Intra-individual Comparison of Therapeutic Responses to Vascular Disrupting Agent CA4P Between Rodent Primary and Secondary Liver Cancers

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2018 Jul 12

PMID 29991876

Citations 5

Authors

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

Affiliations

Soon will be listed here.

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 = 7) or phosphate-buffered saline at 1.0 mL/kg (control group = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). 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 ( < 0.05), followed by further perfusion decrease at 12 h ( < 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%) ( < 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..

Citing Articles

Treatment Effect of a Vascular-Disrupting Agent Dynamically Monitored by DWI: An Animal Experimental Study.

Huang D, Yang R, Zou Y, Lin H, Xu X, Wei X Can J Gastroenterol Hepatol. 2022; 2021:2909189.

PMID: 35004528 PMC: 8739180. DOI: 10.1155/2021/2909189.

Monitoring the therapeutic efficacy of CA4P in the rabbit VX2 liver tumor using dynamic contrast-enhanced MRI.

Han T, Duan Q, Yang R, Wang Y, Yin H, Meng F Diagn Interv Radiol. 2021; 27(5):587-594.

PMID: 34559047 PMC: 8480957. DOI: 10.5152/dir.2021.20010.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors.

Liu L, OKelly D, Schuetze R, Carlson G, Zhou H, Trawick M Molecules. 2021; 26(9).

PMID: 33925707 PMC: 8125421. DOI: 10.3390/molecules26092551.

Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation.

Liu Y, Wang S, Zhao X, Feng Y, Bormans G, Swinnen J Diagnostics (Basel). 2020; 10(2).

PMID: 32024029 PMC: 7168934. DOI: 10.3390/diagnostics10020078.

Predicting Therapeutic Efficacy of Vascular Disrupting Agent CA4P in Rats with Liver Tumors by Hepatobiliary Contrast Agent Mn-DPDP-Enhanced MRI.

Liu Y, Guan Q, Kong X, De Keyzer F, Feng Y, Chen F Transl Oncol. 2019; 13(1):92-101.

PMID: 31810003 PMC: 6909075. DOI: 10.1016/j.tranon.2019.09.010.

References

Zweifel M, Jayson G, Reed N, Osborne R, Hassan B, Ledermann J . Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. Ann Oncol. 2011; 22(9):2036-2041. DOI: 10.1093/annonc/mdq708. View

Maier K . [Cirrhosis of the liver as a precancerous condition]. Praxis (Bern 1994). 1998; 87(44):1462-5. View

Wu X, Ma W, Gurung K, Guo C . Mechanisms of tumor resistance to small-molecule vascular disrupting agents: treatment and rationale of combination therapy. J Formos Med Assoc. 2013; 112(3):115-24. DOI: 10.1016/j.jfma.2012.09.017. View

Ni Y, Marchal G, Yu J, Muhler A, Lukito G, Baert A . Prolonged positive contrast enhancement with Gd-EOB-DTPA in experimental liver tumors: potential value in tissue characterization. J Magn Reson Imaging. 1994; 4(3):355-63. DOI: 10.1002/jmri.1880040322. View

He X, Li S, Huang H, Li Z, Chen L, Ye S . A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours. Br J Clin Pharmacol. 2011; 71(6):860-70. PMC: 3099373. DOI: 10.1111/j.1365-2125.2011.03928.x. View

Yin T, Liu Y, Peeters R, Feng Y, Yu J, Himmelreich U . Vascular disrupting agent in pancreatic and hepatic tumour allografts: observations of location-dependent efficacy by MRI, microangiography and histomorphology. Br J Cancer. 2017; 117(10):1529-1536. PMC: 5680470. DOI: 10.1038/bjc.2017.324. View

Tozer G, Kanthou C, Lewis G, Prise V, Vojnovic B, Hill S . Tumour vascular disrupting agents: combating treatment resistance. Br J Radiol. 2008; 81 Spec No 1:S12-20. DOI: 10.1259/bjr/36205483. View

Liu Y, De Keyzer F, Wang Y, Wang F, Feng Y, Chen F . The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI-microangiography-histopathology in rats. Int J Cancer. 2018; 143(7):1817-1828. DOI: 10.1002/ijc.31567. View

Siemann D, Chaplin D, Walicke P . A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin Investig Drugs. 2009; 18(2):189-97. PMC: 3593193. DOI: 10.1517/13543780802691068. View

10.

Liu Y, Yin T, De Keyzer F, Feng Y, Chen F, Liu J . Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P. Oncotarget. 2017; 8(33):55204-55215. PMC: 5589653. DOI: 10.18632/oncotarget.19339. View

11.

Yang Z, Poon R . Vascular changes in hepatocellular carcinoma. Anat Rec (Hoboken). 2008; 291(6):721-34. DOI: 10.1002/ar.20668. View

12.

Grosios K, Holwell S, McGown A, Pettit G, Bibby M . In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. Br J Cancer. 1999; 81(8):1318-27. PMC: 2362967. DOI: 10.1038/sj.bjc.6692174. View

13.

Schlageter M, Terracciano L, DAngelo S, Sorrentino P . Histopathology of hepatocellular carcinoma. World J Gastroenterol. 2014; 20(43):15955-64. PMC: 4239483. DOI: 10.3748/wjg.v20.i43.15955. View

14.

Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris A . Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment?. Cancer Med. 2013; 2(4):427-36. PMC: 3799277. DOI: 10.1002/cam4.105. View

15.

Maida M, Macaluso F, Galia M, Cabibbo G . Hepatocellular carcinoma and synchronous liver metastases from colorectal cancer in cirrhosis: A case report. World J Hepatol. 2014; 5(12):696-700. PMC: 3879692. DOI: 10.4254/wjh.v5.i12.696. View

16.

Wang H, Van de Putte M, Chen F, De Keyzer F, Jin L, Yu J . Murine liver implantation of radiation-induced fibrosarcoma: characterization with MR imaging, microangiography and histopathology. Eur Radiol. 2008; 18(7):1422-30. DOI: 10.1007/s00330-008-0904-2. View

17.

Ni Y, Wang H, Chen F, Li J, Dekeyzer F, Feng Y . Tumor models and specific contrast agents for small animal imaging in oncology. Methods. 2009; 48(2):125-38. DOI: 10.1016/j.ymeth.2009.03.014. View

18.

Wang H, Sun X, Chen F, De Keyzer F, Yu J, Landuyt W . Treatment of rodent liver tumor with combretastatin a4 phosphate: noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology. Invest Radiol. 2008; 44(1):44-53. DOI: 10.1097/RLI.0b013e31818e5ace. View

19.

Li J, Chen F, Feng Y, Miranda Cona M, Yu J, Verbruggen A . Diverse responses to vascular disrupting agent combretastatin a4 phosphate: a comparative study in rats with hepatic and subcutaneous tumor allografts using MRI biomarkers, microangiography, and histopathology. Transl Oncol. 2013; 6(1):42-50. PMC: 3573653. DOI: 10.1593/tlo.12367. View

20.

Liu Y, Yin T, Feng Y, Miranda Cona M, Huang G, Liu J . Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research. Quant Imaging Med Surg. 2015; 5(5):708-29. PMC: 4671963. DOI: 10.3978/j.issn.2223-4292.2015.06.01. View