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Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth
Molecular cancer therapeutics, 2016-06, Vol.15 (6), p.1344-1352
Huang, Jie
Hu, Wei
Hu, Limin
Previs, Rebecca A
Dalton, Heather J
Yang, Xiao-Yun
Sun, Yunjie
McGuire, Michael
Rupaimoole, Rajesha
Nagaraja, Archana S
Kang, Yu
Liu, Tao
Nick, Alpa M
Jennings, Nicholas B
Coleman, Robert L
Jaffe, Robert B
Sood, Anil K
2016
Details
Autor(en) / Beteiligte
Huang, Jie
Hu, Wei
Hu, Limin
Previs, Rebecca A
Dalton, Heather J
Yang, Xiao-Yun
Sun, Yunjie
McGuire, Michael
Rupaimoole, Rajesha
Nagaraja, Archana S
Kang, Yu
Liu, Tao
Nick, Alpa M
Jennings, Nicholas B
Coleman, Robert L
Jaffe, Robert B
Sood, Anil K
Titel
Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth
Ist Teil von
Molecular cancer therapeutics, 2016-06, Vol.15 (6), p.1344-1352
Ort / Verlag
United States
Erscheinungsjahr
2016
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344-52. ©2016 AACR.
Sprache
Englisch
Identifikatoren
ISSN: 1535-7163
eISSN: 1538-8514
DOI: 10.1158/1535-7163.MCT-15-0144
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4893925
Format
–
Schlagworte
Animals
,
Antibodies, Monoclonal - administration & dosage
,
Antibodies, Monoclonal - pharmacology
,
Antibodies, Monoclonal, Humanized
,
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
,
Antineoplastic Combined Chemotherapy Protocols - pharmacology
,
Cell Line, Tumor
,
Cell Proliferation - drug effects
,
Cell Survival - drug effects
,
Female
,
GATA3 Transcription Factor - metabolism
,
Gene Expression Regulation, Neoplastic - drug effects
,
Humans
,
Intracellular Signaling Peptides and Proteins - metabolism
,
Membrane Proteins - metabolism
,
Mice
,
Neoplasm Transplantation
,
Ovarian Neoplasms - drug therapy
,
Ovarian Neoplasms - metabolism
,
Receptors, Vascular Endothelial Growth Factor - administration & dosage
,
Recombinant Fusion Proteins - administration & dosage
,
Recombinant Fusion Proteins - pharmacology
,
Up-Regulation - drug effects
,
Xenograft Model Antitumor Assays
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