The effect of an angiogenesis inhibitor (FR-118487) on rat experimental hepatoma -Immunohistological analysis-

本文用大鼠DEN实验性肝癌作免疫组化观察了FR-118487（FR）作为血管生成抑制剂的作用。就其临床应用而言，FR有四种给药途径。此外，还检查了其与PEIT（局部使用）和Epi.ADR（动脉使用）的联合作用。考虑到多中心发生，研究FR的化学预防。全身给药组在第12周（DEN肝癌期）未发现明显的淋巴结病变和癌病变，提示其化学预防作用。FR组血清AFP水平明显低于FR未治疗组。至于致癌后FR的作用，癌面积百分比低于FR未处理组。局部和动脉给药后，病灶生长受到明显抑制，具有缩小作用。血清AST、ALT、AFP也能反映其疗效。层粘连蛋白和增殖细胞核抗原在肿瘤生长抑制或减少的部位被抑制出现，提示层粘连蛋白表达在肿瘤发生过程中起重要作用。考虑到肝窦内皮细胞（HSEC）在癌变过程中产生层粘连蛋白，提示FR不仅作用于肿瘤周围的血管，也作用于HSEC，并抑制GST-P的表达。全身治疗组的体重减轻受到批评，但在局部和动脉注射中没有发现显著差异。结果表明，FR与PEIT联合应用可明显减少肿瘤周围的存活细胞、浸润淋巴细胞和纤维化，提示FR单独或与PEIT或化疗联合应用，可能是治疗肝癌的一种新的理想药物。与该系列相关的其他血管形成相关因素，如IL-12、IFN-γ、IP-10和IGIF，目前正在研究中，包括临床病例。

The effect of FR-118487 (FR) as an angiogenesis inhibitor was examined immunohistologically with rat DEN experimental hepatoma. Supposing its clinical application, FR was administered by four routes. In addition, its combined effects with PEIT for local use and with Epi.ADR for arterial use were examined. Taking multicentric occurrence into consideration, chemoprevention of FR was examined. In systemic administration of FR group, no distinct nodal lesion and no cancer lesions were found at Week 12 (DEN hepatoma period), suggesting its chemoprevention. Serum AFP levels in FR group were distinctly lower than those in FR untreated group. As for the effect of FR after carcinogenesis, the percent of cancer area was lower than FR untreated group. After local and intra-arterial administration, the suppressed growth of lesion was evident with a reducing effect. Serum AST,ALT,AFP also reflected its efficacy. Laminin and PCNA were suppressed to appear in the tumor growth suppressed or reduced site, suggesting an important role of laminin expression during carcinogenesis. In consideration of the fact that hepatic sinusoidal endothelial cells (HSEC) produce laminin during carcinogenesis, FR was suggested to act not only on the blood vessel surrounding the tumor but also on HSEC.The expression ofGST-P was also suppressed during carcinogenesis. Body weight loss was criticized in the systemically treated group but no significant difference was found in the local and arterial injection. It was interesting that remaing viable cells, infiltrated lymphocytes, and fibrosis were decreased in surroundings of tumor in the case of FR combined with PEIT.From the evidences mentioned above, FR,administered singly or combined with PEIT or chemotherapy, seems to be a new ideal remedy for treatment of hepatoma. In relation to this series, other vascularization-related factors such as IL-12, IFN-gamma, IP-10, and IGIF are now under investigation, including clinical cases.