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Horm Metab Res 2003; 35(11/12): 836-842
DOI: 10.1055/s-2004-814145
Original
© Georg Thieme Verlag Stuttgart · New York

Combined Effects of Tamoxifen and a Chimeric Humanized Single Chain Antibody against the Type I IGF Receptor on Breast Tumor Growth In vivo

J.-J.  Ye1 , S.-J.  Liang1 , N.  Guo1 , S.-L.  Li1 , A.  M.  Wu1 , S.  Giannini1 [*] , D.  Sachdev2 , D.  Yee2 , N.  Brünner3 , D.  Ikle4 , Y.  Fujita-Yamaguchi1, 5
  • 1Department of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
  • 2Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
  • 3Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
  • 4Department of Biostatistics, City of Hope Medical Center, Duarte, CA 91010, USA
  • 5Department of Applied Biochemistry, School of Engineering, Tokai University, Hiratsuka, Japan
Further Information

Publication History

Received 29 August 2003

Accepted after Revision 3 November 2003

Publication Date:
07 January 2004 (online)

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Abstract

Proliferative and anti-apoptotic actions of IGFs are mediated by the IGF-I receptor (IGF-IR), to which both IGF-I and -II bind with high affinity. We previously reported that αIGF-IR scFv-Fc (scFv-Fc) consisting of the αIGF-IR scFv and human IgG1 Fc domain retained general characteristics of the parental 1H7 monoclonal antibody, and significantly suppressed MCF-7 tumor growth. We proposed IGF-IR down-regulation as a possible mechanism for inhibition of MCF-7 tumor growth. To further determine the therapeutic potentials of this approach, in vivo effects of this antibody on breast tumor growth were evaluated in the absence or presence of tamoxifen (Tam) using a T61 human breast tumor model. T61 xenograft growth in athymic mice was compared under five conditions, PBS, scFv-Fc, Tam, scFv-Fc+Tam, and control antibody. While treatment with PBS and control antibody did not affect T61 tumor growth, scFv-Fc, Tam, and scFv-Fc+Tam treatments significantly suppressed the tumor growth during the first two weeks of treatment. Although the growth inhibitory effect of scFv-Fc during the first two weeks was significant, the tumor grew as rapidly as PBS-treated tumors thereafter. This rapid tumor growth was suppressed when scFv-Fc was combined with Tam. Throughout four weeks, the combined Tam+scFv-Fc treatment was more effective in inhibiting the T61 tumor growth than scFv-Fc or Tam treatment alone. scFv-Fc treatment down-regulated IGF-IR which appears to contribute to tumor growth inhibition. This study provides evidence that simultaneous targeting of IGF-IR and the estrogen receptor may enhance the therapeutic effect.

Key words

IGF - Tamoxifen - Recombinant Antibody - Single Chain Antibody - Breast Tumor Growth · Inhibition

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1 Current address; Department of Clinical Pathophysiology, Endocrinology Unit, Diabetes and Metabolic Diseases Section, University of Florence, Florence, Italy

Y. Fujita-Yamaguchi, Ph. D. 

Department of Applied Biochemistry · Tokai University School of Engineering

1117 Kitakaname · Hiratsuka · Kanagawa 259-1292 · Japan

Phone: + 81 (463) 58-1211 ext. 4188 ·

Fax: + 81 (463) 50-2012

Email: yamaguch@keyaki.cc.u-tokai.ac.jp

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