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Clinical Cancer Research Vol. 5, 257-264, February 1999
© 1999 American Association for Cancer Research

Advances in Brief

Anti-epidermal Growth Factor Receptor Antibody C225 Inhibits Angiogenesis in Human Transitional Cell Carcinoma Growing Orthotopically in Nude Mice1

Paul Perrotte, Takashi Matsumoto, Keiji Inoue, Hiroki Kuniyasu, Beryl Y. Eve, Daniel J. Hicklin, Robert Radinsky and Colin P. N. Dinney2

Departments of Urology [P. P., C. P. N. D.] and Cancer Biology [T. M., K. I., H. K., B. Y. E., R. R.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and ImClone Systems, New York, New York [D. J. H.]

Epidermal growth factor receptor (EGFR) regulates the growth and progression of human transitional cell carcinoma (TCC) of the bladder. We have shown that therapy targeting EGFR inhibited the growth of human TCC established orthotopically in nude mice. The purpose of this study was to evaluate whether EGFR-directed therapy affects angiogenesis associated with the growth and metastasis of human TCC. We determined the cytostatic effect and the effect on production of angiogenic factors after in vitro treatment of the human TCC cell line 253J B-V with MAb C225, a chimerized monoclonal anti-EGFR antibody. The 253J B-V cells were implanted orthotopically into athymic nude mice, and established tumors (4 weeks) were treated with i.p. MAb C225. Expression of the angiogenic factors vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) was evaluated by immunohistochemistry and in situ mRNA hybridization analyses and correlated with microvessel density evaluated after immunohistochemical staining with anti-CD31. In vitro treatment with MAb C225 inhibited mRNA and protein production of VEGF, IL-8, and bFGF by 253J B-V cells in a dose-dependent manner. MAb C225 therapy of nude mice with established TCCs growing orthotopically resulted in inhibition of growth and metastasis compared with controls (P <0.0005). VEGF, IL-8, and bFGF expression was significantly lower in treated tumors than in controls. The down-regulation of these angiogenic factors preceded the involution of blood vessels. These studies indicate that therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis.




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C. I. Spiridon, M.-A. Ghetie, J. Uhr, R. Marches, J.-L. Li, G.-L. Shen, and E. S. Vitetta
Targeting Multiple Her-2 Epitopes with Monoclonal Antibodies Results in Improved Antigrowth Activity of a Human Breast Cancer Cell Line in Vitro and in Vivo
Clin. Cancer Res., June 1, 2002; 8(6): 1720 - 1730.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
A. Hirata, S.-i. Ogawa, T. Kometani, T. Kuwano, S. Naito, M. Kuwano, and M. Ono
ZD1839 (Iressa) Induces Antiangiogenic Effects through Inhibition of Epidermal Growth Factor Receptor Tyrosine Kinase
Cancer Res., May 1, 2002; 62(9): 2554 - 2560.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. C. Prewett, A. T. Hooper, R. Bassi, L. M. Ellis, H. W. Waksal, and D. J. Hicklin
Enhanced Antitumor Activity of Anti-epidermal Growth Factor Receptor Monoclonal Antibody IMC-C225 in Combination with Irinotecan (CPT-11) against Human Colorectal Tumor Xenografts
Clin. Cancer Res., May 1, 2002; 8(5): 994 - 1003.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
S.-M. Huang, J. Li, and P. M. Harari
Molecular Inhibition of Angiogenesis and Metastatic Potential in Human Squamous Cell Carcinomas after Epidermal Growth Factor Receptor Blockade
Mol. Cancer Ther., May 1, 2002; 1(7): 507 - 514.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
T. Karashima, P. Sweeney, J. W. Slaton, S. J. Kim, D. Kedar, J. I. Izawa, Z. Fan, C. Pettaway, D. J. Hicklin, T. Shuin, et al.
Inhibition of Angiogenesis by the Antiepidermal Growth Factor Receptor Antibody ImClone C225 in Androgen-independent Prostate Cancer Growing Orthotopically in Nude Mice
Clin. Cancer Res., May 1, 2002; 8(5): 1253 - 1264.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
C. H. Baker, C. C. Solorzano, and I. J. Fidler
Blockade of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling for Therapy of Metastatic Human Pancreatic Cancer
Cancer Res., April 1, 2002; 62(7): 1996 - 2003.
[Abstract] [Full Text] [PDF]

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 Journal of Pharmacy PracticeHome page
R. S. Finley
New Directions in the Treatment of Cancer: Inhibition of Signal Transduction
Journal of Pharmacy Practice, February 1, 2002; 15(1): 5 - 16.
[Abstract] [PDF]

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 Clin. Cancer Res.Home page
G. Tortora, R. Caputo, V. Damiano, G. Fontanini, D. Melisi, B. Maria Veneziani, F. Zunino, A. R. Bianco, and F. Ciardiello
Oral Administration of a Novel Taxane, an Antisense Oligonucleotide Targeting Protein Kinase A, and the Epidermal Growth Factor Receptor Inhibitor Iressa Causes Cooperative Antitumor and Antiangiogenic Activity
Clin. Cancer Res., December 1, 2001; 7(12): 4156 - 4163.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
F. Ciardiello and G. Tortora
A Novel Approach in the Treatment of Cancer: Targeting the Epidermal Growth Factor Receptor
Clin. Cancer Res., October 1, 2001; 7(10): 2958 - 2970.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. W. Slaton, T. Karashima, P. Perrotte, K. Inoue, S. J. Kim, J. Izawa, D. Kedar, D. J. McConkey, R. Millikan, P. Sweeney, et al.
Treatment with Low-Dose Interferon-{alpha} Restores the Balance between Matrix Metalloproteinase-9 and E-Cadherin Expression in Human Transitional Cell Carcinoma of the Bladder
Clin. Cancer Res., September 1, 2001; 7(9): 2840 - 2853.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. C. Solorzano, C. H. Baker, R. Tsan, P. Traxler, P. Cohen, E. Buchdunger, J. J. Killion, and I. J. Fidler
Optimization for the Blockade of Epidermal Growth Factor Receptor Signaling for Therapy of Human Pancreatic Carcinoma
Clin. Cancer Res., August 1, 2001; 7(8): 2563 - 2572.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
A. Viloria-Petit, T. Crombet, S. Jothy, D. Hicklin, P. Bohlen, J. M. Schlaeppi, J. Rak, and R. S. Kerbel
Acquired Resistance to the Antitumor Effect of Epidermal Growth Factor Receptor-blocking Antibodies in Vivo: A Role for Altered Tumor Angiogenesis
Cancer Res., July 1, 2001; 61(13): 5090 - 5101.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. S. Soukos, M. R. Hamblin, S. Keel, R. L. Fabian, T. F. Deutsch, and T. Hasan
Epidermal Growth Factor Receptor-targeted Immunophotodiagnosis and Photoimmunotherapy of Oral Precancer in Vivo
Cancer Res., June 1, 2001; 61(11): 4490 - 4496.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. Amara, G. S. Palapattu, M. Schrage, Z. Gu, G. V. Thomas, F. Dorey, J. Said, and R. E. Reiter
Prostate Stem Cell Antigen Is Overexpressed in Human Transitional Cell Carcinoma
Cancer Res., June 1, 2001; 61(12): 4660 - 4665.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
F. Ciardiello, R. Caputo, R. Bianco, V. Damiano, G. Fontanini, S. Cuccato, S. De Placido, A. R. Bianco, and G. Tortora
Inhibition of Growth Factor Production and Angiogenesis in Human Cancer Cells by ZD1839 (Iressa), a Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
Clin. Cancer Res., May 1, 2001; 7(5): 1459 - 1465.
[Abstract] [Full Text]

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 CMAJHome page
J. I. Izawa and C. P.N. Dinney
The role of angiogenesis in prostate and other urologic cancers: a review
Can. Med. Assoc. J., March 1, 2001; 164(5): 662 - 670.
[Abstract] [Full Text] [PDF]

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 Arch OphthalmolHome page
A. G. M. Scholes, S. Hagan, P. Hiscott, B. E. Damato, and I. Grierson
Overexpression of Epidermal Growth Factor Receptor Restricted to Macrophages in Uveal Melanoma
Arch Ophthalmol, March 1, 2001; 119(3): 373 - 377.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
P. Gazzaniga, O. Gandini, L. Giuliani, M. Magnanti, A. Gradilone, I. Silvestri, W. Gianni, M. Gallucci, L. Frati, and A. M. Aglianò
Detection of Epidermal Growth Factor Receptor mRNA in Peripheral Blood: A New Marker of Circulating Neoplastic Cells in Bladder Cancer Patients
Clin. Cancer Res., March 1, 2001; 7(3): 577 - 583.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
P. D. Ryan and B. A. Chabner
On Receptor Inhibitors and Chemotherapy
Clin. Cancer Res., December 1, 2000; 6(12): 4607 - 4609.
[Full Text]

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 Clin. Cancer Res.Home page
K. Inoue, J. W. Slaton, T. Karashima, C. Yoshikawa, T. Shuin, P. Sweeney, R. Millikan, and C. P. N. Dinney
The Prognostic Value of Angiogenesis Factor Expression for Predicting Recurrence and Metastasis of Bladder Cancer after Neoadjuvant Chemotherapy and Radical Cystectomy
Clin. Cancer Res., December 1, 2000; 6(12): 4866 - 4873.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
K. Inoue, J. W. Slaton, P. Perrotte, D. W. Davis, C. J. Bruns, D. J. Hicklin, D. J. McConkey, P. Sweeney, R. Radinsky, and C. P. N. Dinney
Paclitaxel Enhances the Effects of the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody ImClone C225 in Mice with Metastatic Human Bladder Transitional Cell Carcinoma
Clin. Cancer Res., December 1, 2000; 6(12): 4874 - 4884.
[Abstract] [Full Text]

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 Am. J. Pathol.Home page
H. Kuniyasu, W. Yasui, H. Shinohara, S. Yano, L. M. Ellis, M. R. Wilson, C. D. Bucana, T. Rikita, E. Tahara, and I. J. Fidler
Induction of Angiogenesis by Hyperplastic Colonic Mucosa Adjacent to Colon Cancer
Am. J. Pathol., November 1, 2000; 157(5): 1523 - 1535.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
K. Inoue, P. Perrotte, C. G. Wood, J. W. Slaton, P. Sweeney, and C. P. N. Dinney
Gene Therapy of Human Bladder Cancer with Adenovirus-mediated Antisense Basic Fibroblast Growth Factor
Clin. Cancer Res., November 1, 2000; 6(11): 4422 - 4431.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S. Yano, H. Shinohara, R. S. Herbst, H. Kuniyasu, C. D. Bucana, L. M. Ellis, D. W. Davis, D. J. McConkey, and I. J. Fidler
Expression of Vascular Endothelial Growth Factor Is Necessary but not Sufficient for Production and Growth of Brain Metastasis
Cancer Res., September 1, 2000; 60(17): 4959 - 4967.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
F. Ciardiello, R. Bianco, V. Damiano, G. Fontanini, R. Caputo, G. Pomatico, Sabino De Placido, A. R. Bianco, J. Mendelsohn, and G. Tortora
Antiangiogenic and Antitumor Activity of Anti-Epidermal Growth Factor Receptor C225 Monoclonal Antibody in Combination with Vascular Endothelial Growth Factor Antisense Oligonucleotide in Human GEO Colon Cancer Cells
Clin. Cancer Res., September 1, 2000; 6(9): 3739 - 3747.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
K. Inoue, J. W. Slaton, D. W. Davis, D. J. Hicklin, D. J. McConkey, T. Karashima, R. Radinsky, and C. P. N. Dinney
Treatment of Human Metastatic Transitional Cell Carcinoma of the Bladder in a Murine Model with the Anti-Vascular Endothelial Growth Factor Receptor Monoclonal Antibody DC101 and Paclitaxel
Clin. Cancer Res., July 1, 2000; 6(7): 2635 - 2643.
[Abstract] [Full Text]

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 Cancer Res.Home page
C. J. Bruns, C. C. Solorzano, M. T. Harbison, S. Ozawa, R. Tsan, D. Fan, J. Abbruzzese, P. Traxler, E. Buchdunger, R. Radinsky, et al.
Blockade of the Epidermal Growth Factor Receptor Signaling by a Novel Tyrosine Kinase Inhibitor Leads to Apoptosis of Endothelial Cells and Therapy of Human Pancreatic Carcinoma
Cancer Res., June 1, 2000; 60(11): 2926 - 2935.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S.-M. Huang and P. M. Harari
Modulation of Radiation Response after Epidermal Growth Factor Receptor Blockade in Squamous Cell Carcinomas: Inhibition of Damage Repair, Cell Cycle Kinetics, and Tumor Angiogenesis
Clin. Cancer Res., June 1, 2000; 6(6): 2166 - 2174.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
C. J. Bruns, M. T. Harbison, D. W. Davis, C. A. Portera, R. Tsan, D. J. McConkey, D. B. Evans, J. L. Abbruzzese, D. J. Hicklin, and R. Radinsky
Epidermal Growth Factor Receptor Blockade with C225 Plus Gemcitabine Results in Regression of Human Pancreatic Carcinoma Growing Orthotopically in Nude Mice by Antiangiogenic Mechanisms
Clin. Cancer Res., May 1, 2000; 6(5): 1936 - 1948.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
K. Inoue, J. W. Slaton, B. Y. Eve, S. J. Kim, P. Perrotte, M. D. Balbay, S. Yano, M. Bar-Eli, R. Radinsky, C. A. Pettaway, et al.
Interleukin 8 Expression Regulates Tumorigenicity and Metastases in Androgen-independent Prostate Cancer
Clin. Cancer Res., May 1, 2000; 6(5): 2104 - 2119.
[Abstract] [Full Text]

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 Cell Growth Differ.Home page
C. V. Ngo, M. Gee, N. Akhtar, D. Yu, O. Volpert, R. Auerbach, and A. Thomas-Tikhonenko
An in Vivo Function for the Transforming Myc Protein: Elicitation of the Angiogenic Phenotype
Cell Growth Differ., April 1, 2000; 11(4): 201 - 210.
[Abstract] [Full Text]

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 Cancer Res.Home page
K. Inoue, J. W. Slaton, S. J. Kim, P. Perrotte, B. Y. Eve, M. Bar-Eli, R. Radinsky, and C. P. N. Dinney
Interleukin 8 Expression Regulates Tumorigenicity and Metastasis in Human Bladder Cancer
Cancer Res., April 1, 2000; 60(8): 2290 - 2299.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
A. D. Perera, E. V. Kleymenova, and C. L. Walker
Requirement for the von Hippel-Lindau Tumor Suppressor Gene for Functional Epidermal Growth Factor Receptor Blockade by Monoclonal Antibody C225 in Renal Cell Carcinoma
Clin. Cancer Res., April 1, 2000; 6(4): 1518 - 1523.
[Abstract] [Full Text]

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 CarcinogenesisHome page
R. S. Kerbel
Tumor angiogenesis: past, present and the near future
Carcinogenesis, March 1, 2000; 21(3): 505 - 515.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. Mendelsohn
Blockade of Receptors for Growth Factors: An Anticancer Therapy -- The Fourth Annual Joseph H. Burchenal American Association for Cancer Research Clinical Research Award Lecture
Clin. Cancer Res., March 1, 2000; 6(3): 747 - 753.
[Full Text]

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 Clin. Cancer Res.Home page
P. M. Harari and S.-M. Huang
Modulation of Molecular Targets to Enhance Radiation
Clin. Cancer Res., February 1, 2000; 6(2): 323 - 325.
[Full Text]

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 Clin. Cancer Res.Home page
L. Milas, K. Mason, N. Hunter, S. Petersen, M. Yamakawa, K. Ang, J. Mendelsohn, and Z. Fan
In Vivo Enhancement of Tumor Radioresponse by C225 Antiepidermal Growth Factor Receptor Antibody
Clin. Cancer Res., February 1, 2000; 6(2): 701 - 708.
[Abstract] [Full Text]

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 Cancer Res.Home page
J. Rak, Y. Mitsuhashi, C. Sheehan, A. Tamir, A. Viloria-Petit, J. Filmus, S. J. Mansour, N. G. Ahn, and R. S. Kerbel
Oncogenes and Tumor Angiogenesis: Differential Modes of Vascular Endothelial Growth Factor Up-Regulation in ras-transformed Epithelial Cells and Fibroblasts
Cancer Res., January 1, 2000; 60(2): 490 - 498.
[Abstract] [Full Text]


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