Document Detail


Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGF(c) chimeric protein targeting tissue factor.
MedLine Citation:
PMID:  21725665     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We evaluated the expression of tissue factor (TF) in ovarian cancer (EOC) and the potential of hI-con1, an antibody-like molecule targeting TF, as a novel form of therapy against chemotherapy-resistant ovarian disease. We studied the expression of TF in 88 EOC by immunohistochemistry (IHC) and real-time-PCR (qRT-PCR) and the levels of membrane-bound-complement-regulatory-proteins CD46, CD55 and CD59 in primary EOC cell lines by flow-cytometry. Sensitivity to hI-con1-dependent-cell-mediated-cytotoxicity (IDCC), complement-dependent-cell-cytotoxicity and inhibition of IDCC by γ-immunoglobulin were evaluated in 5-h (51)chromium-release-assays. Cytoplasmic and/or membrane TF expression was observed in 24 out of 25 (96%) of the EOC samples tested by IHC, but not in normal ovarian-tissue. EOC with clear cell histology significantly overexpress TF when compared to serous, endometrioid, or undifferentiated tumors by qRT-PCR. With a single exception, all primary EOC that overexpressed TF demonstrated high levels of CD46, CD55 and CD59 and regardless of their histology or resistance to chemotherapy, were highly sensitive to IDCC. The effect of complement and physiologic doses of γ-immunoglobulin on IDCC in ovarian cancer cell lines overexpressing TF was tumor specific and related to the overexpression of CD59 on tumor cells. Small-interfering-RNA-mediated knockdown of CD59 expression in ovarian tumors significantly increased hI-con1-mediated cytotoxic activity in vitro. Finally, low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (P < 0.01). hI-con1 molecule induces strong cytotoxicity against primary chemotherapy-resistant ovarian cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of ovarian tumors refractory to standard treatment modalities.
Authors:
Emiliano Cocco; Joyce Varughese; Natalia Buza; Stefania Bellone; Ken-Yu Lin; Marta Bellone; Paola Todeschini; Dan-Arin Silasi; Masoud Azodi; Peter E Schwartz; Thomas J Rutherford; Luisa Carrara; Renata Tassi; Sergio Pecorelli; Charles J Lockwood; Alessandro D Santin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-02
Journal Detail:
Title:  Clinical & experimental metastasis     Volume:  28     ISSN:  1573-7276     ISO Abbreviation:  Clin. Exp. Metastasis     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-21     Completed Date:  2011-12-08     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8409970     Medline TA:  Clin Exp Metastasis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  689-700     Citation Subset:  IM    
Affiliation:
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Factor VII / immunology,  metabolism,  therapeutic use
Female
Gene Expression Regulation, Neoplastic*
Humans
Immunoconjugates / immunology,  metabolism,  therapeutic use*
Immunoglobulin Fc Fragments / immunology,  metabolism,  therapeutic use
Immunotherapy / methods*
Ovarian Neoplasms / drug therapy*,  immunology,  metabolism
Thromboplastin / genetics,  immunology,  metabolism,  therapeutic use*
Grant Support
ID/Acronym/Agency:
CA-16359/CA/NCI NIH HHS; R01 CA122728/CA/NCI NIH HHS; R01 CA122728-01A2/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Immunoconjugates; 0/Immunoglobulin Fc Fragments; 0/hI-con1; 9001-25-6/Factor VII; 9035-58-9/Thromboplastin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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