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Tumor Biology |
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [C. G. L., M. H., E. d. T., G. G-E., M. A., C. K., K. R. P., R. K. J., H. D. S., Y. B.] and Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080 [N. F.]
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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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VEGF is a critical growth factor that promotes endothelial cell proliferation, angiogenesis, and tumor growth, and maintains the elevated vascular permeability of tumor vessels (10, 11, 12) . Pre-clinical studies have demonstrated that the growth of several tumor types is inhibited by blocking antibodies against human VEGF (13, 14, 15, 16) . Both the neutralization of VEGF action and the suppression of VEGF expression are associated with increases in the fraction of apoptotic tumor cells and reductions in vascular density and permeability (8 , 11 , 17) . Grunstein et. al. (11) have recently shown that deletion of the VEGF gene in ras-transformed fibroblasts increased tumor hypoxia as measured by the formation of cellular adducts with the small molecule nitroimidazole EF5.
We designed the present study to determine whether tumor growth inhibition by the combination of radiation and anti-VEGF mAb is dependent on tumor oxygen levels. To discern the role of tumor oxygenation, treatment over 11 days with human anti-VEGF mAb was followed by a single dose of ionizing radiation that was given either under normoxic or clamped hypoxic conditions. To identify other mechanisms that could inhibit tumor growth induced by the antibody or the combination of antibody and radiation, the effects of anti-VEGF mAb on pO2, vascular density, and the fraction of apoptotic cells were measured.
Tumor interstitial hypertension is a likely cause of the poor delivery of large therapeutic molecules to solid tumors (18) . The high vascular permeability and vascular resistance are two mechanisms that contribute to the elevated IFP of solid tumors. VEGF increases vascular permeability (12) and the anti-VEGF mAb decreases vascular permeability (17) . We, thus, tested the hypothesis that VEGF inhibition with anti-VEGF mAb would lower tumor IFP.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Anti-VEGF mAb.
The murine antihuman VEGF mAb A.4.6.1. (anti-VEGF mAb; Genentech, South
San Francisco, CA) was used. Mice bearing 6-mm diameter tumors (100
mm3
) were given six i.p. injections (one every other day)
of anti-VEGF mAb (100 µg/mouse) diluted in saline. Control animals
were injected with saline.
Irradiation Procedures.
A single radiation dose under normal blood flow (20 Gy, 30 Gy) or
hypoxic (30 Gy, 40 Gy) conditions was administered at a rate of about
5.6 Gy/min using a specially designed cesium irradiator. During
irradiation the mice were immobilized using a plastic tube fixed on a
brass plate, and the tumor was centered within the 3-cm diameter
circular irradiation field. In the groups treated with radiation only,
tumors with a diameter of 6 mm were irradiated. In the groups treated
with anti-VEGF mAb and radiation, anti-VEGF treatment was initiated at
a tumor size of 6 mm, and the single radiation dose was given 24 h
after the sixth antibody injection.
Tumors were exposed to single doses under oxygenated (normal blood flow) or hypoxic (clamped tumors) conditions. In the latter case, a clamp was placed across the base of the tumor-bearing leg to occlude the tumor blood flow for 2 min before, and then during, irradiation. The mice were anesthetized with pentobarbital (50 mg/kg body weight i.p.) before clamping. The mice that were irradiated under oxygenated conditions were not anesthetized.
Tumor Volume.
Tumor diameters in control and treated groups were measured every 2
days with a caliper. All experimental animals were observed on a daily
basis, and tumor sizes were measured every other day. Tumor volume was
calculated as V = ab2/2, where a and
b are the long and the short axes, respectively. Mice were
sacrificed with an i.p. injection of pentobarbital (200 mg/kg body
weight) once the tumor reached 12 mm in diameter.
pO2 Measurements.
Oxygen measurements were performed in tumors using a polarographic
pO2 histograph (Eppendorf, Hamburg, Germany). The
pO2 was measured once, 24 h after the sixth
injection of anti-VEGF mAb. pO2 was also measured
in size-matched untreated tumors. The mice were anesthetized with
ketamine/xylazine (100/10 mg/kg body weight) and placed on a heating
pad to maintain the body temperature at 37°C. The skin overlying the
tumor was cut and the cathode was placed through the cut to the surface
of the tumor. The electrode was advanced automatically through the
tumor, each forward step followed by a short backward step to reduce
artifacts in pO2 measurements from compression of
the tissue by the electrode. pO2 measurements
were taken in four tumor regions, and 40–50 measurements were taken in
each tumor. The pO2 values represent the median
of eight mice per group.
IFP Measurements.
The wick-in-needle technique was used to measure IFP as described
previously (19)
. IFP was measured in two locations in the
center of s.c. tumors, 24 h after the sixth injection of anti-VEGF
mAb. Because the IFP increases with tumor size, IFP was measured in
untreated tumors that were size-matched with the volume of
antibody-treated tumors.
Immunohistochemistry.
After the mice were killed, tumors were immediately excised and placed
in neutral-buffered formalin. The tumors were embedded in paraffin
blocks from which 5 µm sections were cut. The degree of apoptosis was
evaluated using Apop-Tag peroxidase kit (Oncor, Gaithersburg, MD)
according to the manufacturer’s recommendations. The apoptotic index
was calculated as the percentage of positive nuclei—defined as stained
with peroxidase combined with the presence of a nuclear halo or
apoptotic bodies—observed in a minimum of 400 cells per histological
section at a final magnification of x1240.
To estimate vessel density, tumor sections were incubated overnight at 4°C with rat antimouse CD31 (PharMingen, San Diego, CA) at a dilution of 1:30. Visualization of the antigen-antibody reaction was carried out using the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA) according to the recommendations of the manufacturer. Vessel density was determined by counting the stained vessels in fields of 0.071 mm2 at a final magnification of x620. A number of 10 to 23 fields per histological section were included in the analysis.
Western Analysis.
Tissue samples were homogenized with lysis buffer containing 10
mM Tris-HCl (pH 7.4), 150 mM NaCl, 1.0% Triton
X-100, 10% NP40, 2 mM EDTA and protease inhibitor cocktail
(Complete Mini EDTA-free, Boehringer Mannheim). 100 µg protein of
each lysate were loaded into 12% SDS-PAGE gel, separated, and
transferred onto the nitrocellulose membrane. One hundred ng of human
recombinant VEGF protein was loaded as positive control. The membranes
were subjected to immunoblotting with rabbit antimurine VEGF antibody,
which was provided by Dr. Donald Senger of Beth Israel Deaconess
Hospital (Boston, MA). The antibody cross-reacts with human VEGF.
Immunodetections were carried out using Western blot chemiluminescence
reagent (New England Nuclear Life Science Products, Boston, MA).
Statistical Analysis.
The TGD calculations were based on the median time in days for tumors
to grow from 100 to 500 mm3
. Some tumors did not
reach 500 mm3
during the experiment because
either the experiment was interrupted before the tumors reached 500
mm3
or the tumors regressed. In these cases, the
duration of experiment was used as a censored measure of time to reach
500 mm3
. Median times to grow from 100 to 500
mm3
were estimated with Kaplan-Meier curves. TGD
attributable to antibody was estimated as a difference of such medians
in groups treated with anti-VEGF mAb and in corresponding controls
(untreated tumors, radiation-treated tumors). The SEs of the medians
and of their differences were obtained with bootstrap methods
(20)
. We used the log-rank test for statistical
comparisons of times to grow from 100 to 500 mm3
.
Differences in apoptosis, vascular density, IFP, and
pO2 between anti-VEGF mAb and control groups were
tested with Student’s t test and ANOVA for normally
distributed data, and with Mann-Whitney U test otherwise.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
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. Anti-VEGF mAb retarded the growth of both U87 and LS174T,
with a significantly greater effect on the growth of U87 (Table 1)
. The median TGD induced by the anti-VEGF mAb was 12 and 22 days for
LS174T and U87, respectively. Furthermore, there were larger variations
in times to grow to 900 mm3
for U87 tumors. In
some U87 tumors the growth retardation during the 11 days of anti-VEGF
mAb treatment was followed at irregular intervals by periods of several
days without growth (Fig. 2a)
.
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. The microvessel density after the third or sixth
injection of anti-VEGF mAb was still significantly lower as compared
with control tumors.
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. However, after six
antibody injections, the percentage of apoptotic cells was similar to
control values. In U87, the increase in apoptosis was not significant.
Anti-VEGF mAb Reduces IFP.
On the basis of the finding that anti-VEGF reduces tumor vascular
permeability and modifies the architecture of tumor vessels
(17)
, we hypothesized that anti-VEGF treatment would
reduce IFP. The mean IFP of LS174T and U87 dropped by 73 and 74%,
respectively (Table 2)
. Some of the IFP values, especially in U87 were close to 0 mm Hg, thus
comparable with the IFP in normal tissues. In four of eight treated U87
tumors, IFP varied between 1.0 and 3.0 mm Hg.
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; Fig. 4a
). In LS174T, the antibody did not change the median
pO2, and the decrease in frequency of
pO2 values below 5 mm Hg was not significant
(Table 2
; Fig. 4b
).
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;
Table 1
). In most of the U87 tumors, the initial growth delay induced
by radiation was followed by a steady and rapid growth phase.
However, in U87 for both oxic (20 and 30 Gy) and hypoxic (40 Gy)
conditions, anti-VEGF mAb plus radiation interrupted the growth or
induced a steady regression of 10–43% of the tumors (Fig. 2c)
. In contrast, radiation alone (30 Gy oxic) induced the
regression of only one U87 tumor. The combination of anti-VEGF mAb and
radiation was significantly less effective in LS174T than in U87
tumors, as shown by the time that it took to grow from 100 to 500
mm3
and the estimation of the TGD induced by the
antibody (Fig. 5
; Table 1
).
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. In LS174T, the combination of
radiation (40 Gy hypoxic) and antibody induced a TGD that was greater
than additive. At all other radiation doses, the effect was at best
additive. In U87, at all radiation doses and for both aerobic and clamp
hypoxia conditions, the TGD induced by the anti-VEGF mAb was greater
than additive (Fig. 5)
. For U87, it was possible to calculate the TGD
based on the time after radiation for the tumors to triple in size. The
TGD calculations based on a 3-fold increase in tumor size (data not
shown) or the time for the tumors to grow from 100 to 500
mm3
gave comparable results. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Previous studies have also shown that the tumor
vasculature regressed rapidly after VEGF down-regulation (21
, 22)
. The reduction in tumor VEGF levels leads to endothelial
cell detachment and apoptosis (21
, 22)
. After VEGF
withdrawal, Benjamin and Keshet (21)
found that the marked
decrease in the vessels of C6 glioma was associated with hemorrhage. In
contrast, we found no evidence of hemorrhage. The reduction in tumor
IFP is consistent with the decrease in vascular permeability after
treatment with anti-VEGF mAb or VEGF down-regulation (11
, 17)
. Variations in vascular response after VEGF withdrawal or
anti-VEGF mAb treatment could be attributable to differences in the
tumor levels of active VEGF, other survival factors for endothelial
cells or the presence of periendothelial cells (e.g.,
pericytes). Benjamin et al. (23)
have recently
shown that tumor vessels devoid of periendothelial cells regress after
the down-regulation of VEGF levels in the C6 glioma. Antiangiogenic agents like squalamine, and TNP-470 combined with minocycline can reduce the degree of hypoxia in tumors (1 , 9) . Interestingly, in U87 the vessel regression induced by the anti-VEGF mAb was associated with an increase in median pO2 and a decrease in hypoxic values below 5.0 mm Hg. The increase in pO2 despite a decrease in vascular density suggests that it is the quality of the vascular organization and not just the quantity of vessels that determines the oxygen levels in a tumor. The improvement in tumor oxygenation could also be explained by a decrease in the number of tumor and endothelial cells consuming oxygen. Oxygen consumption by endothelial cells is significant, and it most likely influences the pO2 values in tissues (24 , 25) .
Elevated IFP is a hallmark of solid tumors (26) . Anti-VEGF mAb reduced IFP from 12.0 to 3.0 mm Hg in U87 and from 13.5 to 3.5 mm Hg in LS174T, thus showing that VEGF is an important molecule responsible for the interstitial hypertension in solid tumors. Furthermore, especially in some anti-VEGF-treated U87 tumors, the IFP was reduced to 1–2 mm Hg, which is comparable with the pressure in the subcutis and other normal tissues, which varies between 0 and -2.0 mm Hg (27) . Two vascular factors contribute to interstitial hypertension in solid tumors: the high permeability of tumor vessels and the tortuous nature including compression (reduction in vessel diameter) of vessels. The high vascular permeability and hydraulic conductivity of tumor vessels favor the equilibration of the MVP and IFP (28) . The tortuous architecture of the vasculature and the vessel compression by tumor cells increase the vascular resistance and thus the MVP (29) . Treatment with anti-VEGF mAb decreases vascular permeability (17) and could directly lower IFP. Furthermore, the loss of endothelial cells would reduce the tortuosity of vessels or eliminate vessels altogether. This modification in vascular architecture would reduce flow resistance and, hence, lower both MVP and IFP. Thus, VEGF contributes significantly to the high IFP in solid tumors, and normalization in vascular permeability and architecture is probably responsible for the lower IFP induced by the anti-VEGF mAb.
Antitumoral Effects of Anti-VEGF mAb.
Similar to other studies, we found that the anti-VEGF mAb retards tumor
growth and has differential effects dependent on the tumor type
(13, 14, 15, 16)
. Anti-VEGF mAb induced a TGD of only 6 days in a
human sarcoma (data not shown), whereas the growth delays in LS174T and
U87 were of 12 and 22 days, respectively. The differential tumor
response to anti-VEGF mAb could be attributable to the relative levels
of host (murine) versus human VEGF, the absolute levels of
VEGF, or other growth factors that stimulate angiogenesis. The mAb
A.4.6.1 binds and neutralizes human VEGF and does not block murine
VEGF. Fukumura et al. (30)
have recently shown
that host (mouse) stromal cells in human tumor xenografts can be a
source of VEGF. The expression of VEGF varies from one tumor type to
another. In accord with the finding that the levels of VEGF protein
were higher in U87 than in LS174T tumors (Fig. 1)
, the anti-VEGF mAb
did effect a greater TGD in U87 as compared with LS174T. However, other
reports have found no correlation between the levels of VEGF produced
in vitro or in vivo and the antitumor response
induced by the antihuman VEGF mAb MV833 (13
, 15)
.
Potential differences in antibody specificity or affinity could also
affect antitumor response. In the present study, the mAb 4.6.1 against
human-VEGF induced a significant delay in the growth of s.c. U87 tumors
in nude mice. In contrast, mAb 293 against human VEGF did not inhibit
the growth of U87 that was also implanted s.c. in nude mice
(4)
.
In comparison with LS174T, the greater reduction in vascular density in U87 could be responsible for the larger TGD in that tumor. Tumor volume doubling times were comparable in untreated U87 (4.5 days) and LS174T (4.0 days), whereas the vessel density was of 27 and 15 vessels/mm2, respectively. Vessel loss induced by the anti-VEGF mAb was 2.5 fold greater in U87 as compared with LS174T. Modifications in tumor cell proliferation or apoptosis induced by antiangiogenic agents could also explain the TGD induced by the anti-VEGF mAb. The in vitro proliferation of U87 tumor cells is not modified by the anti-VEGF mAb 4.6.1 (17) . Yoshigi et al. (31) have shown that the in vivo inhibition of the VEGF signaling pathway in endothelial cells is associated with an increase in tumor cell apoptosis; however, the number of proliferating tumor cells was not modified (31) . Increases in tumor cell apoptosis are also induced by various antiangiogenic agents (5, 6, 7 , 32) including anti-VEGF mAb treatment and deletion of the VEGF gene in ras-transformed fibroblasts (8 , 11) . The small increase in apoptosis in U87 and LS174T probably plays a minor role in the inhibition of growth by the anti-VEGF mAb. Furthermore, the greater induction of apoptosis in LS174T was associated with a smaller antitumor response as compared with U87. We did not quantify necrosis; however, the examination of histological slides did not reveal obvious differences in necrosis between control and anti-VEGF mAb-treated tumors. Thus, based on the present results, the inhibition of angiogenesis is probably the dominant factor responsible for the TGD induced by the anti-VEGF mAb in both U87 and LS174T tumors.
Combination of Radiation and Anti-VEGF Improves Tumor Response.
One of the aims of the present study was to determine whether the
increased TGD induced by the combination of anti-VEGF and radiation was
dependent on the oxygenation status at the time of radiation. Similar
to previous studies with other antiangiogenic agents (1
, 9)
, the anti-VEGF mAb treatment reduced the hypoxia in U87
tumors. However, the TGD induced by the combination treatment was found
to be essentially independent of tumor oxygenation. At the radiation
dose of 30 Gy for both oxic and hypoxic conditions, the anti-VEGF mAb
induced a TGD of 16 days in LS174T (Fig. 5)
. Similarly, in U87 tumors,
there was no significant difference in TGD between aerobic and clamp
hypoxia conditions. The increased TGD at 40 Gy hypoxic in LS174T
also supports the interpretation that the oxygen level in a tumor is
probably not the major cause of the increased radioresponse induced by
the anti-VEGF mAb.
In U87, the combination of anti-VEGF mAb and radiation induced a TGD that was greater than additive. This enhancement in TGD could be attributable to vessel loss resulting from both antibody and radiation treatment. Radiation doses of 16–21 Gy resulted in the loss of 50% of the vessels in a human melanoma implanted in nude mice (33) . Furthermore, the cytotoxic effects of radiation could be enhanced by the inhibition of VEGF in the tumor at the time of radiation. VEGF protects against radiation-induced endothelial cell killing and the addition of anti-VEGF mAb to endothelial cells in vitro increased the cytotoxic effects of radiation (4) .
In conclusion, our results show that the anti-VEGF mAb significantly reduces tumor IFP and hypoxia. The improvement in tumor oxygenation was associated with a major decrease in vascular density in U87. The efficacy of the combined radiation and anti-VEGF mAb treatment was tumor-dependent. The TGD induced by the combination treatment was greater than additive in U87, whereas in LS174T (except for 40 the Gy hypoxic group) the TGD was additive. In both U87 and LS174T, the enhanced TGD resulting from the anti-VEGF mAb was independent of the radiation dose and tumor oxygenation at the time of irradiation. The insignificant difference in TGD when radiation is given under oxic and hypoxic conditions suggests that the reduced hypoxia in U87 plays a minor role in the antitumor effect of the anti-VEGF mAb and radiation combination. The reduced vascular density induced by the anti-VEGF mAb is probably a significant factor that enhances the radiation effect under both oxic and hypoxic conditions.
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FOOTNOTES |
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1 This work was supported by Outstanding
Investigator Grant (R35-CA-56591; to R. K. J.) and a MERIT
Grant (R37-CA-13111 to H. D. S.) from the National Cancer
Institute. 
2 To whom requests for reprints should be
addressed, at Department of Radiation Oncology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA 02114. Phone: (617)
726-8150; Fax: (617) 726-3603; E-mail: hsuit{at}partners.org
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; pO2, partial oxygen tension;
IFP, interstitial fluid pressure; MVP, microvascular pressure; mAb,
monoclonal antibody; TGD, tumor growth delay.
Received 1/17/00. Accepted 8/ 2/00.
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J. V. Skliarenko, S. J. Lunt, M. L. Gordon, A. Vitkin, M. Milosevic, and R. P. Hill Effects of the Vascular Disrupting Agent ZD6126 on Interstitial Fluid Pressure and Cell Survival in Tumors Cancer Res., February 15, 2006; 66(4): 2074 - 2080. [Abstract] [Full Text] [PDF]
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I. Sakimoto, K. Ohta, T. Yamazaki, S. Ohtani, H. Sahara, F. Sugawara, K. Sakaguchi, and M. Miura {alpha}-Sulfoquinovosylmonoacylglycerol Is a Novel Potent Radiosensitizer Targeting Tumor Angiogenesis Cancer Res., February 15, 2006; 66(4): 2287 - 2295. [Abstract] [Full Text] [PDF]
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T. Nakahara, S. M. Norberg, D. R. Shalinsky, D. D. Hu-Lowe, and D. M. McDonald Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors Cancer Res., February 1, 2006; 66(3): 1434 - 1445. [Abstract] [Full Text] [PDF]
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 C. R. Pradeep, E. S. Sunila, and G. Kuttan Expression of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptors in Tumor Angiogenesis and Malignancies Integr Cancer Ther, December 1, 2005; 4(4): 315 - 321. [Abstract] [PDF]
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C. G. Willett, Y. Boucher, D. G. Duda, E. di Tomaso, L. L. Munn, R. T. Tong, S. V. Kozin, L. Petit, R. K. Jain, D. C. Chung, et al. Surrogate Markers for Antiangiogenic Therapy and Dose-Limiting Toxicities for Bevacizumab With Radiation and Chemotherapy: Continued Experience of a Phase I Trial in Rectal Cancer Patients J. Clin. Oncol., November 1, 2005; 23(31): 8136 - 8139. [Full Text] [PDF]
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A. Kaliski, L. Maggiorella, K. A. Cengel, D. Mathe, V. Rouffiac, P. Opolon, N. Lassau, J. Bourhis, and E. Deutsch Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion Mol. Cancer Ther., November 1, 2005; 4(11): 1717 - 1728. [Abstract] [Full Text] [PDF]
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S. Ferretti, P. R. Allegrini, T. O'Reilly, C. Schnell, M. Stumm, M. Wartmann, J. Wood, and P. M.J. McSheehy Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure Clin. Cancer Res., November 1, 2005; 11(21): 7773 - 7784. [Abstract] [Full Text] [PDF]
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 Z. Kan, S. Phongkitkarun, S. Kobayashi, Y. Tang, L. M. Ellis, T. Y. Lee, and C. Charnsangavej Functional CT for Quantifying Tumor Perfusion in Antiangiogenic Therapy in a Rat Model Radiology, October 1, 2005; 237(1): 151 - 158. [Abstract] [Full Text] [PDF]
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A. Abdollahi, D. W. Griggs, H. Zieher, A. Roth, K. E. Lipson, R. Saffrich, H.-J. Grone, D. E. Hallahan, R. A. Reisfeld, J. Debus, et al. Inhibition of {alpha}v{beta}3 Integrin Survival Signaling Enhances Antiangiogenic and Antitumor Effects of Radiotherapy Clin. Cancer Res., September 1, 2005; 11(17): 6270 - 6279. [Abstract] [Full Text] [PDF]
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W. P. Tew, D. P. Kelsen, and D. H. Ilson Targeted Therapies for Esophageal Cancer Oncologist, September 1, 2005; 10(8): 590 - 601. [Abstract] [Full Text] [PDF]
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V. Damiano, D. Melisi, C. Bianco, D. Raben, R. Caputo, G. Fontanini, R. Bianco, A. Ryan, A. R. Bianco, S. De Placido, et al. Cooperative Antitumor Effect of Multitargeted Kinase Inhibitor ZD6474 and Ionizing Radiation in Glioblastoma Clin. Cancer Res., August 1, 2005; 11(15): 5639 - 5644. [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. E. Huber, M. Bischof, J. Jenne, S. Heiland, P. Peschke, R. Saffrich, H.-J. Grone, J. Debus, K. E. Lipson, and A. Abdollahi Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy Cancer Res., May 1, 2005; 65(9): 3643 - 3655. [Abstract] [Full Text] [PDF]
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A. G. Taghian, R. Abi-Raad, S. I. Assaad, A. Casty, M. Ancukiewicz, E. Yeh, P. Molokhia, K. Attia, T. Sullivan, I. Kuter, et al. Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical Implications J. Clin. Oncol., March 20, 2005; 23(9): 1951 - 1961. [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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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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H.-P. Gerber and N. Ferrara Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies Cancer Res., February 1, 2005; 65(3): 671 - 680. [Abstract] [Full Text] [PDF]
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R. Ansiaux, C. Baudelet, B. F. Jordan, N. Beghein, P. Sonveaux, J. De Wever, P. Martinive, V. Gregoire, O. Feron, and B. Gallez Thalidomide Radiosensitizes Tumors through Early Changes in the Tumor Microenvironment Clin. Cancer Res., January 15, 2005; 11(2): 743 - 750. [Abstract] [Full Text] [PDF]
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 R. K. Jain Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy Science, January 7, 2005; 307(5706): 58 - 62. [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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 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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 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
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R. T. Tong, Y. Boucher, S. V. Kozin, F. Winkler, D. J. Hicklin, and R. K. Jain Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors Cancer Res., June 1, 2004; 64(11): 3731 - 3736. [Abstract] [Full Text] [PDF]
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N. Ferrara Vascular Endothelial Growth Factor as a Target for Anticancer Therapy Oncologist, June 1, 2004; 9(suppl_1): 2 - 10. [Abstract] [Full Text] [PDF]
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N. H. Fernando and H. I. Hurwitz Targeted Therapy of Colorectal Cancer: Clinical Experience with Bevacizumab Oncologist, June 1, 2004; 9(suppl_1): 11 - 18. [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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H. X. Chen Expanding the Clinical Development of Bevacizumab Oncologist, June 1, 2004; 9(suppl_1): 27 - 35. [Abstract] [Full Text] [PDF]
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H. S. Rugo Bevacizumab in the Treatment of Breast Cancer: Rationale and Current Data Oncologist, June 1, 2004; 9(suppl_1): 43 - 49. [Abstract] [Full Text] [PDF]
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M. Bockhorn, Y. Tsuzuki, L. Xu, A. Frilling, C. E. Broelsch, and D. Fukumura Differential Vascular and Transcriptional Responses to Anti-Vascular Endothelial Growth Factor Antibody in Orthotopic Human Pancreatic Cancer Xenografts Clin. Cancer Res., September 15, 2003; 9(11): 4221 - 4226. [Abstract] [Full Text] [PDF]
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K. Pietras, M. Stumm, M. Hubert, E. Buchdunger, K. Rubin, C.-H. Heldin, P. McSheehy, M. Wartmann, and A. Ostman STI571 Enhances the Therapeutic Index of Epothilone B by a Tumor-selective Increase of Drug Uptake Clin. Cancer Res., September 1, 2003; 9(10): 3779 - 3787. [Abstract] [Full Text] [PDF]
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A. J. Schueneman, E. Himmelfarb, L. Geng, J. Tan, E. Donnelly, D. Mendel, G. McMahon, and D. E. Hallahan SU11248 Maintenance Therapy Prevents Tumor Regrowth after Fractionated Irradiation of Murine Tumor Models Cancer Res., July 15, 2003; 63(14): 4009 - 4016. [Abstract] [Full Text] [PDF]
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E. K. Rofstad, K. Henriksen, K. Galappathi, and B. Mathiesen Antiangiogenic Treatment with Thrombospondin-1 Enhances Primary Tumor Radiation Response and Prevents Growth of Dormant Pulmonary Micrometastases after Curative Radiation Therapy in Human Melanoma Xenografts Cancer Res., July 15, 2003; 63(14): 4055 - 4061. [Abstract] [Full Text] [PDF]
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B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]
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A. Abdollahi, K. E. Lipson, X. Han, R. Krempien, T. Trinh, K. J. Weber, P. Hahnfeldt, L. Hlatky, J. Debus, A. R. Howlett, et al. SU5416 and SU6668 Attenuate the Angiogenic Effects of Radiation-induced Tumor Cell Growth Factor Production and Amplify the Direct Anti-endothelial Action of Radiation in Vitro Cancer Res., July 1, 2003; 63(13): 3755 - 3763. [Abstract] [Full Text] [PDF]
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 J. Ma, S. Li, K. Reed, P. Guo, and J. M. Gallo Pharmacodynamic-Mediated Effects of the Angiogenesis Inhibitor SU5416 on the Tumor Disposition of Temozolomide in Subcutaneous and Intracerebral Glioma Xenograft Models J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 833 - 839. [Abstract] [Full Text] [PDF]
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P. Wachsberger, R. Burd, and A. P. Dicker Tumor Response to Ionizing Radiation Combined with Antiangiogenesis or Vascular Targeting Agents: Exploring Mechanisms of Interaction Clin. Cancer Res., June 1, 2003; 9(6): 1957 - 1971. [Abstract] [Full Text] [PDF]
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C. Roca, L. Primo, D. Valdembri, A. Cividalli, P. Declerck, P. Carmeliet, P. Gabriele, and F. Bussolino Hyperthermia Inhibits Angiogenesis by a Plasminogen Activator Inhibitor 1-dependent Mechanism Cancer Res., April 1, 2003; 63(7): 1500 - 1507. [Abstract] [Full Text] [PDF]
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P. Sonveaux, A. Brouet, X. Havaux, V. Gregoire, C. Dessy, J.-L. Balligand, and O. Feron Irradiation-induced Angiogenesis through the Up-Regulation of the Nitric Oxide Pathway: Implications for Tumor Radiotherapy Cancer Res., March 1, 2003; 63(5): 1012 - 1019. [Abstract] [Full Text] [PDF]
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A. Stevens, J. Soden, P. E. Brenchley, S. Ralph, and D. W. Ray Haplotype Analysis of the Polymorphic Human Vascular Endothelial Growth Factor Gene Promoter Cancer Res., February 15, 2003; 63(4): 812 - 816. [Abstract] [Full Text] [PDF]
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F. Kabbinavar, H. I. Hurwitz, L. Fehrenbacher, N. J. Meropol, W. F. Novotny, G. Lieberman, S. Griffing, and E. Bergsland Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer J. Clin. Oncol., January 1, 2003; 21(1): 60 - 65. [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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K. Pietras, K. Rubin, T. Sjoblom, E. Buchdunger, M. Sjoquist, C.-H. Heldin, and A. Ostman Inhibition of PDGF Receptor Signaling in Tumor Stroma Enhances Antitumor Effect of Chemotherapy Cancer Res., October 1, 2002; 62(19): 5476 - 5484. [Abstract] [Full Text] [PDF]
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P. A. Burke, S. J. DeNardo, L. A. Miers, K. R. Lamborn, S. Matzku, and G. L. DeNardo Cilengitide Targeting of {alpha}v{beta}3 Integrin Receptor Synergizes with Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts Cancer Res., August 1, 2002; 62(15): 4263 - 4272. [Abstract] [Full Text] [PDF]
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R. J. Griffin, B. W. Williams, R. Wild, J. M. Cherrington, H. Park, and C. W. Song Simultaneous Inhibition of the Receptor Kinase Activity of Vascular Endothelial, Fibroblast, and Platelet-derived Growth Factors Suppresses Tumor Growth and Enhances Tumor Radiation Response Cancer Res., March 1, 2002; 62(6): 1702 - 1706. [Abstract] [Full Text] [PDF]
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 R.K. JAIN Angiogenesis and Lymphangiogenesis in Tumors: Insights from Intravital Microscopy Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 239 - 248. [Abstract] [PDF]
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M. Milosevic, A. Fyles, D. Hedley, M. Pintilie, W. Levin, L. Manchul, and R. Hill Interstitial Fluid Pressure Predicts Survival in Patients with Cervix Cancer Independent of Clinical Prognostic Factors and Tumor Oxygen Measurements Cancer Res., September 1, 2001; 61(17): 6400 - 6405. [Abstract] [Full Text] [PDF]
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S. V. Kozin, Y. Boucher, D. J. Hicklin, P. Bohlen, R. K. Jain, and H. D. Suit Vascular Endothelial Growth Factor Receptor-2-blocking Antibody Potentiates Radiation-induced Long-Term Control of Human Tumor Xenografts Cancer Res., January 1, 2001; 61(1): 39 - 44. [Abstract] [Full Text]
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 S. Patan, S. Tanda, S. Roberge, R. C. Jones, R. K. Jain, and L. L. Munn Vascular Morphogenesis and Remodeling in a Human Tumor Xenograft: Blood Vessel Formation and Growth After Ovariectomy and Tumor Implantation Circ. Res., October 12, 2001; 89(8): 732 - 739. [Abstract] [Full Text] [PDF]
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