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Experimental Therapeutics |
Department of Medical Oncology [J. D., I. H., C. W., M. M., C. U.] and Institute of Molecular Oncology [H. H., G. M-B., D. M.], Tumor Biology Center, 79106 Freiburg, Germany; Department of Obstetrics, Albert-Ludwigs University Hospital, 79106 Freiburg, Germany [H.M.]; and Department of Oncology Research, Novartis Pharmaceuticals, CH-4002 Basel, Switzerland [J. W.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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More than 25 years ago, Judah Folkman (3) proposed that the growth of solid tumors and the formation of metastases are dependent on the development of new blood vessels. Tumors originate from a single cell, which has been transformed by genetic events such as activation of oncogenes, e.g., ras and erbB2, inactivation of tumor suppressor genes, e.g., p53 and von Hippel-Lindau, or both. The transformed cells gain growth advantage and form tumor cell clones of a few millimeters in diameter before the supply of nutrients becomes limited. The tumor clone will remain in this stage until cells acquire an angiogenic phenotype, which means increased secretion of angiogenic factors and reduced production of negative regulators of angiogenesis. As a consequence, endothelial cells change their genetic program, produce proteolytic enzymes, migrate, proliferate, and form new vessels oriented toward and growing into the tumor cell clone (4) . This process has been clarified by the discovery and molecular sequencing of various endothelial cell growth factors and endogenous angiogenesis inhibitors. Various angiogenic factors produced by solid tumors have been identified, and their role in the formation of new blood vessels has been elucidated. The VEGF3 is one of the most potent and endothelial cell specific angiogenic factors with a key role in tumor angiogenesis (5) . VEGF is also known to induce vascular hyperpermeability. Its specificity is explained by the preferential expression of its two receptors, VEGF-R1 (FLT-1) and VEGF-R2 (KDR), on the surface of endothelial cells of the tumor vessels. Therefore, VEGF-Rs are promising targets for the inhibition of angiogenesis in growing tumors.
To investigate novel therapeutic strategies for the treatment of human renal cell carcinoma, such as adoptive immunotherapy or cytokine therapy, murine renal cell carcinoma has been a particularly suitable animal model for assessing novel therapeutic approaches (6 , 7) . In this model, primary kidney tumors are induced by subcapsular renal injection of renal carcinoma (RENCA) cells with subsequent development of metastases in the lungs, lymph nodes, and spleen (8) .
Our aim was to study the antiangiogenic and antitumoral effects on murine renal cell carcinoma using the compound PTK787/ZK 222584 which is known to be a potent inhibitor of both VEGF-R-tyrosine kinases and which can be applied p.o. Its pharmacological properties have been described elsewhere (9) . Here we describe the effect of PTK787/ZK 222584 on the primary tumor, metastasis, and vessel density in murine renal cell carcinoma. TNP-470, a compound known for its antiangiogenic and antitumor activity in the murine RENCA model, was used for comparison (10) . The effect of treatment with PTK787/ZK 222584 on blood flow in afferent tumor vessels was monitored using the color Doppler imaging ultrasound technique.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
Murine RENCA cells were originally obtained from a tumor that
arose spontaneously in the kidney of BALB/c mice. Histologically, RENCA
consists of granular cell type adenocarcinoma, which is pleomorphic
with large nuclei. Monolayers of murine RENCA cells were grown in RPMI
1640 with phenol red supplemented with 10% FCS, 2 mM
L-glutamine, 100 units penicillin/ml, and 100 µg of
streptomycin/ml. RENCA cells were cultured in a humidified atmosphere
of 95% air and 5% carbon dioxide at 37°C. Media were routinely
changed every 3 days. Cells were released from the tissue flasks by
treatment with 0.05% (versene) trypsin/EDTA, and viability was
monitored using the cell analyzer system Casy 1 from Schärfe
System (Reutlingen, Germany). For the experiments, cells were collected
during logarithmic growth phase.
Animal Experiments.
All experiments were carried out according to the guidelines
of the Ethical Committee of the Regierungspräsidium (Freiburg,
Germany). Female BALB/c mice were housed under controlled conditions
and were routinely used at 6–8 weeks of age (approximate weight,
20 g).
The injection of 106 RENCA cells in
0.2-ml aliquots into the subcapsular space of the left kidney was
performed through a flank incision after the animals were anesthetized
with 0.5–1.5 volume percent isoflurane, which is used in combination
with an oxygen flow of 1.5 l/min. The subcapsular renal injection of
106 RENCA cells in a syngeneic BALB/c mouse is
followed by the progressive development of a primary tumor mass in the
left kidney. One week after application, the primary tumor is
macroscopically visible; after 10 days, spontaneous metastases develop
in the regional lymph nodes, in the lung, the peritoneum, and the
liver, allowing the RENCA model to be staged similarly to human renal
cell carcinoma. The mean survival time of RENCA-bearing mice is 
32
days when 106 RENCA cells are injected.
Administration of Drugs.
Drug treatments with PTK787/ZK 222584 or TNP-470 were
initiated 1 day after tumor cell inoculation into the subcapsular space
of the left kidney. Mice received either PTK787/ZK 222584 (50 mg/kg
dihydrochloride, p.o. once daily) or TNP-470 (30 mg/kg, s.c. every
other day). Oral applications were performed using a gastric tube. The
dose for TNP-470 has been reported previously to be effective in the
RENCA model (10)
. The animals of the control groups
received either the vehicle for PTK787/ZK 222584, which was dissolved
in distilled water, or the vehicle for TNP-470, which had to be diluted
in 1 ml of 0.9% NaCl with 3% ethanol and 5% gum arabicum. The
vehicles were applied in the same way as the drug formulations. Animal
weights were taken every other day.
Evaluation of Tumors.
Two or 3 weeks after starting treatment, 6 or 10 mice,
respectively, were sacrificed in each group for determination of weight
and volume of primary tumors, weight, and number of metastasis of the
lung and metastasis formation in the abdominal lymph nodes. Volumes of
primary tumors were taken macroscopically by taking and multiplying the
distances of all three dimensions. Number of metastases in the lung and
abdominal lymph nodes were counted using a dissection microscope. In
the abdominal cave, all visible lymph nodes were counted for detection
of metastasis, knowing that in healthy animals visible lymph nodes are
usually absent. Random lymph nodes were inspected microscopically and
confirmed tumor-bearing material.
Immunohistochemistry.
For histological examination of the tumor vasculature, the
tumor tissues and lungs of all groups were quickly frozen in liquid
nitrogen. Cryosections of the tissues at a thickness of 5–10 µm were
taken from both treatment groups and control groups. For the
visualization of the blood vessels, immunohistochemical staining for
CD31 (PECAM-1 and MEC13.3; PharMingen, San Diego, CA) was
performed, and vessels were counted microscopically using a defined
magnification. For all sections, counting was done in three different
parts of the sections, with each section being counted twice. The
evaluation was performed by two persons, without knowledge of the
animal treatment.
Color Doppler Imaging Studies.
To determine whether PTK787/ZK 222584 influences blood flow in
afferent vessels to the primary tumor, color Doppler imaging ultrasound
technique was used in the RENCA model. Drug treatment was initiated 1
day after tumor cell inoculation into the subcapsular space of the left
kidney. Mice received either PTK787/ZK 222584 (50 mg/kg, p.o. once
daily) or vehicle. Ten animals were used for each group. Twenty days
after tumor cell inoculation, primary tumors were located in all
animals using a sonograph (Kranzbühler GE, Logic 700,
München, Germany) with direct-contact, high-frequency ultrasound
transducer. By color imaging, the left renal artery was detected, and
measurements on systolic and diastolic blood flow and resistance index
were performed. To rule out a systemic effect of PTK787/ZK 222584,
blood flow was also determined in the abdominal aorta. Measurements of
the heart rate were also performed.
Statistical Analysis.
For statistical evaluation of the data, the Mann-Whitney
t test was significant at a level of P < 0.05. To determine whether the detected changes in blood flow
in the left renal artery of RENCA mice treated with PTK787/ZK 222584
correlated with the changes in primary tumor volume or the changes in
microvessel density of primary tumors, the Spearmans coefficient of
rank correlation [rs = 1 - 6 
Di2/(n3
- n)] was calculated. A correlation coefficient
>0.514 was considered significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PTK787/ZK 222584 was well tolerated in all of the experiments and had no significant effects on body weight or general well-being of the animals (data not shown). One of six animals in the group treated with PTK787/ZK 222584 for 14 days and one of six animals in the group receiving vehicle for 14 days died because of tumor burden. In the groups planned to be sacrificed 21 days after inoculation of the cells, 8 of 10 animals in each group reached the end point. Two animals in both groups had to be sacrificed earlier because of tumor burden.
The primary tumor volume in the left kidney of the PTK787/ZK
222584 treatment group was compared with the volume of primary tumors
in the control group. Treatment with PTK787/ZK 222584 for 14 days
resulted in 61% (P < 0,07) inhibition of
primary tumor growth; this effect reached statistical significance
after 21 days of treatment by showing a reduction of 67%
(P < 0.01; Fig. 1
). The effect of PTK787/ZK 222584 on lung metastases was assessed by
comparing the number of lung metastases in treated animals with those
in untreated animals. Here, treatment with PTK787/ZK 222584 resulted in
98% (P < 0.0001) decrease of the number of
lung metastases after 14 days and 78% (P < 0.007) decrease after 21 days showing high significance (Fig. 1)
.
Visible lymph nodes were detectable after 14 days in untreated animals
only. Only one of six animals that had been treated with PTK787/ZK
222584 developed visible lymph nodes. In the group of animals
sacrificed 21 days after inoculation of the RENCA cells, treatment with
PTK787/ZK 222584 resulted in a highly significant reduction in lymph
node metastases of 87.4% (P < 0.01; Fig. 1
).
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shows the macroscopic pictures of examples of the different tumor
responses under treatment with PTK787/ZK 222584. Fig. 2A
represents the group of untreated animals, whereas Fig. 2B
represents the group of animals treated with PTK787/ZK 222584. In Fig. 2
B, the tumor with lowest response is located on
top, and the tumor with best response is located at the
bottom. From these macroscopic pictures, it is obvious that
the tumors of the control group were very homogeneous, whereas the
treatment group shows substantial variation. In Fig. 3
, the macroscopic pictures of examples of lung metastases are shown. The
high amount of metastases in the control group (Fig. 3A)
resulted in lung edemas, which were obviously avoided in the group of
animals treated with PTK787/ZK 222584 (Fig. 3B)
.
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In the experiments with TNP-470, a reduction in primary tumor
volume of 58% (P < 0.1) after 14 days and
66% (P < 0.3) after 21 days of RENCA cell
inoculation was not significant (Fig. 4)
. The effect of TNP-470 on lung metastases was assessed by comparing
the number of lung metastases in treated animals with those in
untreated animals. Treatment with TNP-470 resulted in a significant
decrease of 70% (P < 0.05) after 14 days
and a decrease of 35% (P < 0.2) after 21
days, which was not significant (Fig. 4)
. The 58%
(P < 0.1) reduction of visible lymph nodes
in the treated animals at the 14-day time point was not significant. In
the group of animals sacrificed 21 days after inoculation of the RENCA
cells, the number of visible lymph nodes was significantly reduced by
71% (P < 0.02; Fig. 4
).
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. Evaluation of the histological pictures revealed a significant
decrease of vessel density of 61% (P < 0.007) in primary tumors of animals treated for 14 days with PTK787/ZK
222584 and of 38% (P < 0.02) in the group
of animals treated for 21 days (Fig. 6)
. In two of six animals treated with PTK787/ZK 222584 for 14 days, no
lung metastases could be detected. Histological examination of blood
vessels in the lung metastases of the remaining four animals revealed a
significant reduction of vessel density of 36% (P < 0.02; Fig. 6
). Lung metastases in the group for 21 days showed
also a significant reduction of vessel density of 60%
(P < 0.05; Fig. 6
). It is noteworthy that in
mice treated with vehicle only, fewer vessels in primary tumors could
be detected after 3 weeks as compared with 2 weeks of tumor growth
(Fig. 6)
. The vessel density decreased significantly by 48%
(P < 0.01).
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Blood Flow Changes under PTK787/ZK 222584 Treatment.
To evaluate whether the decrease in vessel density
induced by PTK787/ZK 222584 affected blood flow in afferent tumor
vessels, the color Doppler imaging ultrasound technique was used.
Twenty days after tumor cell inoculation, primary tumors could be
located by sonography in all animals (n = 20;
Fig. 7A
). The resolution of the sonographic image allowed a
distinction between the kidney, which showed a hydronephrosis, and the
surrounding primary tumor. Color imaging was used to locate the left
renal artery, which could be detected reproducibly in all animals (Fig. 7B)
. The measurements of blood flow and resistance index in
the left renal artery were performed by Doppler technique, resulting in
a flow-time curve (Fig. 7C)
, which gives information on
systolic blood flow (cm/s), diastolic blood flow (cm/s), resistance
index, and heart rate (beats/min). A highly significant difference
between control group (n = 10) and PTK787/ZK
222584-treated animals (n = 10) could be
detected for systolic (inhibition of 60%; P < 0.01) and diastolic (inhibition of 58.7%;
P < 0.006) blood flow (Fig. 8)
. The resistance index and the heart rate were not affected by
PTK787/ZK 222584 (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Because of its excellent bioavailability, this low molecular synthetic molecule was administered p.o. at a dose of 50 mg/kg body weight (13) . This dose was shown previously to be active in a VEGF-driven in vivo angiogenesis model (A431 alginate beads model), as well as in rodent tumor models like A431 epithelial carcinoma, Ls174T colon carcinoma, HT-29 colon carcinoma, PC-3 prostate carcinoma, DU145 prostate carcinoma, and CWR-22 prostate carcinoma (9) . In all our experiments, daily treatment was initiated 1 day after inoculation of the RENCA cells to the lower pole of the left kidney and resulted in a significant reduction of primary tumor growth of 61% after 14 days and 67% after 21 days. An even more pronounced inhibition was observed for the development of metastases to the lung (98 and 78%, respectively) and to the abdominal lymph nodes (97.4%) after 21 days. The antitumoral effects of PTK787/ZK 222584 are very likely attributable to the inhibition of blood vessel formation because a significant decrease of vessel density in primary tumors as well as in metastases of the lung was observed. The application of PTK787/ZK 222584 was well tolerated in all animals. Control animals with high tumor burden, treated with vehicle only, lost weight. This effect could be prevented by treatment with PTK787/ZK 222584. In contrast, treatment with TNP-470 resulted in severe weight loss and ataxia, as described previously in other studies (14 , 15) and in clinical trials (16, 17, 18) . Therefore, application of TNP-470 had to be discontinued after 13 days of treatment, which probably accounts for the poor significance in reduction in primary tumor volume and number of metastases.
Interestingly, in all untreated animals we found a lower vessel density in tumors 3 weeks after inoculation as compared with 2 weeks after inoculation. This may be because of the high proliferation rate of murine tumor cells. We hypothesize that the proliferation rate of RENCA cells is superior to the proliferation rate of endothelial cells, resulting in decreasing vessel density in this fast-growing tumor. Even greater antitumor efficacy with PTK787/ZK 222584 might be obtained with slower growing tumors, and future studies will address this question.
Our finding, that a well-tolerated, selective inhibitor of VEGF-receptors has potent antitumor and antiangiogenic activity after oral application, suggests the therapeutic properties of PTK787/ZK 222584. The selective inhibition of VEGF-driven angiogenesis avoids side effects of conventional chemotherapy. This needs to be confirmed in clinical trials. A murine renal cell carcinoma, which closely simulates the human disease, indicates that renal cell carcinoma will be an appropriate indication for clinical studies with PTK787/ZK 222584.
Currently, determination of vessel density in human
tumors can only be done in biopsies or by angiography. Noninvasive
methods to detect vessel density changes under therapy, like dynamic
magnetic resonance imaging or sonography, are therefore needed for
ongoing clinical studies with promising antiangiogenic substances
(19)
. Therefore, we investigated whether a color Doppler
imaging ultrasound technique could be used to monitor blood flow in the
renal artery feeding the tumor, as a potential surrogate for vessel
density. Comparisons of systolic and diastolic blood flow in
vehicle-treated animals and PTK787/ZK 222584-treated animals revealed a
highly significant decrease of blood flow in the treated animals. The
blood flow was decreased by 60% as compared with untreated animals.
Resistance index and heart rate were not affected. A systemic effect of
the compound is unlikely because blood flow and resistance index in the
abdominal aorta remained unchanged. Changes in blood flow were found to
significantly correlate with vessel density but not with tumor volume.
Because our observation from the histological staining shows a
homogeneous distribution of vessels throughout the tumor tissue with
the lack of hot spots, these findings underline the above-made
hypothesis that in fast-growing tumors such as RENCA, the proliferation
rate of tumor cells is superior to the proliferation rate of
endothelial cells, resulting in a partially angiogenesis-independent
growth of tumor. Nonetheless, blood flow could be an indirect measure
of vessel density in the tumor in the case of one major tumor feeding
vessel. The use of blood flow measurements in primary breast tumors in
patients to differentiate between benign and malignant lesions supports
this hypotheses (20)
.
Our experiments show that selective inhibition of VEGF-Rs by PTK787/ZK 222584 leads to inhibition of primary tumor growth and development of metastases in murine renal cell carcinoma. This effect correlates with a reduction of vessel density in the primary tumor as well as in metastases. In contrast to TNP-470, an antiangiogenic substance with an unknown mode of action, or to cytotoxic substances (21) , PTK787/ZK 222584 caused no obvious side effects in the RENCA model. Furthermore, we demonstrated that changes in vessel density of tumor tissue correlate with blood flow in one major tumor feeding vessel. This suggests that color Doppler imaging might be an attractive, noninvasive method for indirect detection of vessel density in clinical studies.
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FOOTNOTES |
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1 This work has been supported by Novartis Pharma
AG, Basel, Switzerland; Schering AG Berlin, Germany; Kranzbühler
GE, Munich, Germany; and Kirstins Weg, Neuwied, Germany. 
2 To whom requests for reprints should be
addressed, at Tumor Biology Center, Department of Medical Oncology,
Breisacher Strasse 117, D-079106 Freiburg, Germany. Phone:
49-761-206-2178; Fax: 49-761-206-2180; E-mail: drevs{at}tumorbio.uni-freiburg.de
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; VEGF-R, VEGF-receptor; PTK787/ZK 222584,
1-[4-chloroanilino]-4-[4-pyridylmethyl].
Received 11/ 3/99. Accepted 6/30/00.
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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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W. P. J. Leenders, B. Kusters, K. Verrijp, C. Maass, P. Wesseling, A. Heerschap, D. Ruiter, A. Ryan, and R. de Waal Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option Clin. Cancer Res., September 15, 2004; 10(18): 6222 - 6230. [Abstract] [Full Text] [PDF]
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W. G. Kaelin Jr. The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer Clin. Cancer Res., September 15, 2004; 10(18): 6290S - 6295S. [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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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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 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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 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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L. Sepp-Lorenzino, E. Rands, X. Mao, B. Connolly, J. Shipman, J. Antanavage, S. Hill, L. Davis, S. Beck, K. Rickert, et al. A Novel Orally Bioavailable Inhibitor of Kinase Insert Domain-Containing Receptor Induces Antiangiogenic Effects and Prevents Tumor Growth in Vivo Cancer Res., January 15, 2004; 64(2): 751 - 756. [Abstract] [Full Text] [PDF]
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 M. El-Mousawi, L. Tchistiakova, L. Yurchenko, G. Pietrzynski, M. Moreno, D. Stanimirovic, D. Ahmad, and V. Alakhov A Vascular Endothelial Growth Factor High Affinity Receptor 1-specific Peptide with Antiangiogenic Activity Identified Using a Phage Display Peptide Library J. Biol. Chem., November 21, 2003; 278(47): 46681 - 46691. [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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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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W. G. Kaelin Jr. The von Hippel-Lindau Gene, Kidney Cancer, and Oxygen Sensing J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2703 - 2711. [Abstract] [Full Text] [PDF]
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F. Denis, S. Colas, L. Chami, P. Louisot, O. le Floch, F. Tranquart, and P. Bougnoux Changes in Tumor Vascularization after Irradiation, Anthracyclin, or Antiangiogenic Treatment in Nitrosomethyl Ureas-Induced Rat Mammary Tumors Clin. Cancer Res., October 1, 2003; 9(12): 4546 - 4552. [Abstract] [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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Y. Saishin, Y. Saishin, K. Takahashi, M.-S. Seo, M. Melia, and P. A. Campochiaro The Kinase Inhibitor PKC412 Suppresses Epiretinal Membrane Formation and Retinal Detachment in Mice with Proliferative Retinopathies Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3656 - 3662. [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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 S. Sengupta, E. Gherardi, L. A. Sellers, J. M. Wood, R. Sasisekharan, and T.-P. D. Fan Hepatocyte Growth Factor/Scatter Factor Can Induce Angiogenesis Independently of Vascular Endothelial Growth Factor Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 69 - 75. [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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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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G. C. Jayson, J. Zweit, A. Jackson, C. Mulatero, P. Julyan, M. Ranson, L. Broughton, J. Wagstaff, L. Hakannson, G. Groenewegen, et al. Molecular Imaging and Biological Evaluation of HuMV833 Anti-VEGF Antibody: Implications for Trial Design of Antiangiogenic Antibodies J Natl Cancer Inst, October 2, 2002; 94(19): 1484 - 1493. [Abstract] [Full Text] [PDF]
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B. Lin, K. Podar, D. Gupta, Y.-T. Tai, S. Li, E. Weller, T. Hideshima, S. Lentzsch, F. Davies, C. Li, et al. The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Inhibits Growth and Migration of Multiple Myeloma Cells in the Bone Marrow Microenvironment Cancer Res., September 1, 2002; 62(17): 5019 - 5026. [Abstract] [Full Text] [PDF]
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 J. Holash, S. Davis, N. Papadopoulos, S. D. Croll, L. Ho, M. Russell, P. Boland, R. Leidich, D. Hylton, E. Burova, et al. VEGF-Trap: A VEGF blocker with potent antitumor effects PNAS, August 20, 2002; 99(17): 11393 - 11398. [Abstract] [Full Text] [PDF]
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P. Lee, K. Goishi, A. J. Davidson, R. Mannix, L. Zon, and M. Klagsbrun Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish PNAS, August 6, 2002; 99(16): 10470 - 10475. [Abstract] [Full Text] [PDF]
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J. Drevs, R. Muller-Driver, C. Wittig, S. Fuxius, N. Esser, H. Hugenschmidt, M. A. Konerding, P. R. Allegrini, J. Wood, J. Hennig, et al. PTK787/ZK 222584, a Specific Vascular Endothelial Growth Factor-Receptor Tyrosine Kinase Inhibitor, Affects the Anatomy of the Tumor Vascular Bed and the Functional Vascular Properties as Detected by Dynamic Enhanced Magnetic Resonance Imaging Cancer Res., July 15, 2002; 62(14): 4015 - 4022. [Abstract] [Full Text] [PDF]
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D. O. Bates, T.-G. Cui, J. M. Doughty, M. Winkler, M. Sugiono, J. D. Shields, D. Peat, D. Gillatt, and S. J. Harper VEGF165b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Is Down-Regulated in Renal Cell Carcinoma Cancer Res., July 15, 2002; 62(14): 4123 - 4131. [Abstract] [Full Text] [PDF]
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H. Goto, S. Yano, H. Zhang, Y. Matsumori, H. Ogawa, D. C. Blakey, and S. Sone Activity of a New Vascular Targeting Agent, ZD6126, in Pulmonary Metastases by Human Lung Adenocarcinoma in Nude Mice Cancer Res., July 1, 2002; 62(13): 3711 - 3715. [Abstract] [Full Text] [PDF]
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 B. S. Conklin, W. Zhao, D.-S. Zhong, and C. Chen Nicotine and Cotinine Up-Regulate Vascular Endothelial Growth Factor Expression in Endothelial Cells Am. J. Pathol., February 1, 2002; 160(2): 413 - 418. [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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J. Ma, S. Pulfer, S. Li, J. Chu, K. Reed, and J. M. Gallo Pharmacodynamic-mediated Reduction of Temozolomide Tumor Concentrations by the Angiogenesis Inhibitor TNP-470 Cancer Res., July 1, 2001; 61(14): 5491 - 5498. [Abstract] [Full Text] [PDF]
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D. J. George, S. Halabi, T. F. Shepard, N. J. Vogelzang, D. F. Hayes, E. J. Small, and P. W. Kantoff Prognostic Significance of Plasma Vascular Endothelial Growth Factor Levels in Patients with Hormone-refractory Prostate Cancer Treated on Cancer and Leukemia Group B 9480 Clin. Cancer Res., July 1, 2001; 7(7): 1932 - 1936. [Abstract] [Full Text] [PDF]
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M. Yang, E. Baranov, X.-M. Li, J. W. Wang, P. Jiang, L. Li, A. R. Moossa, S. Penman, and R. M. Hoffman Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors PNAS, February 27, 2001; 98(5): 2616 - 2621. [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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I. Iordanescu, C. Becker, B. Zetter, P. Dunning, and G. A. Taylor Tumor Vascularity: Evaluation in a Murine Model with Contrast-enhanced Color Doppler US—Effect of Angiogenesis Inhibitors Radiology, February 1, 2002; 222(2): 460 - 467. [Abstract] [Full Text] [PDF]
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) with means of the control group (
)
using the Mann Whitney t test. *, significant.
