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Clinical Cancer Research Vol. 6, 1936-1948, May 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Epidermal Growth Factor Receptor Blockade with C225 Plus Gemcitabine Results in Regression of Human Pancreatic Carcinoma Growing Orthotopically in Nude Mice by Antiangiogenic Mechanisms1

Christiane J. Bruns, Matthew T. Harbison, Darren W. Davis, Charles A. Portera, Rachel Tsan, David J. McConkey, Douglas B. Evans, James L. Abbruzzese, Daniel J. Hicklin and Robert Radinsky2

Departments of Cancer Biology [C. J. B., M. T. H., D. W. D., C. A. P., R. T., D. J. M., R. R.], Surgical Oncology [D. B. E.], and Gastrointestinal Medical Oncology [J. L. A.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and ImClone Systems, Inc., New York, New York 10014 [D. J. H.]

Both epidermal growth factor receptor (EGF-R) signaling mechanisms and angiogenesis have been evaluated as independent targets for therapy of human pancreatic carcinoma, but a link between the two processes has been identified only recently. This study evaluated whether EGF-R blockade therapy with anti-EGF-R antibody C225 inhibits pancreatic carcinoma growth and metastasis in an orthotopic nude mouse model via tumor-mediated angiogenesis and whether gemcitabine potentiates this effect. In vitro treatment of human pancreatic carcinoma L3.6pl cells with C225 inhibited EGF-R autophosphorylation, producing a maximum of 20% cytostasis. Treatment with C225 plus gemcitabine resulted in additive cytotoxic effects that increased with increasing gemcitabine concentrations. Dose-dependent decreases in expression of the angiogenic factors vascular endothelial growth factor and interleukin 8 (but not basic fibroblast growth factor) were observed in the C225-treated cells (mRNA and protein levels). In L3.6pl tumors established in the pancreas of nude mice, systemic therapy with C225 alone and C225 in combination with gemcitabine resulted in growth inhibition, tumor regression, and abrogation of metastasis; median tumor volume was reduced from 538 to 0.3 and to 0 mm3, respectively. Gemcitabine treatment alone reduced median tumor volume from 538 to 152 mm3. Liver metastases were present in 50% of the controls, 30% of the gemcitabine-treated animals, and 20% of C225-treated animals. No macroscopically visible liver metastases were observed in the combination treatment group. As early as 11 days after C225 treatment, the median percentage of proliferating cell nuclear antigen-positive cells was substantially reduced compared with gemcitabine treatment alone (26% versus 73%, respectively) versus controls (92%), correlating with in vivo blockade of EGF-R activation. Similarly after 11 days treatment, production of vascular endothelial growth factor and interleukin 8 was significantly lower in C225 and C225 plus gemcitabine-treated tumors versus gemcitabine-treated and control tumors. Significant differences in microvessel density were observed 18 days after C225 or combination treatments (but not gemcitabine alone) in direct correlation with the difference in percentage of apoptotic endothelial cells, as visualized by double immunofluorescence microscopy. These experiments indicate that therapeutic strategies targeting EGF-R have a significant antitumor effect on human L3.6pl pancreatic carcinoma growing in nude mice which is mediated in part by inhibition of tumor-induced angiogenesis, leading to tumor cell apoptosis and regression. Furthermore, this effect is potentiated in combination with gemcitabine.




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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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 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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 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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 The OncologistHome page
J. D. Wayne, E. K. Abdalla, R. A. Wolff, C. H. Crane, P. W.T. Pisters, and D. B. Evans
Localized Adenocarcinoma of the Pancreas: The Rationale for Preoperative Chemoradiation
Oncologist, February 1, 2002; 7(1): 34 - 45.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
E. M. Gibson, E. S. Henson, N. Haney, J. Villanueva, and S. B. Gibson
Epidermal Growth Factor Protects Epithelial-derived Cells from Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Inhibiting Cytochrome c Release
Cancer Res., January 1, 2002; 62(2): 488 - 496.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. Mundhenke, J. P. Thomas, G. Wilding, F. T. Lee, F. Kelzc, R. Chappell, R. Neider, L. A. Sebree, and A. Friedl
Tissue Examination to Monitor Antiangiogenic Therapy: A Phase I Clinical Trial with Endostatin
Clin. Cancer Res., November 1, 2001; 7(11): 3366 - 3374.
[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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 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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 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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 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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