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Experimental Therapeutics |
Departments of Cancer and Infection Research [S. R. W., D. J. O., M. D., J. K., J. O. C., B. C., A. P. T., E. S. E. S.] and Safety of Medicines [G. H. P. R., P. F. W.], AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom, and AstraZeneca Pharma, Centre de Recherches, 51064 Reims, France [L. F. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.5 cm3) human tumor
xenografts (breast, lung, prostate, and ovarian) elicited significant
antitumor activity and at doses that would not be expected to have any
direct antiproliferative effect on tumor cells. Prolonged tumor
cytostasis was further demonstrated in a PC-3 xenograft model with 10
weeks of ZD4190 dosing, and upon withdrawal of therapy, tumor growth
resumed after a short delay. These observations are entirely consistent
with the proposed mode of action. ZD4190 is one of a series of VEGF RTK
inhibitors that may have utility in the treatment of a range of
histologically diverse solid tumor types. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Diverse stimuli are suggested to elevate VEGF expression, including many growth factors and cytokines, such as platelet-derived growth factor, transforming growth factor ß, and interleukin 6 (16, 17, 18) , glucose deprivation (19) , proto-oncogene activation (20, 21, 22, 23) , and the loss of tumor suppressor function (24) . Rapid increases in VEGF expression also accompany the onset of hypoxia, which frequently arises in solid tumors because of inadequate perfusion. This hypoxic response is known to involve both transcriptional activation and stabilization of the VEGF mRNA (25 , 26) .
Two high-affinity receptors for VEGF with associated tyrosine
kinase activity have been identified on human vascular endothelium:
Flt-1 and KDR. Except for expression of Flt-1 on monocyte/macrophage
lineages (27)
, pericytes (28)
, and smooth
muscle cells (29)
, the receptors are endothelial specific
and preferentially expressed at sites of active angiogenesis
(30)
. The binding of VEGF as a disulfide-linked homodimer
stimulates receptor dimerization (31)
and activation of
the RTK domain. The kinase autophosphorylates cytoplasmic receptor
tyrosine residues, which then serve as binding sites for molecules
involved in the propagation of a signaling cascade. Although multiple
pathways are likely to be elucidated for both receptors, KDR signaling
is most extensively studied, with a mitogenic response suggested to
involve ERK-1 and ERK-2 mitogen-activated protein kinases
(32)
, largely through activation of a
PLC-
-PKC-Raf-1-MEK (33)
, and cellular motility
attributed to activation of the mitogen-activated protein kinase p38
and/or tyrosine phosphorylation of focal adhesion kinase and paxillin
(34
, 35)
.
Disruption of VEGF receptor signaling is a highly attractive therapeutic target, given the specificity of receptor expression, that angiogenesis is a prerequisite for all macroscopic solid tumor growth, and that the mature endothelium remains comparatively quiescent (with the exception of the female reproductive system and wound healing). A number of experimental approaches to inhibiting VEGF signal transduction have been examined, including use of neutralizing antibodies (36, 37, 38) , receptor antagonists (39) , soluble receptors (40) , antisense constructs (41) , dominant-negative strategies (42) , and ribozymes (43) . However, because continual abrogation of the VEGF pathway in tumor endothelium is likely to be required to constrain tumor growth, we aimed to produce a therapy compatible with chronic oral administration.
We have identified ZD4190, a novel p.o.-active tyrosine kinase inhibitor, and investigated its activity in vitro and in vivo. The results obtained are consistent with VEGF signaling blockade.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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was synthesized as described by Hennequin et al.
(44)
. RTKs used in isolated enzyme assays were lysates
from insect cells infected with recombinant baculoviruses containing
cytoplasmic receptor domains. VEGF165 and bFGF
were similarly prepared using S. frugiperda
21 insect cells and Escherichia coli strain
BL21(DE3)pLysS, respectively, and purified using a heparin-Sepharose
column.3
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Inhibition of Growth Factor-mediated HUVEC Proliferation
HUVEC proliferation in the presence and absence of growth factors
was evaluated using [3H]thymidine incorporation
(44)
. Briefly, HUVECs isolated from umbilical cords were
plated (at passages 2–8) in 96-well plates (1000 cells/well) and dosed
with ZD4190 ± VEGF (3 ng/ml) or bFGF (0.3 ng/ml). The
cultures were then incubated for 4 days (37°C; 7.5%
CO2). On day 4, the cultures were pulsed with 1
µCi/well of [3H]thymidine (Amersham) and
reincubated for 4 h. The cells were then harvested and assayed for
the incorporation of tritium using a beta counter.
IC50 data were interpolated as described above.
Tumor Cell Lines.
Four human tumor cell lines were used: PC-3 (prostate
adenocarcinoma), Calu-6 (lung carcinoma), MDA-MB-231 (mammary gland
adenocarcinoma), and SKOV-3 (ovarian adenocarcinoma), each of which
were obtained from the American Type Culture Collection (Manassas, VA).
All cell culture reagents, where not specified, were obtained from Life
Technologies, Inc. (Paisley, United Kingdom). Cells were maintained as
exponentially growing monolayers in the following media containing 10%
FCS (Labtech International, Ringmer, United Kingdom) and 2
mM L-glutamine (Sigma Chemical Co., Poole,
United Kingdom): PC-3 in Iscove’s Modified Dulbecco’s Medium;
Calu-6 in Eagle’s Minimal Essential Medium with 1% sodium
pyruvate (100 mM) and 1% non-essential amino acids;
MDA-MB-231 in DMEM; and SKOV-3 in Ham’s F12. Cell lines were
periodically screened for the presence of Microplasma in
culture and analyzed for 15 types of virus in a mouse antibody
production test (AstraZeneca Central Toxicology Laboratories, Alderley
Park, United Kingdom) prior to routine use in vivo.
Cytotoxicity Assay
Cells were plated in their respective media at predetermined
densities that were known to enable logarithmic cell growth during the
period of assay (PC-3 at 500 cells/well; all others at 1000
cells/well). Plates were incubated for 24 h (37°C; 7.5%
CO2) prior to the addition of ZD4190 (0.1–100
µM) or vehicle (0.1% DMSO in medium), and reincubated
for an additional 72 h. Cell proliferation was assessed by
[3H]thymidine incorporation as described in
HUVEC experiments.
Epiphyseal Growth Plate Hypertrophy Studies
For all in vivo work, ZD4190 was suspended in a 1%
(v/v) solution of polyoxyethylene (20)
sorbitan
mono-oleate in deionized water and administered by oral gavage. Young
female Alderley Park rats (Wistar derived, 150 g in weight, 4–8
weeks of age) were dosed daily for 14 days with ZD4190 (at 0.25 ml/100
g body weight) or vehicle. Histological paraffin wax sections of the
femoro-tibial joints were produced by standard histological techniques
and stained with H&E. The sections were examined by light microscopy,
and the area of the epiphyseal growth plate was measured using
morphometric image analysis (Joyce-Loebl Magiscan Image Analyser;
Applied Imaging Ltd.).
Tumor Xenograft Models
Female Swiss athymic (nu/nu genotype) mice were bred
and maintained at Alderley Park in negative pressure isolators (PFI
Systems Ltd., Oxon, United Kingdom). Mice were housed in a barrier
facility with 12-h light/dark cycles and provided with sterilized food
and water ad libitum. All procedures were performed on mice
of at least 8 weeks of age. PC-3, Calu-6, and SKOV-3 tumor xenografts
were established in the hind flank by s.c. injection of 1 x 106 cells in 100 µl of 50:50 Matrigel
(Fred Baker, Liverpool, United Kingdom) and the relevant serum-free
media. MDA-MB-231 tumor xenografts were initially established by
implantation of 1 x 107 cells in
serum-free DMEM, and cubic tumor fragments of 0.5–1
mm3 diameter were implanted for therapy
experiments in mice receiving 100 µg of estradiol benzoate the day
before tumor implant and an additional 50 µg at weekly intervals (50
µl, s.c.). Mice were randomized into groups of 10 prior to treatment
at a point when tumors reached a volume of 0.3–0.55
cm3. Mice then received either ZD4190 or vehicle,
administered once-daily at 0.1 ml/10 g body weight. Tumor volume was
assessed twice weekly by bilateral Vernier caliper measurement, using
the formula (length x width) x 
(length x
width) x (
/6), where length was the longest diameter across
the tumor, and width was the corresponding perpendicular. Growth
inhibition from the start of treatment was calculated by comparison of
the mean change in tumor volume for the control and treated groups, and
statistical significance between the two groups was evaluated using a
one-tailed t test. Linear regression analysis of
log-transformed xenograft data was used to estimate the control tumor
doubling time.
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RESULTS |
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. Selectivity versus FGFR1 tyrosine kinase activity was
demonstrated, with at least a 30-fold difference in the
IC50 required to inhibit HUVEC proliferation
stimulated by VEGF or bFGF, respectively. No effects on basal HUVEC
growth were observed, even at the maximum ZD4190 concentration examined
in these assays (10 µM). Collectively, these
data suggest that the ability of ZD4190 to inhibit VEGF-stimulated
proliferation in endothelial cells at only 50 nM
is via a specific effect on KDR or Flt-1-mediated signal transduction.
IC50s for the inhibition of tumor cell growth
in vitro were found to be >25 µM in
each cell line examined.
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; increases of 22, 75, and 182% were evident after treatment with 15,
50, and 150 mg/kg/day ZD4190, respectively.
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. Treatment with 100 mg/kg/day of ZD4190 for 21 days conferred between
a 79 and 95% inhibition of tumor growth, and statistically significant
effects on tumor growth (one-tailed t test) were evident in
two xenograft models (Calu-6 and PC-3) with only 12.5 mg/kg/day ZD4190
(Table 2)
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. When therapy was withdrawn, tumor growth resumed at a rate comparable
with that of controls after a lag period of 10 days.
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DISCUSSION |
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The initial selection of ZD4190 for further preclinical evaluation was in part driven by the fact that it possessed pharmacokinetic properties compatible with chronic oral dosing. This criterion was seen as necessary to satisfy the perceived clinical requirements of an antiangiogenic compound (i.e., chronic for continual inhibition of tumor angiogenesis and once-daily oral administration for patient convenience and compliance). A retrospective analysis of acute plasma pharmacokinetic data and antitumor data in the Calu-6 xenograft model (after oral administration) indicated that for a series of 50 substituted 4-anilinoquinazolines with a similar in vitro profile, greatest antitumor activity correlated with sustained plasma levels of compound (>0.5 µM at 24 h) rather than total area under the plasma concentration versus time curve or peak plasma levels (data not shown). This correlation was not merely a consequence of compound accumulation on repeat dosing, suggesting that sustained inhibition of VEGF signaling is indeed required for optimal therapeutic effect in a human tumor xenograft model.
ZD4190 produced a dose-dependent increase in the femoral epiphyseal growth plate in growing rats, which is consistent with an ability to inhibit VEGF signaling and elicit an antiangiogenic effect in vivo. Angiogenesis is an essential event in endochondral ossification during long bone elongation (46) , and vascular invasion of the growth plate has been suggested to depend upon VEGF production by hypertrophic chondrocytes (47) . Expansion of the hypertrophic chondrocyte zone and inhibition of angiogenesis have also been demonstrated recently after treatment with agents that specifically sequester VEGF (45 , 48) . It is possible that in addition to direct effects on endothelial cell biology, the inhibition of VEGF signaling may also partly influence osteogenic remodeling through direct or indirect effects on osteoblast, chondrocyte, and chondroclast function (45) .
Daily oral administration of ZD4190 was found to impart significant antitumor activity in histologically diverse human tumor xenograft models. This activity is attributed to inhibition of VEGF signaling in the tumor vasculature and not to a direct antiproliferative effect on tumor cells. The inhibition of tumor cell proliferation by ZD4190 in vitro occurs at concentrations that are >500-fold greater than those required to inhibit VEGF-stimulated HUVEC proliferation (comparison of IC50s). ZD4190 was found to be 97.5 ± 0.5% (mean ± SE, n = 5) protein bound in mouse plasma, and the free drug exposure produced by oral administration of 100 mg/kg/day ZD4190 (the maximum dose examined) is less than that required to produce a direct antiproliferative effect on tumor cells in vitro (data not shown). Although only four tumor types were studied, a prototype compound was found to confer significant antitumor activity in each of nine different tumor models examined, including a rhabdomyosarcoma, fibrosarcoma, and vulval and colon carcinomas. Other approaches aimed at inhibiting VEGF signaling have also produced broad spectrum antitumor activity, including use of a VEGF antibody (49) , dominant-negative inhibition of KDR (42) , and a small molecular weight KDR RTK inhibitor dosed i.p. from the day of tumor implantation (50) . This broad-spectrum antitumor profile contrasts with that of tumor cell-directed therapies.
ZD4190 was found to be a significantly more potent (24-fold) inhibitor of KDR RTK activity in vitro than of that associated with Flt-1. KDR has a lower affinity for VEGF binding than Flt-1 but has been found to be more abundantly expressed on endothelial cells in culture (51 , 52) and has a much greater signaling capacity (53) . Although the relative contributions of KDR and Flt-1 signaling in mediating tumor progression have not been resolved, a number of studies suggest that KDR may perform a predominant role. A KDR blocking antibody has been shown to disrupt tumor angiogenesis and invasion in a human malignant keratinocyte model (54) , and activation of KDR alone with a selective agonist has been found to increase tumor vascularization and proliferation and induce angiogenesis in a corneal pocket assay (55) . The Orf virus-derived NZ-7 VEGF gene product (VEGF-E), which can only bind to KDR, has also been found to elicit an endothelial mitotic and vascular permeabilizing response comparable with that of native VEGF (56) , whereas placenta growth factor, which can only bind to Flt-1, has little appreciable effect on either (57) . VEGF-E also promotes endothelial cell migration and tubule formation in vitro and angiogenesis in the rabbit cornea (58) . In addition, vascular expression of KDR, but not Flt-1, has been found to be associated with the development of high-grade glioma (59) and metastatic colon carcinoma (60) .
Although ZD4190 may have some effect on Flt-1 signaling in vivo, it remains unclear as to whether inhibition of Flt-1 RTK activity would contribute significantly to the constraint of tumor angiogenesis. Experiments with deletion of the Flt-1 tyrosine kinase domain indicate that normal angiogenesis during development is not reliant on signaling from this receptor (61) . Homozygous Flt-1 gene deletion confers an embryo lethal phenotype that results from the abnormal assembly of vascular vessels (62) . Collectively, these studies suggest that Flt-1 may regulate matrix/vessel assembly in development through sequestration of VEGF. The role of Flt-1 signaling in endothelial cell migration is still equivocal (55 , 63) , although a confirmed functional role has been demonstrated in the promotion of monocyte/macrophage migration and tissue factor production (64 , 65) , the stimulation of pericyte mitogenesis and migration (28) , and the inhibition of functional dendritic cell maturation (66) . It is therefore conceivable that inhibition of these effects could provide additional therapeutic benefit by reducing macrophage-mediated thrombolytic events, preventing blood vessel stabilization, or increasing the capacity to direct an antitumor immune response (in an immunocompetent host), respectively.
It has been suggested that because endothelial cells are of a stable genetic background, they may be less likely to acquire resistance to an antiangiogenic therapy, which is a common failure of many tumor cell-directed treatments (67) . Prolonged dosing of ZD4190 to mice bearing PC-3 prostate tumor xenografts for 10 weeks was found to constrain tumor growth for the duration of dosing and was well-tolerated throughout. Regrowth of tumors after withdrawal of treatment was expected because removal of ZD4190 will enable tumor vasculature to respond to VEGF and thereby facilitate rapid tumor expansion through stimulation of angiogenesis.
Given that many factors have been suggested to have angiogenic activity, it is possible that alternative stimuli could eventually circumvent the constraint imposed by a VEGF signaling blockade. However, there is increasing evidence that VEGF may also function as a survival factor for newly formed vasculature (68 , 69) . This effect may be partly attributable to increased expression of the antiapoptotic protein Bcl-2 in endothelial cells, in response to VEGF (70) . It is possible therefore, that if VEGF does play a major role in enhancing neovascular survival, inhibition of VEGF signaling may confer a therapeutic advantage regardless of the initial angiogenic stimulus. In addition, the antitumor activity of ZD4190 in histologically disparate tumor types may partly be attributable to a common effect on tumor vascular permeability. Acute dosing of ZD4190 to mice bearing PC-3 tumors has been found to reduce vascular permeability in xenografts using contrast medium-enhanced magnetic resonance imaging and at doses that elicit antitumor activity during chronic administration (71) .
In comparison with the use of conventional cytotoxic agents, VEGF RTK inhibitors may provide a more tolerable cytostatic treatment with clinical utility in a wide range of solid tumor types, either as a monotherapy or in combination with radiation and/or additional chemotherapy. VEGF RTK inhibition may also have application in the treatment of other angiogenesis-dependent pathologies, such as rheumatoid arthritis (72) and diabetic retinopathy (73) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at AstraZeneca Pharmaceuticals, Mereside, Alderley Park,
Macclesfield, Cheshire, SK 10 4TG, United Kingdom. Phone:
44-1625-513236; Fax: 4-1625-516033. 
2 The abbreviations used are: VEGF, vascular
endothelial growth factor; ZD4190,
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]quinazolin-4-amine;
Flt-1, fms-like tyrosine kinase; bFGF, basic fibroblast growth factor;
KDR, kinase insert domain-containing receptor; FGFR, fibroblast growth
factor receptor; HUVEC, human umbilical vein endothelial cell; RTK,
receptor tyrosine kinase; PLC-, phospholipase Cy; PKC, protein
kinase C; MEK, mitogen-activated ERK kinase.
3 J. O. Curwen, C. Grundy, R. Davies, P. Elvin,
and D. J. Ogilvie. VEGF and bFGF induce blood pressure falls in
anesthetized rats which are mediated by their individual receptors and
are sensitive to the novel receptor tyrosine kinase inhibitors ZD4190
and ZM325473, submitted for publication.
Received 9/ 2/99. Accepted 12/15/99.
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REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
vß3 integrin, osteopontin, and thrombin. Am. J. Pathol., 149: 293-305, 1996.[Abstract]
1ß1 and 2ß2 integrins. Proc. Natl. Acad. Sci. USA, 94: 13612-13617, 1997.. Biochem. Biophys. Res. Commun., 238: 487-491, 1997.[Medline]
and migration of endothelial cells expressing Flt 1. Oncogene, 16: 359-367, 1998.[Medline]
B activation in hemopoietic progenitor cells. J. Immunol., 160: 1224-1232, 1998.This article has been cited by other articles:
|
|
 |
|
  K. F. Byth, A. Thomas, G. Hughes, C. Forder, A. McGregor, C. Geh, S. Oakes, C. Green, M. Walker, N. Newcombe, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts Mol. Cancer Ther., July 1, 2009; 8(7): 1856 - 1866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Morrison, S.-A. Ricketts, J. Barnett, A. Cuthbertson, J. Tessier, and S. R. Wedge Use of a Novel Arg-Gly-Asp Radioligand, 18F-AH111585, to Determine Changes in Tumor Vascularity After Antitumor Therapy J. Nucl. Med., January 1, 2009; 50(1): 116 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Lee, A. Lyshchik, J. Huamani, D. E. Hallahan, and A. C. Fleischer Relationship Between Retention of a Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)-Targeted Ultrasonographic Contrast Agent and the Level of VEGFR2 Expression in an In Vivo Breast Cancer Model J. Ultrasound Med., June 1, 2008; 27(6): 855 - 866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Cai and X. Chen Multimodality Molecular Imaging of Tumor Angiogenesis J. Nucl. Med., June 1, 2008; 49(Suppl_2): 113S - 128S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Frazier, R. Thomas, M. Scicchitano, R. Mirabile, R. Boyce, D. Zimmerman, E. Grygielko, J. Nold, A.-C. DeGouville, S. Huet, et al. Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats Toxicol Pathol, February 1, 2007; 35(2): 284 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Cai, K. Chen, K. A. Mohamedali, Q. Cao, S. S. Gambhir, M. G. Rosenblum, and X. Chen PET of Vascular Endothelial Growth Factor Receptor Expression J. Nucl. Med., December 1, 2006; 47(12): 2048 - 2056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Cai, J. Rao, S. S. Gambhir, and X. Chen How molecular imaging is speeding up antiangiogenic drug development. Mol. Cancer Ther., November 1, 2006; 5(11): 2624 - 2633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-D. Nguyen, S. Rodrigues, C. M. Rodrigue, C. Rivat, C. Grijelmo, E. Bruyneel, S. Emami, S. Attoub, and C. Gespach Inhibition of vascular endothelial growth factor (VEGF)-165 and semaphorin 3A-mediated cellular invasion and tumor growth by the VEGF signaling inhibitor ZD4190 in human colon cancer cells and xenografts. Mol. Cancer Ther., August 1, 2006; 5(8): 2070 - 2077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. P. Brown, C. L. Courtney, L. M. King, S. C. Groom, and M. J. Graziano Cartilage Dysplasia and Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase Inhibitor Toxicol Pathol, June 1, 2005; 33(4): 449 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Lloyd, B. M. Prior, H. Li, H. T. Yang, and R. L. Terjung VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H759 - H768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Nicholson, K. Gulding, M. Conaway, S. R. Wedge, and D. Theodorescu Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer: A Promising Therapeutic Approach Clin. Cancer Res., December 15, 2004; 10(24): 8728 - 8734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sun, M. A. Blaskovich, R. K. Jain, F. Delarue, D. Paris, S. Brem, M. Wotoczek-Obadia, Q. Lin, D. Coppola, K. Choi, et al. Blocking Angiogenesis and Tumorigenesis with GFA-116, a Synthetic Molecule that Inhibits Binding of Vascular Endothelial Growth Factor to its Receptor Cancer Res., May 15, 2004; 64(10): 3586 - 3592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Y. Ueda, T. Yamagishi, K. Samata, H. Ikeya, N. Hirayama, H. Takashima, S. Nakaike, M. Tanaka, and I. Saiki A novel low molecular weight antagonist of vascular endothelial growth factor receptor binding: VGA1155 Mol. Cancer Ther., November 1, 2003; 2(11): 1105 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Williams, C. Pettaway, R. Song, C. Papandreou, C. Logothetis, and D. J. McConkey Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts Mol. Cancer Ther., September 1, 2003; 2(9): 835 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. T. Ballock and R. J. O'Keefe The Biology of the Growth Plate J. Bone Joint Surg. Am., March 31, 2003; 85(4): 715 - 726. [Full Text] [PDF]
|
|
|
|
|
|
F. Carlomagno, D. Vitagliano, T. Guida, F. Ciardiello, G. Tortora, G. Vecchio, A. J. Ryan, G. Fontanini, A. Fusco, and M. Santoro ZD6474, an Orally Available Inhibitor of KDR Tyrosine Kinase Activity, Efficiently Blocks Oncogenic RET Kinases Cancer Res., December 15, 2002; 62(24): 7284 - 7290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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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S. R. Wedge, D. J. Ogilvie, M. Dukes, J. Kendrew, R. Chester, J. A. Jackson, S. J. Boffey, P. J. Valentine, J. O. Curwen, H. L. Musgrove, et al. ZD6474 Inhibits Vascular Endothelial Growth Factor Signaling, Angiogenesis, and Tumor Growth following Oral Administration Cancer Res., August 15, 2002; 62(16): 4645 - 4655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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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|
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C. L. Reimer, N. Agata, J. G. Tammam, M. Bamberg, W. M. Dickerson, G. D. Kamphaus, S. L. Rook, M. Milhollen, R. Fram, R. Kalluri, et al. Antineoplastic Effects of Chemotherapeutic Agents Are Potentiated by NM-3, an Inhibitor of Angiogenesis Cancer Res., February 1, 2002; 62(3): 789 - 795. [Abstract] [Full Text] [PDF]
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C. J. Kuo, F. Farnebo, E. Y. Yu, R. Christofferson, R. A. Swearingen, R. Carter, H. A. von Recum, J. Yuan, J. Kamihara, E. Flynn, et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer PNAS, March 22, 2001; (2001) 81615298. [Abstract] [Full Text]
|
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|
|
|
|
C. J. Kuo, F. Farnebo, E. Y. Yu, R. Christofferson, R. A. Swearingen, R. Carter, H. A. von Recum, J. Yuan, J. Kamihara, E. Flynn, et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer PNAS, April 10, 2001; 98(8): 4605 - 4610. [Abstract] [Full Text] [PDF]
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, 12.5 mg/kg/day; 
, 25 mg/kg/day;
, 50 mg/kg/day; 
, 100 mg/kg/day) or vehicle (
) on growth of
human tumor xenografts [(a) PC-3; (b)
Calu-6; (c) MDA-MB-231; and (d) SKOV-3].
Xenografts were established s.c. in athymic mice and allowed to reach a
volume of 0.3–0.55 cm3 prior to treatment. Oral once-daily
treatment with ZD4190 or vehicle then commenced and was continued for
the duration of the experiment. ZD4190 produced a dose-dependent
inhibition of tumor xenograft growth in each of the models examined.
Data points represent means for 10 mice, with errors being illustrated
in one direction; bars, SE.