title: Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin.
abstract: OBJECTIVE
  The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody.
  
  
  METHODS
  Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4β1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines.
  
  
  RESULTS
  Treatment of tumor-bearing mice with human-specific α4β1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time.
  
  
  CONCLUSIONS
  Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Scalici
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Harrer
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Allen
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA; The Cancer Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Jazaeri
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA; The Cancer Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Atkins
authors.affiliation: Biogen Idec, Inc., San Diego, CA, USA.
authors.forename: Karen R
authors.initials: KR
authors.lastname: McLachlan
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA; The Cancer Center, University of Virginia, Charlottesville, VA, USA. Electronic address: jks6a@virginia.edu.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000069442:Natalizumab; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039041:Integrin alpha4beta1; D000069442:Natalizumab; D016190:Carboplatin
keywords: Chemotherapy; Ovarian cancer; Platinum agents; VCAM-1; α4β1 integrin