Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2018; 24(25): 2710-2721
Published online Jul 7, 2018. doi: 10.3748/wjg.v24.i25.2710
Intra-individual comparison of therapeutic responses to vascular disrupting agent CA4P between rodent primary and secondary liver cancers
Ye-Wei Liu, Frederik De Keyzer, Yuan-Bo Feng, Feng Chen, Shao-Li Song, Johan Swinnen, Guy Bormans, Raymond Oyen, Gang Huang, Yi-Cheng Ni
Ye-Wei Liu, Gang Huang, Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
Ye-Wei Liu, Frederik De Keyzer, Yuan-Bo Feng, Feng Chen, Johan Swinnen, Guy Bormans, Raymond Oyen, Yi-Cheng Ni, Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
Ye-Wei Liu, Shao-Li Song, Gang Huang, Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Ye-Wei Liu, Gang Huang, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
Author contributions: Ni YC, Liu YW, Huang G, Swinnen J, Bormans G and Oyen R designed the research; Liu YW, Feng YB, Chen F and Ni YC performed the research; Liu YW, De Keyzer F and Chen F analyzed the data; Liu YW, Ni YC and Song SL prepared the manuscript; Ni YC, Swinnen J, Bormans G and Oyen R reviewed the manuscript; all authors approved the final version for publication.
Institutional review board statement: This study was reviewed and approved by the ethics committee of KU Leuven.
Institutional animal care and use committee statement: This animal experiment was performed in compliance with European and national regulations after approval by KU Leuven university ethics committee (P147/2013) for animal care and use.
Conflict-of-interest statement: The authors declare no potential conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yi-Cheng Ni, MD, PhD, Full Professor, Theragnostic Laboratory, Department of Imaging and Pathology, Biomedical Group, KU Leuven, Herestraat 49, Leuven 3000, Belgium. yicheng.ni@kuleuven.be
Telephone: +32-16-330165 Fax: +32-16-343765
Received: March 5, 2018
Peer-review started: March 6, 2018
First decision: March 14, 2018
Revised: April 1, 2018
Accepted: April 9, 2018
Article in press: April 9, 2018
Published online: July 7, 2018
Processing time: 121 Days and 11.6 Hours
Abstract
AIM

To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology.

METHODS

Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg (control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). In vivo MRI findings were verified by postmortem techniques.

RESULTS

On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h (P < 0.05), followed by further perfusion decrease at 12 h (P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) (P < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors.

CONCLUSION

This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents.​

Keywords: Hepatocellular carcinoma; Combretastatin A4 phosphate; Rhabdomyosarcoma; Vascular-disrupting agent; Magnetic resonance imaging; Rats

Core tip: Complex animal models combining primary and secondary liver malignancies proved feasible in rats. The therapeutic efficacy of the leading vascular disrupting agent combretastatin-A4-phosphate (CA4P) could be intra-individually compared between primary and secondary liver malignancies in the same cirrhotic rats. Clinical 3.0T magnetic resonance imaging allowed real-time monitoring of in vivo therapeutic responses within 12 h, and ex vivo microangiography and histopathology could validate the CA4P-induced tumoricidal effects. The therapeutic responses appeared superior with secondary liver tumors over that with primary hepatocellular carcinomas, which are of translational significance for planning future clinical trials of CA4P in cancer patients.