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[Cancer Research 60, 2178-2189, April 15, 2000]
© 2000 American Association for Cancer Research

Experimental Therapeutics

PTK787/ZK 222584, a Novel and Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Impairs Vascular Endothelial Growth Factor-induced Responses and Tumor Growth after Oral Administration

Jeanette M. Wood1, Guido Bold, Elizabeth Buchdunger, Robert Cozens, Stefano Ferrari, Jörg Frei, Francesco Hofmann, Jürgen Mestan, Helmut Mett, Terence O’Reilly, Elke Persohn, Johannes Rösel, Christian Schnell, David Stover, Andreas Theuer, Harry Towbin, Fritz Wenger, Kathie Woods-Cook, Andreas Menrad, Gerhard Siemeister, Michael Schirner, Karl-Heinz Thierauch, Martin R. Schneider, Joachim Drevs, Georg Martiny-Baron, Frank Totzke and Dieter Marmé

Oncology Research, Novartis Pharma AG, CH-4002 Basel, Switzerland [J. M. W., G. B., E. B., R. C., S. F., J. F., F. H., J. M., H. M., T. O., E. P., J. R., C. S., D. S., A. T., H. T., F. W., K. W-C.]; Research Laboratories of Schering AG, D-13342 Berlin, Germany [A. M., G. S., M. S., K-H. T., M. R. S.]; and Institute of Molecular Medicine, Tumor Biology Center, D-79106 Freiburg, Germany [J. D., G. M-B., F. T., D. M.]

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor ß tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-{alpha}. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 µM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 µM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25–100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.




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G. Li, L. Tian, J.-m. Hou, Z.-y. Ding, Q.-m. He, P. Feng, Y.-j. Wen, F. Xiao, B. Yao, R. Zhang, et al.
Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors
Clin. Cancer Res., June 1, 2005; 11(11): 4217 - 4224.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S. R. Wedge, J. Kendrew, L. F. Hennequin, P. J. Valentine, S. T. Barry, S. R. Brave, N. R. Smith, N. H. James, M. Dukes, J. O. Curwen, et al.
AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer
Cancer Res., May 15, 2005; 65(10): 4389 - 4400.
[Abstract] [Full Text] [PDF]

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 JCOHome page
R. S. Herbst, A. Onn, and A. Sandler
Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications
J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
Y. Liu, R. T. Poon, Q. Li, T. W. Kok, C. Lau, and S. T. Fan
Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine Kinase Inhibitor PTK787/ZK222584
Cancer Res., May 1, 2005; 65(9): 3691 - 3699.
[Abstract] [Full Text] [PDF]

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 Postgrad. Med. J.Home page
K Gupta and J Zhang
Angiogenesis: a curse or cure?
Postgrad. Med. J., April 1, 2005; 81(954): 236 - 242.
[Abstract] [Full Text] [PDF]

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 JCOHome page
B. P. Schneider and K. D. Miller
Angiogenesis of Breast Cancer
J. Clin. Oncol., March 10, 2005; 23(8): 1782 - 1790.
[Full Text] [PDF]

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 The OncologistHome page
B. I. Rini
VEGF-Targeted Therapy in Metastatic Renal Cell Carcinoma
Oncologist, March 1, 2005; 10(3): 191 - 197.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Murga, O. Fernandez-Capetillo, and G. Tosato
Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2
Blood, March 1, 2005; 105(5): 1992 - 1999.
[Abstract] [Full Text] [PDF]

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 JCOHome page
G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher
Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions
J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311.
[Abstract] [Full Text] [PDF]

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 BloodHome page
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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 JCOHome page
B. I. Rini and E. J. Small
Biology and Clinical Development of Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma
J. Clin. Oncol., February 10, 2005; 23(5): 1028 - 1043.
[Abstract] [Full Text] [PDF]

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 JCOHome page
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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 Proc. Natl. Acad. Sci. USAHome page
M. Hagedorn, S. Javerzat, D. Gilges, A. Meyre, B. de Lafarge, A. Eichmann, and A. Bikfalvi
Accessing key steps of human tumor progression in vivo by using an avian embryo model
PNAS, February 1, 2005; 102(5): 1643 - 1648.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
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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 J Biomol ScreenHome page
R. L. Yauch, E. E. Kadel III, C. Nicholas, S. Tetangco, and D. O. Clary
Transcriptional-Based Screens for Pathway-Specific, High-Throughput Target Discovery in Endothelial Cells
J Biomol Screen, December 1, 2004; 9(8): 704 - 711.
[Abstract] [PDF]

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 Pharmacol. Rev.Home page
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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 Molecular Cancer TherapeuticsHome page
K. Nakamura, A. Yamamoto, M. Kamishohara, K. Takahashi, E. Taguchi, T. Miura, K. Kubo, M. Shibuya, and T. Isoe
KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth
Mol. Cancer Ther., December 1, 2004; 3(12): 1639 - 1649.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al.
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis
Cancer Res., October 1, 2004; 64(19): 7099 - 7109.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
G. Bocci, S. Man, S. K. Green, G. Francia, J. M. L. Ebos, J. M. du Manoir, A. Weinerman, U. Emmenegger, L. Ma, P. Thorpe, et al.
Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies
Cancer Res., September 15, 2004; 64(18): 6616 - 6625.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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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 Clin. Cancer Res.Home page
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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 Mol. Pharmacol.Home page
S. Emanuel, R. H. Gruninger, A. Fuentes-Pesquera, P. J. Connolly, J. A. Seamon, S. Hazel, R. Tominovich, B. Hollister, C. Napier, M. R. D'Andrea, et al.
A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models
Mol. Pharmacol., September 1, 2004; 66(3): 635 - 647.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
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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 Cancer Res.Home page
D. Zingg, O. Riesterer, D. Fabbro, C. Glanzmann, S. Bodis, and M. Pruschy
Differential Activation of the Phosphatidylinositol 3'-Kinase/Akt Survival Pathway by Ionizing Radiation in Tumor and Primary Endothelial Cells
Cancer Res., August 1, 2004; 64(15): 5398 - 5406.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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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 The OncologistHome page
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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 Am. J. Physiol. Cell Physiol.Home page
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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 BloodHome page
S. Langlois, D. Gingras, and R. Beliveau
Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation
Blood, April 15, 2004; 103(8): 3020 - 3028.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
K. D. Burman
A New Paradigm in the Treatment of Carcinoma: Specific Molecular Targeting
Endocrinology, March 1, 2004; 145(3): 1027 - 1030.
[Full Text] [PDF]

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 EndocrinologyHome page
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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 Clin. Cancer Res.Home page
M. Zangari, E. Anaissie, A. Stopeck, A. Morimoto, N. Tan, J. Lancet, M. Cooper, A. Hannah, G. Garcia-Manero, S. Faderl, et al.
Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma
Clin. Cancer Res., January 1, 2004; 10(1): 88 - 95.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
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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 Cancer Res.Home page
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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 JCOHome page
L. M. Ellis
Antiangiogenic Therapy: More Promise and, Yet Again, More Questions
J. Clin. Oncol., November 1, 2003; 21(21): 3897 - 3899.
[Full Text] [PDF]

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 JCOHome page
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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 Mol. Pharmacol.Home page
M.-T. Lin, M.-L. Yen, C.-Y. Lin, and M.-L. Kuo
Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis by Resveratrol through Interruption of Src-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation
Mol. Pharmacol., November 1, 2003; 64(5): 1029 - 1036.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
J. A. Sosman
Targeting of the VHL-Hypoxia-Inducible Factor-Hypoxia-Induced Gene Pathway for Renal Cell Carcinoma Therapy
J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2695 - 2702.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
Y. Ueda, T. Yamagishi, K. Samata, H. Ikeya, N. Hirayama, H. Takashima, S. Nakaike, M. Tanaka, and I. Saiki
A novel low molecular weight antagonist of vascular endothelial growth factor receptor binding: VGA1155
Mol. Cancer Ther., November 1, 2003; 2(11): 1105 - 1111.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Lu, J. Shen, M. D. Vil, H. Zhang, X. Jimenez, P. Bohlen, L. Witte, and Z. Zhu
Tailoring in Vitro Selection for a Picomolar Affinity Human Antibody Directed against Vascular Endothelial Growth Factor Receptor 2 for Enhanced Neutralizing Activity
J. Biol. Chem., October 31, 2003; 278(44): 43496 - 43507.
[Abstract] [Full Text] [PDF]


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