A small molecule antagonist of the α v β3 integrin suppresses MDA-MB-435 skeletal metastasis

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作者：John F. Harms (1) Danny R. Welch (1) (2) (3) (4) (5) Rajeev S. Samant (1) (2) (3) Lalita A. Shevde (1) (2) (3) Mary E. Miele (6) Geetha R. Babu (1) Steven F. Goldberg (1) Virginia R. Gilman (7) Donna M. Sosnowski (7) Dianalee A. Campo (7) Carol V. Gay (5) (7) Lynn R. Budgeon (1) Robin Mercer (7) Jennifer Jewell (7) Andrea M. Mastro (5) (7) Henry J. Donahue (5) (8) Nuray Erin (1) Michael T. Debies (1) William J. Meehan (1) Amy L. Jones (9) Gabriel Mbalaviele (9) Allen Nickols (9) Neil D. Christensen (1) Robert Melly (1) Lisa N. Beck (1) Julia Kent (1) Randall K. Rader (8) John J. Kotyk (9) M.D. Pagel (9) William F. Westlin (9) David W. Griggs (9)
关键词：breast cancer ; metastasis ; bone ; MDA ; MB ; 435 ; green fluorescent protein
刊名：Clinical & Experimental Metastasis
出版年：2004
出版时间：March 2004
年：2004
卷：21
期：2
页码：119-128
全文大小：767KB
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作者单位：John F. Harms (1) Danny R. Welch (1) (2) (3) (4) (5) Rajeev S. Samant (1) (2) (3) Lalita A. Shevde (1) (2) (3) Mary E. Miele (6) Geetha R. Babu (1) Steven F. Goldberg (1) Virginia R. Gilman (7) Donna M. Sosnowski (7) Dianalee A. Campo (7) Carol V. Gay (5) (7) Lynn R. Budgeon (1) Robin Mercer (7) Jennifer Jewell (7) Andrea M. Mastro (5) (7) Henry J. Donahue (5) (8) Nuray Erin (1) Michael T. Debies (1) William J. Meehan (1) Amy L. Jones (9) Gabriel Mbalaviele (9) Allen Nickols (9) Neil D. Christensen (1) Robert Melly (1) Lisa N. Beck (1) Julia Kent (1) Randall K. Rader (8) John J. Kotyk (9) M.D. Pagel (9) William F. Westlin (9) David W. Griggs (9) 1. Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA 2. Department of Pathology, University of Alabama at Birmingham, 1670 University Blvd. Volker Hall, Rm G-019, Birmingham, Alabama, USA 3. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA 4. Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA 5. National Foundation for Cancer Research - Center for Metastasis Research, USA 6. Department of Medical Technology, University of Delaware, Newark, Delaware, USA 7. Department of Biochemistry & MOlecular Biology, Penn State University, University Park, Pennsylvania, USA 8. Department of Orthopaedics & Rehabilitation, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA 9. Discovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation, St. Louis, Missouri, USA
ISSN：1573-7276

文摘

Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvb>β3b> integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvb>β3b>-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100?mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50b> for S247 adhesion to αvb>β3b> or αIIBb>β3ab> substrates was 0.2?nM vs. 244?nM, respectively. Likewise, S247 was not toxic at doses up to 1000?μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-0% of vehicle-only-treated mice; P=0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvb>β3b> integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvb>β3b> inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

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