Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer.
Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer.
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DOI：
10.1007/s101470200025
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发表时间：
2002-06-01
影响因子：
3.3
通讯作者：
Kitano, Seigo
中科院分区：
文献类型：
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作者：
Ohno, Tsuyoshi;Kawano, Katsunori;Kitano, Seigo
背景：与许多化疗药物不能有效阻止肝细胞癌的血流或诱导坏死不同，AC-7700已被证明可以抑制微管蛋白聚合并选择性地阻止肿瘤血流。本研究旨在探讨AC-7700对大鼠肝癌的抗血管和抗肿瘤作用。方法：将大鼠肝癌细胞系AH-130细胞固化后植入东流大鼠肝脏。注射10 mg/kg AC-7700后0 ~ 60 min，用活体荧光显微镜直接观察肝肿瘤的血管分布。为观察AC-7700的抗血管作用，以注射前与注射后的比值测定肿瘤血管密度。通过组织病理学检查和动物生存分析来评价其抗肿瘤作用。结果：体内显微镜观察显示，AC-7700给药后30min内肿瘤灌注减少。AC-7700组60 min血管密度显著低于对照组（AC-7700为26.3 +/- 16.4%，对照组为88.5 +/- 9.2%,P < 0.001）。注射AC-7700后，组织学观察到肿瘤细胞明显坏死，肿瘤面积明显缩小（AC-7700为11.5 +/- 15.4 mm2，对照组为43.5 +/- 18.3 mm2, P < 0.05）。AC-7700组动物的成活率（50%）优于对照组（0%,P < 0.01）。结论：AC-7700在30 min内诱导肿瘤灌注明显减少，这种减少可能有助于治疗组肿瘤坏死，预后良好。AC-7700似乎是一种很有前途的治疗肝细胞癌的药物。
BACKGROUND: Unlike the many chemotherapeutic agents that do not effectively stop blood flow or induce necrosis in hepatocellular carcinoma, AC-7700 has been shown to inhibit tubulin polymerization and selectively stop tumor blood flow. The aim of this study was to elucidate the antivascular and antitumor effects of AC-7700 on rat hepatoma.METHODS: AH-130 cells, a rat hepatoma cell line, were solidified and implanted into the liver of Donryu rats. Vascularity of the liver tumor was directly identified by in-vivo fluorescence microscopy from 0 to 60 min after the injection of 10 mg/kg AC-7700. To observe the antivascular effect of AC-7700, the vascular density of the tumor was measured and assessed as the ratio of preinjection to postinjection values. The antitumor effects were evaluated with histopathologic findings and analysis of animal survival.RESULTS: In-vivo microscopic observation showed that tumor perfusion diminished within 30 min after AC-7700 administration. Vascular density in the AC-7700 group was significantly less than that in the control group at 60 min (AC-7700, 26.3 +/- 16.4%; control, 88.5 +/- 9.2%; P < 0.001). After AC-7700 injection, marked necrosis of tumor cells was observed histologically, and tumor area was decreased significantly (AC-7700, 11.5 +/- 15.4 mm2; control, 43.5 +/- 18.3 mm2; P < 0.05). The survival rate (50%) of the AC-7700 group animals was better than that of the control group (0%; P < 0.01).CONCLUSION: Markedly decreased tumor perfusion was induced by AC-7700 within 30 min, and this decrease may have contributed to the tumor necrosis and favorable outcome in the treatment group. AC-7700 appears to be a promising agent for the treatment of hepatocellular carcinoma.