苏拉明联合顺铂对肺腺癌小鼠移植瘤生长和转移的影响

背景与目的:新近研究发现新生血管生成在肿瘤生长、转移以及转移灶的生长过程中起重要作用。本研究观察苏拉明联合顺铂对肺腺癌细胞LA795的T739小鼠异体移植瘤生长和转移的抑制作用,并初步探讨其作用机制。方法:建立肺腺癌细胞LA795的T739小鼠异体移植瘤模型,将32只接种LA795细胞T739小鼠随机分成4组,每组8只。对照组:每只小鼠每天生理盐水0.2ml腹腔注射;顺铂组:顺铂2mg·(kg·d)-1于接种后第4、11、18天各一次;苏拉明组:苏拉明10mg·(kg·d)-1;顺铂 苏拉明组:顺铂2mg·(kg·d)-1于接种后第4、11、18天各腹腔注射一次 苏拉明10mg·(kg·d)-1。用药16日,用药中观察肿瘤生长情况,于接种后第24天处死各组小鼠,取出双肺并剥离皮下肿瘤,计算出肺转移发生率,计数各组小鼠肺表面转移结节数并算出肺表面结节转移抑制率。收集移植瘤标本行光镜观察,采用免疫组化和图像分析系统定量检测肿瘤组织微血管密度(microvesseldensity,MVD),血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)及核因子-κB(nuclearfactor-kappaB,NF-κB)的表达和原位凋亡TUNEL法检测肿瘤细胞凋亡指数。结果:顺铂组、苏拉明组、顺铂加苏拉明组肿瘤的生长明显受到抑制,瘤重明显低于对照组,其抑瘤率分别为23.0%、34.4%、56.3%,而联合用药组抗瘤作用进一步增强。光镜观察顺铂组、苏拉明组、顺铂加苏拉明组肿瘤细胞出现坏死,苏拉明组和顺铂加苏拉明组肿瘤间质中血管数减少。各用药组NF-#B的表达都比对照组减少,凋亡指数比对照组明显提高,差异有显著性(P<0.01);苏拉明组及联合组与对照组和顺铂组相比肺表面转移结节数明显下降,同时肺转移发生率、皮下肿瘤MVD、VEGF的表达也明显下降,相反顺铂组对此则无明显改变。结论:苏拉明可明显抑制肺腺癌细胞在小鼠体内的生长和转移,与顺铂联用有协同作用,其作用机制可能与抑制其微血管形成、促进细胞凋亡有关。

Effects of suramin in combination with cisplatin on growth and metastasis of lung adenocarcinoma xenografts in mice

BACKGROUND & OBJECTIVE: Recent study found angiogenesis plays some important roles in tumor growth and metastasis. This study was to explore the inhibitory effect of angiogenesis inhibitor Suramin in combination with cisplatin (DDP) on the growth and lung metastasis of lung adenocarcinoma LA795 cell xenografts in mice. METHODS: Highly metastatic LA795 cells were inoculated into the mammary fatty pad of 32 T739 mice to establish lung adenocarcinoma models. Four days after inoculation, the mice were randomized into 4 groups: the mice in control group received intraperitoneal injection of 0.2 ml normal saline everyday; the mice in DDP group received injection of DDP 2 mg. (kg.day)-1] at the 4th, 11th, and 18th days; the mice in Suramin group received injection of Suramin 10 mg. (kg.day)-1] everyday; the mice in combination group received injection of DDP 2 mg. (kg.day)-1] at the 4th, 11th, and 18th days, and Suramin 10 mg. (kg day)-1] everyday. All mice were killed 24 days later. Lung and subcutaneous tumors were examined histologically. The metastatic tumor foci on lung surface were observed, lung weight was measured, the occurrence rate of lung metastasis and the inhibitory rate of metastatic foci were calculated, subcutaneous tumor microvessel density (MVD), vascular endothelial growth factor (VEGF), and nuclear factor-kappaB (NF-kappaB) were determined by immunohistochemistry, and tumor cell apoptosis was measured by TUNEL method. RESULTS: In DDP, Suramin, and combination groups, tumor growth was suppressed significantly, with growth inhibitory rates of 23.0%, 34.4%, and 56.3%, respectively (P<0.05). Necrosis and decrease of tumor vessels were observed in Suramin and combination groups. The expression of NF-kappaB was significantly lower and tumor cell apoptosis index was significantly higher in DDP, Suramin, and combination groups than in control group (P<0.01). The metastatic foci on lung surface were less in Suramin and combination groups than in DDP and control groups. The expression of MVD and VEGF in subcutaneous tumors and the occurrence rate of lung metastasis were also obviously lower in Suramin and combination groups. CONCLUSION: Suramin has synergetic inhibitory effect with DDP on growth and metastasis of lung adenocarcinoma LA795 cell xenografts in mice through inhibiting angiogenesis and inducing cell apoptosis.