title: Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.
abstract: A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.
authors: Theragnostic Laboratory, Department of Imaging and Pathology, University Hospital, University of Leuven, Leuven, Belgium. feng.chen@med.kuleuven.be
authors: Feng
authors: F
authors: Chen
authors: Yingmei
authors: Y
authors: Feng
authors: Kaier
authors: K
authors: Zheng
authors: Frederik
authors: F
authors: De Keyzer
authors: Junjie
authors: J
authors: Li
authors: Yuanbo
authors: Y
authors: Feng
authors: Marlein Miranda
authors: MM
authors: Cona
authors: Huaijun
authors: H
authors: Wang
authors: Yansheng
authors: Y
authors: Jiang
authors: Jie
authors: J
authors: Yu
authors: Guy
authors: G
authors: Marchal
authors: Catherine
authors: C
authors: Verfaillie
authors: Bart
authors: B
authors: De Geest
authors: Raymond
authors: R
authors: Oyen
authors: Yicheng
authors: Y
authors: Ni
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D054377:Chemokine CXCL12 / Q000097:blood; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008833:Microcirculation; D009336:Necrosis; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D051381:Rats; D013234:Stem Cells / Q000166:cytology; D013792:Thalidomide / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D013792:Thalidomide