期刊
ONCOTARGET
卷 8, 期 33, 页码 55204-55215出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19339
关键词
vascular-disrupting agents; combretastatin A4 phosphate; therapeutic response; microcancer; hepatocellular carcinoma
资金
- KU Leuven project [IOF-HB/08/009, IOF-HB/12/018]
- KU Leuven Molecular Small Animal Imaging Center MoSAIC [KUL EF/05/08]
- European Union [Asia-Link CfP 2006-EuropeAid/123738/ACT/Multi, 128-498/111]
- 973 Project [2012CB932604]
- New Drug Discovery Project [2012ZX09506-001-005]
- National Natural Science Foundation of China [81530053, 81471685]
- center of excellence in vivo molecular imaging research (IMIR)
We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8-20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor-diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusionweighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 microHCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADCdiff) suggested tumor necrosis, perfusion coefficient (ADCperf) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo-and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro-HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis.
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