Clinical & Experimental Metastasis

, Volume 21, Issue 2, pp 119–128

A small molecule antagonist of the αvβ3 integrin suppresses MDA-MB-435 skeletal metastasis

  • John F. Harms
  • Danny R. Welch
  • Rajeev S. Samant
  • Lalita A. Shevde
  • Mary E. Miele
  • Geetha R. Babu
  • Steven F. Goldberg
  • Virginia R. Gilman
  • Donna M. Sosnowski
  • Dianalee A. Campo
  • Carol V. Gay
  • Lynn R. Budgeon
  • Robin Mercer
  • Jennifer Jewell
  • Andrea M. Mastro
  • Henry J. Donahue
  • Nuray Erin
  • Michael T. Debies
  • William J. Meehan
  • Amy L. Jones
  • Gabriel Mbalaviele
  • Allen Nickols
  • Neil D. Christensen
  • Robert Melly
  • Lisa N. Beck
  • Julia Kent
  • Randall K. Rader
  • John J. Kotyk
  • M.D. Pagel
  • William F. Westlin
  • David W. Griggs
Article

DOI: 10.1023/B:CLIN.0000024763.69809.64

Cite this article as:
Harms, J.F., Welch, D.R., Samant, R.S. et al. Clin Exp Metastasis (2004) 21: 119. doi:10.1023/B:CLIN.0000024763.69809.64

Abstract

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 αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-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: IC50 for S247 adhesion to αvβ3 or αIIBβ3a 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 (25–50% 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 αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

breast cancermetastasisboneMDA-MB-435green fluorescent protein

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • 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. 1.Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of MedicineHersheyUSA
  2. 2.Department of PathologyUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Center for Metabolic Bone DiseaseUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.National Foundation for Cancer Research - Center for Metastasis ResearchUSA
  6. 6.Department of Medical TechnologyUniversity of DelawareNewarkUSA
  7. 7.Department of Biochemistry & MOlecular BiologyPenn State UniversityUSA
  8. 8.Department of Orthopaedics & RehabilitationPennsylvania State University College of MedicineHersheyUSA
  9. 9.Discovery Oncology Pharmacology & Analytical Sciences CenterPfizer CorporationSt. LouisUSA
  10. 10.Department of Gastroenterology and HepatologyPennsylvania State University College of MedicineHersheyUSA
  11. 11.Department of PharmacologyPraecis Pharmaceuticals, Inc.WalthamUSA