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[Cancer Research 53, 4637-4642, October 1, 1993]
© 1993 American Association for Cancer Research
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Antitumor Effect of Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies plus cis-Diamminedichloroplatinum on Well Established A431 Cell Xenografts1

Zhen Fan, Jose Baselga, Hideo Masui and John Mendelsohn2

Laboratory of Receptor Biology, Memorial Sloan-Kettering Cancer Center [Z. F., J. B., H. M., J. M.] and Cornell University Medical School [J. M.], New York, New York 10021

2 To whom requests for reprints should be addressed, at Box 156, 1275 York Avenue, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

We have explored the therapeutic effects of anti-epidermal growth factor receptor monoclonal antibodies (MAbs) 225 and 528 on well established A431 epidermoid carcinoma xenografts, approximately 400 mm3 (1 cm in diameter) at the start of treatment. In previous reports we demonstrated that MAbs 225 and 528 prevented the growth of A431 cell xenografts in nude mice when treatment was begun on the day of tumor cell inoculation. Since anti-epidermal growth factor receptor MAb therapy of well established tumors was unable to retard growth, we explored combination therapy with MAb plus the chemotherapeutic agent c/5-diamminedichloroplatinum (cis-DDP). Additive and concentration-dependent growth-inhibitory effects of MAb with cis-DDP were observed in cultures of A431 cells. Neither intensive treatment with 225 MAb (1 mg/ mouse, i.p. on day 8 after tumor inoculation, and twice weekly for 4 weeks) nor a maximally tolerated single dose of cis-DDP [150 µg/25 g (6 mg/kg) mouse weight, i.p. on day 8] had significant effects on tumor growth. However, the two treatments in combination resulted in substantial xenograft growth inhibition, compared with both an untreated control group and animals treated with a single modality. When a second dose of cis-DDP (150 µg/25 g) was added after 10 days, combination therapy with 225 MAb produced striking antitumor effects. At the end of 1 month tumor xenografts had disappeared in all but one mouse, and no tumor relapses occurred during 6 months of observation. Identical results were obtained with anti-epidermal growth factor receptor MAb 528 in combination with cis-DDP. The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.

1 This work was supported by The Dror Friedenberg Foundation and NIH Grants CA42060 and CA37641.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/10/93. Accepted 8/19/93.




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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.
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 Clin. Cancer Res.Home page
N. J. Donato, M. Perez, H. Kang, Z. H. Siddik, Y.-H. Ling, and R. Perez-Soler
EGF Receptor and p21WAF1 Expression are Reciprocally Altered as ME-180 Cervical Carcinoma Cells Progress from High to Low Cisplatin Sensitivity
Clin. Cancer Res., January 1, 2000; 6(1): 193 - 202.
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 J. Pharmacol. Exp. Ther.Home page
V. A. Pollack, D. M. Savage, D. A. Baker, K. E. Tsaparikos, D. E. Sloan, J. D. Moyer, E. G. Barbacci, L. R. Pustilnik, T. A. Smolarek, J. A. Davis, et al.
Inhibition of Epidermal Growth Factor Receptor-Associated Tyrosine Phosphorylation in Human Carcinomas with CP-358,774: Dynamics of Receptor Inhibition In Situ and Antitumor Effects in Athymic Mice
J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 739 - 748.
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 Clin. Cancer Res.Home page
G. Tortora, R. Caputo, G. Pomatico, S. Pepe, A. R. Bianco, S. Agrawal, J. Mendelsohn, and F. Ciardiello
Cooperative Inhibitory Effect of Novel Mixed Backbone Oligonucleotide Targeting Protein Kinase A in Combination with Docetaxel and Anti-Epidermal Growth Factor-Receptor Antibody on Human Breast Cancer Cell Growth
Clin. Cancer Res., April 1, 1999; 5(4): 875 - 881.
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 Clin. Cancer Res.Home page
F. Ciardiello, R. Bianco, V. Damiano, S. De Lorenzo, S. Pepe, S. De Placido, Z. Fan, J. Mendelsohn, A. R. Bianco, and G. Tortora
Antitumor Activity of Sequential Treatment with Topotecan and Anti-Epidermal Growth Factor Receptor Monoclonal Antibody C225
Clin. Cancer Res., April 1, 1999; 5(4): 909 - 916.
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 Cancer Res.Home page
X.-D. Yang, X.-C. Jia, J. R. F. Corvalan, P. Wang, C. G. Davis, and A. Jakobovits
Eradication of Established Tumors by a Fully Human Monoclonal Antibody to the Epidermal Growth Factor Receptor without Concomitant hemotherapy
Cancer Res., March 1, 1999; 59(6): 1236 - 1243.
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 J. Biol. Chem.Home page
R. V. Iozzo, D. K. Moscatello, D. J. McQuillan, and I. Eichstetter
Decorin Is a Biological Ligand for the Epidermal Growth Factor Receptor
J. Biol. Chem., February 19, 1999; 274(8): 4489 - 4492.
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 J. Biol. Chem.Home page
D. Bandyopadhyay, M. Mandal, L. Adam, J. Mendelsohn, and R. Kumar
Physical Interaction between Epidermal Growth Factor Receptor and DNA-dependent Protein Kinase in Mammalian Cells
J. Biol. Chem., January 16, 1998; 273(3): 1568 - 1573.
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 Proc. Natl. Acad. Sci. USAHome page
G. Tortora, R. Caputo, V. Damiano, R. Bianco, S. Pepe, A. R. Bianco, Z. Jiang, S. Agrawal, and F. Ciardiello
Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A
PNAS, November 11, 1997; 94(23): 12586 - 12591.
[Abstract] [Full Text] [PDF]

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 JAMAHome page
B. A. Burtness
Oncology and Hematology
JAMA, June 7, 1995; 273(21): 1702 - 1703.
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 Cold Spring Harb Symp Quant BiolHome page
R.S. Kerbel, J. Rak, H. Kobayashi, M.S. Man, B. St. Croix, and C.H. Graham
Multicellular Resistance: A New Paradigm to Explain Aspects of Acquired Drug Resistance of Solid Tumors
Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 661 - 672.
[Abstract] [PDF]


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