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Cancer Therapy: Preclinical |
Authors' Affiliations: Departments of 1 Medicine, Gerontology and Geriatric Medicine, and 2 Urology and Immunology, University of Washington, Seattle, Washington; 3 Geriatric Research and Education Clinical Center, Veterans Affairs Puget Sound Health Care Systems, Seattle, Washington; and 4 ImClone Systems, New York
Requests for reprints: Jennifer D. Wu, Department of Medicine, University of Washington, Box 359625, Seattle, WA 98104. Phone: 206-341-5349; Fax: 206-341-5302; E-mail: wuj{at}u.washington.edu.
Purpose: The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth.
Experimental Design: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm3, A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks.
Results: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G1 cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G2-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells.
Conclusions: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR–dependent activity of the androgen receptor in androgen-independent prostate cancer cells.
Key Words: Prostate cancer • targeting IGF-IR • xenograft
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