Abstract
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 diffusion-weighted 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 micro-HCCs, 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.
Highlights
Combretastatin A4 phosphate (CA4P), as a Combretastatin family member initially derived from the South African willow tree Combretum caffrum [1], has become a leading vascular disrupting agent (VDA) for cancer therapy over the past decades [2]
Vascular responses and tissue necrosis were detected by diffusionweighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1weighted imaging (T1WI)) and dynamic contrast enhanced (DCE-) magnetic resonance imaging (MRI), which were validated by microangiography and histopathology
We first compared combretastatin A-4 phosphate (CA4P)-induced tumoral necrosis among 43 hepatocellular carcinoma (HCC) in various tumor diameters to investigate the relationship between antitumor efficacy of CA4P and tumor size of primary HCCs (Figure 2)
Summary
Combretastatin A4 phosphate (CA4P), as a Combretastatin family member initially derived from the South African willow tree Combretum caffrum [1], has become a leading vascular disrupting agent (VDA) for cancer therapy over the past decades [2]. VDA therapy features a viable rim consisting of layers of residual cancer cells at tumor periphery [5], subsequently leading to tumor relapse over several days [6]. This accentuates the necessity to combine CA4P treatment with other therapeutics such as chemotherapy [7], conventional radiotherapy [8], internal targeted radiotherapy [6] and antiangiogenic therapy [9, 10]. Neither animal models of implanted tumors nor advanced clinical investigations on human cancers could forecast how CA4P functions in the early stage of primary HCCs
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