Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Tumor Immunology: New Perspectives
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sachdev, D.
Right arrow Articles by Yee, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sachdev, D.
Right arrow Articles by Yee, D.
[Cancer Research 63, 627-635, February 1, 2003]
© 2003 American Association for Cancer Research

Experimental Therapeutics

A Chimeric Humanized Single-Chain Antibody against the Type I Insulin-like Growth Factor (IGF) Receptor Renders Breast Cancer Cells Refractory to the Mitogenic Effects of IGF-I1

Deepali Sachdev, Shu-Lian Li, Julie S. Hartell, Yoko Fujita-Yamaguchi, Jeffrey S. Miller and Douglas Yee2

Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455 [D. S., J. S. H., J. S. M., D. Y.]; Molecular Biology Division, Beckman Research Institute of the City of Hope, Duarte, California 91010 [S-L. L.]; and Department of Applied Biochemistry, School of Engineering, Tokai University, Hiratsuka 259-1292, Japan [Y. F-Y.]

Insulin-like growth factors (IGFs) stimulate breast cancer proliferation, motility, and survival.The type I IGF receptor (IGF1R) mediates the effects of IGF-I. Thus, inhibition of IGF1R activation could inhibit IGF action in breast cancer cells. A single-chain antibody directed against IGF1R (IGF1R scFv-Fc) has been shown to partially inhibit xenograft growth of MCF-7 cells in athymic mice. In this study, we have examined the effects of scFv-Fc on IGF1R signaling in the estrogen receptor-positive (ER+) MCF-7 breast cancer cells in vitro and in vivo. The antibody stimulated IGF1R activation in vitro in MCF-7 cells and was unable to block IGF-I effects. The antibody also stimulated proliferation of MCF-7 cells in monolayer growth assays. To determine how scFv-Fc could stimulate in vitro growth yet inhibit in vivo tumor growth, we examined the effect of scFv-Fc on IGF1R expression. In MCF-7 cells, scFv-Fc down-regulated IGF1R levels after 2 h, and the levels were greatly reduced after 24 h. In contrast, IGF-I treatment over the same time period did not affect IGF1R levels. Twenty-four-h pretreatment of cells with scFv-Fc blocked IGF-I mediated phosphorylation of insulin receptor substrate-1 and subsequent extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phosphatidylinositol 3'-kinase activation. In contrast, cells treated with 5 nM IGF-I for 24 h still retained the ability to further activate downstream signaling pathways in response to IGF-I. Moreover, pretreatment of MCF-7 cells with scFv-Fc rendered them refractory to further proliferation induced by additional IGF-I. Twenty-four-h pretreatment of cells with scFv-Fc also inhibited IGF-I stimulated anchorage-independent growth. scFv-Fc did not enhance antibody-dependent cell-mediated cytotoxicity. In vivo, treatment of mice bearing MCF-7 xenograft tumors with scFv-Fc resulted in near complete down-regulation of IGF1R. Our data show that scFv-Fc stimulates biochemical activation of IGF1R, then causes receptor down-regulation, making MCF-7 cells refractory to additional IGF-I exposure. These results indicate that such chimeric single-chain antibodies against IGF1R have future potential in breast cancer therapy by causing down-regulation of receptor.




This article has been cited by other articles:


Home page
 J BiochemHome page
Y. Kusada, T. Morizono, A. Matsumoto-Takasaki, K. Sakai, S. Sato, H. Asanuma, A. Takayanagi, and Y. Fujita-Yamaguchi
Construction and Characterization of Single-chain Antibodies Against Human Insulin-like Growth Factor-I Receptor from Hybridomas Producing 1H7 or 3B7 Monoclonal Antibody
J. Biochem., January 1, 2008; 143(1): 9 - 19.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
P. D. Ryan and P. E. Goss
The Emerging Role of the Insulin-Like Growth Factor Pathway as a Therapeutic Target in Cancer
Oncologist, January 1, 2008; 13(1): 16 - 24.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. R. Daniel, E. J. Faivre, and C. A. Lange
Phosphorylation-Dependent Antagonism of Sumoylation Derepresses Progesterone Receptor Action in Breast Cancer Cells
Mol. Endocrinol., December 1, 2007; 21(12): 2890 - 2906.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
P. Haluska, H. M. Shaw, G. N. Batzel, D. Yin, J. R. Molina, L. R. Molife, T. A. Yap, M. L. Roberts, A. Sharma, A. Gualberto, et al.
Phase I Dose Escalation Study of the Anti Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors
Clin. Cancer Res., October 1, 2007; 13(19): 5834 - 5840.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
Y. Fujita-Yamaguchi, M. Ohtani, M. Numasaki, and Y. Yajima
Down-regulation pathways of insulin-like growth factor I receptor induced by anti-IGFIR antibodies
FASEB J, April 1, 2007; 21(6): A1191 - A1191.


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
M. Li, Z. He, S. Ermakova, D. Zheng, F. Tang, Y.-Y. Cho, F. Zhu, W.-Y. Ma, Y. Sham, E. A. Rogozin, et al.
Direct Inhibition of Insulin-Like Growth Factor-I Receptor Kinase Activity by (-)-Epigallocatechin-3-Gallate Regulates Cell Transformation
Cancer Epidemiol. Biomarkers Prev., March 1, 2007; 16(3): 598 - 605.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt
The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights
Endocr. Rev., February 1, 2007; 28(1): 20 - 47.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
G. W. Allen, C. Saba, E. A. Armstrong, S.-M. Huang, S. Benavente, D. L. Ludwig, D. J. Hicklin, and P. M. Harari
Insulin-like Growth Factor-I Receptor Signaling Blockade Combined with Radiation
Cancer Res., February 1, 2007; 67(3): 1155 - 1162.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
E. J. Faivre and C. A. Lange
Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells
Mol. Cell. Biol., January 15, 2007; 27(2): 466 - 480.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Zhang, A. M. Pelzer, D. T. Kiang, and D. Yee
Down-regulation of Type I Insulin-like Growth Factor Receptor Increases Sensitivity of Breast Cancer Cells to Insulin
Cancer Res., January 1, 2007; 67(1): 391 - 397.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
D. Sachdev and D. Yee
Disrupting insulin-like growth factor signaling as a potential cancer therapy
Mol. Cancer Ther., January 1, 2007; 6(1): 1 - 12.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
J Riedemann and V M Macaulay
IGF1R signalling and its inhibition
Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S33 - S43.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. D. Wu, K. Haugk, I. Coleman, L. Woodke, R. Vessella, P. Nelson, R. B. Montgomery, D. L. Ludwig, and S. R. Plymate
Combined In vivo Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and Docetaxel against Prostate Cancer Tumors.
Clin. Cancer Res., October 15, 2006; 12(20): 6153 - 6160.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
B. A. Whitson, B. A. Jacobson, S. Frizelle, M. R. Patel, D. Yee, M. A. Maddaus, and R. A. Kratzke
Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma.
Ann. Thorac. Surg., September 1, 2006; 82(3): 996 - 1001.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. L. Gable, B. A. Maddux, C. Penaranda, M. Zavodovskaya, M. J. Campbell, M. Lobo, L. Robinson, S. Schow, J. A. Kerner, I. D. Goldfine, et al.
Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth.
Mol. Cancer Ther., April 1, 2006; 5(4): 1079 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Sachdev, R. Singh, Y. Fujita-Yamaguchi, and D. Yee
Down-regulation of Insulin Receptor by Antibodies against the Type I Insulin-Like Growth Factor Receptor: Implications for Anti-Insulin-Like Growth Factor Therapy in Breast Cancer
Cancer Res., February 15, 2006; 66(4): 2391 - 2402.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Lu, D. Katsaros, A. Wiley, I. A. Rigault de la Longrais, H. A. Risch, M. Puopolo, and H. Yu
The Relationship of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor Binding Protein-3, and Estrogen Receptor-{alpha} Expression to Disease Progression in Epithelial Ovarian Cancer
Clin. Cancer Res., February 15, 2006; 12(4): 1208 - 1214.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Al-Zahrani, M. S. Sandhu, R. N. Luben, D. Thompson, C. Baynes, K. A. Pooley, C. Luccarini, H. Munday, B. Perkins, P. Smith, et al.
IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer
Hum. Mol. Genet., January 1, 2006; 15(1): 1 - 10.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Feng, Z. Zhu, X. Xiao, V. Choudhry, J. C. Barrett, and D. S. Dimitrov
Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function
Mol. Cancer Ther., January 1, 2006; 5(1): 114 - 120.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. S. Miller and D. Yee
Type I Insulin-like Growth Factor Receptor as a Therapeutic Target in Cancer
Cancer Res., November 15, 2005; 65(22): 10123 - 10127.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Wang, J. Hailey, D. Williams, Y. Wang, P. Lipari, M. Malkowski, X. Wang, L. Xie, G. Li, D. Saha, et al.
Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody
Mol. Cancer Ther., August 1, 2005; 4(8): 1214 - 1221.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Lu, H. Zhang, H. Koo, J. Tonra, P. Balderes, M. Prewett, E. Corcoran, V. Mangalampalli, R. Bassi, D. Anselma, et al.
A Fully Human Recombinant IgG-like Bispecific Antibody to Both the Epidermal Growth Factor Receptor and the Insulin-like Growth Factor Receptor for Enhanced Antitumor Activity
J. Biol. Chem., May 20, 2005; 280(20): 19665 - 19672.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Miyamoto, M. Nakamura, K. Shitara, K. Nakamura, Y. Ohki, G. Ishii, M. Goya, K. Kodama, T. Sangai, H. Maeda, et al.
Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers
Clin. Cancer Res., May 1, 2005; 11(9): 3494 - 3502.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. D. Wu, A. Odman, L. M. Higgins, K. Haugk, R. Vessella, D. L. Ludwig, and S. R. Plymate
In vivo Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors
Clin. Cancer Res., April 15, 2005; 11(8): 3065 - 3074.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. S. Warshamana-Greene, J. Litz, E. Buchdunger, C. Garcia-Echeverria, F. Hofmann, and G. W. Krystal
The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy
Clin. Cancer Res., February 15, 2005; 11(4): 1563 - 1571.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. H. Ibrahim and D. Yee
Insulin-Like Growth Factor-I and Breast Cancer Therapy
Clin. Cancer Res., January 15, 2005; 11(2): 944s - 950s.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Sachdev, J. S. Hartell, A. V. Lee, X. Zhang, and D. Yee
A Dominant Negative Type I Insulin-like Growth Factor Receptor Inhibits Metastasis of Human Cancer Cells
J. Biol. Chem., February 6, 2004; 279(6): 5017 - 5024.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Lu, H. Zhang, D. Ludwig, A. Persaud, X. Jimenez, D. Burtrum, P. Balderes, M. Liu, P. Bohlen, L. Witte, et al.
Simultaneous Blockade of Both the Epidermal Growth Factor Receptor and the Insulin-like Growth Factor Receptor Signaling Pathways in Cancer Cells with a Fully Human Recombinant Bispecific Antibody
J. Biol. Chem., January 23, 2004; 279(4): 2856 - 2865.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Burtrum, Z. Zhu, D. Lu, D. M. Anderson, M. Prewett, D. S. Pereira, R. Bassi, R. Abdullah, A. T. Hooper, H. Koo, et al.
A Fully Human Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor Blocks Ligand-Dependent Signaling and Inhibits Human Tumor Growth in Vivo
Cancer Res., December 15, 2003; 63(24): 8912 - 8921.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. K. Maloney, J. L. McLaughlin, N. E. Dagdigian, L. M. Garrett, K. M. Connors, X.-M. Zhou, W. A. Blattler, T. Chittenden, and R. Singh
An Anti-Insulin-like Growth Factor I Receptor Antibody That Is a Potent Inhibitor of Cancer Cell Proliferation
Cancer Res., August 15, 2003; 63(16): 5073 - 5083.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.