title: Comparison of two vascular-disrupting agents at a clinically relevant dose in rodent liver tumors with multiparametric magnetic resonance imaging biomarkers.
abstract: We sought to compare the therapeutic efficacy between two vascular-disrupting agents, combretastatin A4 phosphate (CA4P) and ZD6126, at a clinically relevant dose on tumor models with magnetic resonance imaging (MRI). Thirty rats with liver rhabdomyosarcoma were randomized into CA4P (10 mg/kg), ZD6126 (10 mg/kg), and control group (n=10 for each group). Multiparametric MRI biomarkers including tumor volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC), and K (volume transfer constant) derived from T2-weighted, T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging, and dynamic contrast-enhanced MRI were compared at pretreatment, 1 h, 6 h, 24 h, 48 h, and 120 h posttreatment; they were validated using ex-vivo techniques. Relative to rapidly growing tumors without necrosis in control rats, tumors grew slower in the CA4P group compared with the ZD6126 group with a higher necrosis ratio at 120 h (P<0.05), as proven by histopathology. In the CA4P group, K decreased from 1 h until 6 h, and partially recovered at 120 h. In the ZD6126 group, the reduced K at 1 h began to rebound from 6 h and exceeded the baseline value at 120 h (P<0.05), parallel to evolving enhancement ratios (P<0.05). ADC revealed more necrotic tumors with CA4P versus ZD6126 at 120 h (P<0.05). The different tumor responses were confirmed by ex-vivo microangiography and histopathology. CA4P was more effective than ZD6126 in impairing blood supply, inducing necrosis, and delaying growth in rat liver tumors at a clinically relevant dose. A single dose of vascular-disrupting agent was insufficient to destroy the tumor. The multiparametric MRI biomarkers enabled in-vivo noninvasive comparison of therapeutic efficacy between CA4P and ZD6126.
authors.affiliation: Department of Radiology, University Hospitals, University of Leuven, Belgium.
authors.forename: Huaijun
authors.initials: H
authors.lastname: Wang
authors.forename: Marlein Miranda
authors.initials: MM
authors.lastname: Cona
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Feng
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.forename: Frederik De
authors.initials: FD
authors.lastname: Keyzer
authors.forename: Guy
authors.initials: G
authors.lastname: Marchal
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D003287:Contrast Media; D004354:Drug Screening Assays, Antitumor; D007275:Injections, Intravenous; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D055806:Microvessels / Q000187:drug effects; D009336:Necrosis; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D003287:Contrast Media; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D013267:Stilbenes; C058728:fosbretabulin