Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in H22 hepatocarcinoma cells?
Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in H22 hepatocarcinoma cells?
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DOI：
10.1111/j.1365-2613.2009.00684.x
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发表时间：
2010-02-01
影响因子：
3
通讯作者：
Wang, Yan-Tao
中科院分区：
文献类型：
--
作者：
Shen, Fang-Zhen;Wang, Jing;Wang, Yan-Tao
低剂量化疗药物可以通过抑制肿瘤血管生长和阻止受损血管内皮细胞的修复来抑制肿瘤。顺铂是一种广谱、细胞周期非特异性药物，但如果大剂量使用，则会产生严重的副作用。小剂量顺铂抗血管生成作用的研究较少，因此本研究探讨了小剂量节律化疗对H22肝癌细胞增殖和血管生成的影响。采用MTT法检测LDM联合顺铂对人脐静脉内皮细胞（HUVECs）和人肝癌细胞株HepG（2）增殖的影响。LDM组给予顺铂0.6 mg/kg/d，对照组给予生理盐水0.2 ml，MTD组给予顺铂9 mg/kg/d。免疫组化法检测血管内皮生长因子（VEGF）和基质金属肽酶2（MMP-2）。采用鸡胚绒毛尿囊膜（CAM）模型观察LDM化疗联合顺铂对体内新生血管的抑制作用。低剂量顺铂以剂量和时间依赖性方式抑制HUVEC增殖，但对HepG（2）细胞增殖无效。与接受MTD顺铂的小鼠相比，接受LDM顺铂的小鼠的肿瘤生长延迟，而没有明显的体重减轻。LDM顺铂组的微血管密度、VEGF和MMP-2表达明显低于对照组和MTD组。连续低剂量顺铂抑制CAM血管生成在体内。LDM联合顺铂化疗在体外可抑制血管内皮细胞的生长，在体内表现出抗血管生成的作用。
P>Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays. The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo. Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups. Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.