDF]
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G. Korpanty, J. G. Carbon, P. A. Grayburn, J. B. Fleming, and R. A. Brekken Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature Clin. Cancer Res., January 1, 2007; 13(1): 323 - 330. [Abstract] [Full Text] [PDF]
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 T.-H. Lee, S. Seng, H. Li, S. J. Kennel, H. K. Avraham, and S. Avraham Integrin Regulation by Vascular Endothelial Growth Factor in Human Brain Microvascular Endothelial Cells: ROLE OF {alpha}6beta1 INTEGRIN IN ANGIOGENESIS J. Biol. Chem., December 29, 2006; 281(52): 40450 - 40460. [Abstract] [Full Text] [PDF]
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K. A. Mohamedali, A. T. Poblenz, C. R. Sikes, N. M. Navone, P. E. Thorpe, B. G. Darnay, and M. G. Rosenblum Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF121/rGel. Cancer Res., November 15, 2006; 66(22): 10919 - 10928. [Abstract] [Full Text] [PDF]
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 Y. Liang, R. A Brekken, and S. M Hyder Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr. Relat. Cancer, September 1, 2006; 13(3): 905 - 919. [Abstract] [Full Text] [PDF]
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 S. E. Holloway, A. W. Beck, L. Shivakumar, J. Shih, J. B. Fleming, and R. A. Brekken Selective Blockade of Vascular Endothelial Growth Factor Receptor 2 With an Antibody Against Tumor-Derived Vascular Endothelial Growth Factor Controls the Growth of Human Pancreatic Adenocarcinoma Xenografts Ann. Surg. Oncol., August 1, 2006; 13(8): 1145 - 1155. [Abstract] [Full Text] [PDF]
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M. Saint-Geniez, A. E. Maldonado, and P. A. D'Amore VEGF Expression and Receptor Activation in the Choroid during Development and in the Adult. Invest. Ophthalmol. Vis. Sci., July 1, 2006; 47(7): 3135 - 3142. [Abstract] [Full Text] [PDF]
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T. Troiani, O. Lockerbie, M. Morrow, F. Ciardiello, and S. G. Eckhardt Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases. Mol. Cancer Ther., July 1, 2006; 5(7): 1883 - 1894. [Abstract] [Full Text] [PDF]
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J. R. Tonra, D. S. Deevi, E. Corcoran, H. Li, S. Wang, F. E. Carrick, and D. J. Hicklin Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin. Cancer Res., April 1, 2006; 12(7): 2197 - 2207. [Abstract] [Full Text] [PDF]
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 C. A. Glass, S. J. Harper, and D. O. Bates The anti-angiogenic VEGF isoform VEGF165b transiently increases hydraulic conductivity, probably through VEGF receptor 1 in vivo J. Physiol., April 1, 2006; 572(1): 243 - 257. [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. Kurup, C.-W. Lin, D. J. Murry, L. Dobrolecki, D. Estes, C. T. Yiannoutsos, L. Mariano, C. Sidor, R. Hickey, and N. Hanna Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University Ann. Onc., January 1, 2006; 17(1): 97 - 103. [Abstract] [Full Text] [PDF]
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K. D. Miller, M. Miller, S. Mehrotra, B. Agarwal, B. H. Mock, Q.-H. Zheng, S. Badve, G. D. Hutchins, and G. W. Sledge Jr. A Physiologic Imaging Pilot Study of Breast Cancer Treated with AZD2171 Clin. Cancer Res., January 1, 2006; 12(1): 281 - 288. [Abstract] [Full Text] [PDF]
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T. A. Jackson, H. E. Taylor, D. Sharma, S. Desiderio, and S. K. Danoff Vascular Endothelial Growth Factor Receptor-2: COUNTER-REGULATION BY THE TRANSCRIPTION FACTORS, TFII-I AND TFII-IRD1 J. Biol. Chem., August 19, 2005; 280(33): 29856 - 29863. [Abstract] [Full Text] [PDF]
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 J. Fang, C. Xia, Z. Cao, J. Z. Zheng, E. Reed, and B.-H. Jiang Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways FASEB J, March 1, 2005; 19(3): 342 - 353. [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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 R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, G. Molema, P. Y. Lu, P. V. Scaria, and M. C. Woodle Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle Nucleic Acids Res., November 1, 2004; 32(19): e149 - e149. [Abstract] [Full Text] [PDF]
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J. V. Heymach, J. Desai, J. Manola, D. W. Davis, D. J. McConkey, D. Harmon, D. P. Ryan, G. Goss, T. Quigley, A. D. Van den Abbeele, et al. Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas Clin. Cancer Res., September 1, 2004; 10(17): 5732 - 5740. [Abstract] [Full Text] [PDF]
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E. Castro-Rivera, S. Ran, P. Thorpe, and J. D. Minna Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect PNAS, August 3, 2004; 101(31): 11432 - 11437. [Abstract] [Full Text] [PDF]
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 Mechanisms and Limits of Induced Postnatal Lung Growth Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 319 - 343. [Full Text] [PDF]
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A. C. Peterson, S. Swiger, W. M. Stadler, M. Medved, G. Karczmar, and T. F. Gajewski Phase II Study of the Flk-1 Tyrosine Kinase Inhibitor SU5416 in Advanced Melanoma Clin. Cancer Res., June 15, 2004; 10(12): 4048 - 4054. [Abstract] [Full Text] [PDF]
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 M. T. Sweetwyne, R. A. Brekken, G. Workman, A. D. Bradshaw, J. Carbon, A. W. Siadak, C. Murri, and E. H. Sage Functional Analysis of the Matricellular Protein SPARC with Novel Monoclonal Antibodies J. Histochem. Cytochem., June 1, 2004; 52(6): 723 - 733. [Abstract] [Full Text] [PDF]
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R. A. Brekken, M. M. Sullivan, G. Workman, A. D. Bradshaw, J. Carbon, A. Siadak, C. Murri, P. E. Framson, and E. H. Sage Expression and Characterization of Murine Hevin (SC1), a Member of the SPARC Family of Matricellular Proteins J. Histochem. Cytochem., June 1, 2004; 52(6): 735 - 748. [Abstract] [Full Text] [PDF]
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Y. Takei, K. Kadomatsu, Y. Yuzawa, S. Matsuo, and T. Muramatsu A Small Interfering RNA Targeting Vascular Endothelial Growth Factor as Cancer Therapeutics Cancer Res., May 15, 2004; 64(10): 3365 - 3370. [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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 P. A. Puolakkainen, R. A. Brekken, S. Muneer, and E. H. Sage Enhanced Growth of Pancreatic Tumors in SPARC-Null Mice Is Associated With Decreased Deposition of Extracellular Matrix and Reduced Tumor Cell Apoptosis Mol. Cancer Res., April 1, 2004; 2(4): 215 - 224. [Abstract] [Full Text] [PDF]
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 S. H. Rudolfsson, P. Wikstrom, A. Jonsson, O. Collin, and A. Bergh Hormonal Regulation and Functional Role of Vascular Endothelial Growth Factor A in the Rat Testis Biol Reprod, February 1, 2004; 70(2): 340 - 347. [Abstract] [Full Text] [PDF]
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M. Krix, F. Kiessling, S. Vosseler, N. Farhan, M. M. Mueller, P. Bohlen, N. E. Fusenig, and S. Delorme Sensitive Noninvasive Monitoring of Tumor Perfusion during Antiangiogenic Therapy by Intermittent Bolus-Contrast Power Doppler Sonography Cancer Res., December 1, 2003; 63(23): 8264 - 8270. [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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 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. Ruggeri, J. Singh, D. Gingrich, T. Angeles, M. Albom, H. Chang, C. Robinson, K. Hunter, P. Dobrzanski, S. Jones-Bolin, et al. CEP-7055: A Novel, Orally Active Pan Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models Cancer Res., September 15, 2003; 63(18): 5978 - 5991. [Abstract] [Full Text] [PDF]
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P. J. Mahasreshti, M. Kataram, M. H. Wang, C. R. Stockard, W. E. Grizzle, D. Carey, G. P. Siegal, H. J. Haisma, R. D. Alvarez, and D. T. Curiel Intravenous Delivery of Adenovirus-mediated Soluble FLT-1 Results in Liver Toxicity Clin. Cancer Res., July 1, 2003; 9(7): 2701 - 2710. [Abstract] [Full Text] [PDF]
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F. Ciardiello, R. Caputo, V. Damiano, R. Caputo, T. Troiani, D. Vitagliano, F. Carlomagno, B. M. Veneziani, G. Fontanini, A. R. Bianco, et al. Antitumor Effects of ZD6474, a Small Molecule Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, with Additional Activity against Epidermal Growth Factor Receptor Tyrosine Kinase Clin. Cancer Res., April 1, 2003; 9(4): 1546 - 1556. [Abstract] [Full Text] [PDF]
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T.-H. Lee, H. K. Avraham, S. Jiang, and S. Avraham Vascular Endothelial Growth Factor Modulates the Transendothelial Migration of MDA-MB-231 Breast Cancer Cells through Regulation of Brain Microvascular Endothelial Cell Permeability J. Biol. Chem., February 7, 2003; 278(7): 5277 - 5284. [Abstract] [Full Text] [PDF]
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C. Menon, M. Iyer, I. Prabakaran, R. J. Canter, S. C. Lehr, and D. L. Fraker TNF-alpha downregulates vascular endothelial Flk-1 expression in human melanoma xenograft model Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H317 - H329. [Abstract] [Full Text] [PDF]
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N. Gao, B.-H. Jiang, S. S. Leonard, L. Corum, Z. Zhang, J. R. Roberts, J. Antonini, J. Z. Zheng, D. C. Flynn, V. Castranova, et al. p38 Signaling-mediated Hypoxia-inducible Factor 1alpha and Vascular Endothelial Growth Factor Induction by Cr(VI) in DU145 Human Prostate Carcinoma Cells J. Biol. Chem., November 15, 2002; 277(47): 45041 - 45048. [Abstract] [Full Text] [PDF]
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N. Cheng, D. M. Brantley, H. Liu, Q. Lin, M. Enriquez, N. Gale, G. Yancopoulos, D. P. Cerretti, T. O. Daniel, and J. Chen Blockade of EphA Receptor Tyrosine Kinase Activation Inhibits Vascular Endothelial Cell Growth Factor-Induced Angiogenesis Mol. Cancer Res., November 1, 2002; 1(1): 2 - 11. [Abstract] [Full Text] [PDF]
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 R. Gomez, C. Simon, J. Remohi, and A. Pellicer Vascular Endothelial Growth Factor Receptor-2 Activation Induces Vascular Permeability in Hyperstimulated Rats, and this Effect Is Prevented by Receptor Blockade Endocrinology, November 1, 2002; 143(11): 4339 - 4348. [Abstract] [Full Text] [PDF]
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H. F. Dvorak Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy J. Clin. Oncol., November 1, 2002; 20(21): 4368 - 4380. [Abstract] [Full Text] [PDF]
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 M. Stoner, B. Saville, M. Wormke, D. Dean, R. Burghardt, and S. Safe Hypoxia Induces Proteasome-Dependent Degradation of Estrogen Receptor {alpha} in ZR-75 Breast Cancer Cells Mol. Endocrinol., October 1, 2002; 16(10): 2231 - 2242. [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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L. M. Veenendaal, H. Jin, S. Ran, L. Cheung, N. Navone, J. W. Marks, J. Waltenberger, P. Thorpe, and M. G. Rosenblum In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors PNAS, June 11, 2002; 99(12): 7866 - 7871. [Abstract] [Full Text] [PDF]
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N. K. Ozaki, K. D. Beharry, K. C. Nishihara, Y. Akmal, J. G. Ang, R. Sheikh, and H. D. Modanlou Regulation of Retinal Vascular Endothelial Growth Factor and Receptors in Rabbits Exposed to Hyperoxia Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1546 - 1557. [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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 A. M. Matthies, Q. E. H. Low, M. W. Lingen, and L. A. DiPietro Neuropilin-1 Participates in Wound Angiogenesis Am. J. Pathol., January 1, 2002; 160(1): 289 - 296. [Abstract] [Full Text] [PDF]
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 C. Halin, L. Zardi, and D. Neri Antibody-Based Targeting of Angiogenesis Physiology, August 1, 2001; 16(4): 191 - 194. [Abstract] [Full Text] [PDF]
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 R. J. Klasa, A. F. List, and B. D. Cheson Rational Approaches to Design of Therapeutics Targeting Molecular Markers Hematology, January 1, 2001; 2001(1): 443 - 462. [Abstract] [Full Text] [PDF]
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