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目的观察α-干扰素(IFN-α)治疗肝癌产生耐药性的过程,探讨其机制。方法裸鼠肝内原位接种裸鼠人肝癌高转移裸鼠模型LCI-D20肿瘤组织,随机分为7组,每组6只。其中治疗组于接种肿瘤后第2天皮下注射给予IFN-α(1．5×10~7 U/kg体重/d)20 d,治疗组A和B裸鼠于停药后第1和21天分别被处死；治疗组C和D于停药后第21天再次给予同剂量IFN-α(1．5×10~7 U/kg体重/d)联合格列卫(100mg/kg体重/d,灌胃)治疗20 d。对照组E～G分别在接种肿瘤后第28、48、68天被处死。观察裸鼠体重,肿瘤大小、体积,检测血清血管内皮细胞生长因子(VEGF)浓度、肿瘤组织微血管密度。抽提A、D、E、G各组总RNA做关于血管生成SuperArray基因芯片。结果A～G组肿瘤的大小分别为0．27、1．54、3．22、2．23、0．68、1．93、3．98 g,其中组A和组E,组D和组G相比,肿瘤大小差异有统计学意义(P＜0．05)。外周血VEGF浓度组A和组E,组C、D和组G相比差异有统计学意义(P＜0．05)。芯片结果提示在IFN-α治疗过程中,肝癌组织VEGF mRNA和裸鼠血清中的VEGF仍保持较低水平,而PDGF-AA mRNA的表达水平逐渐升高。组A微血管密度显著低于组E,而在组C和组G间差异无统计学意义。HE染色显示治疗组与对照组相比,异常核分裂象增多,肿瘤周围包膜变薄,纤维成分减少。结论肝癌可对IFN-α治疗产生耐药性,可能的机制为肝癌肿瘤血管生成由VEGF依赖转化为PDGF依赖。
Objective To observe the process of interferon-α (IFN-α) in the treatment of hepatocarcinoma and to explore its mechanism. Methods The nude mice were inoculated in vivo with LCI-D20 tumor model of human hepatoma with high metastasis in nude mice and were randomly divided into 7 groups with 6 mice in each group. In the treatment group, IFN-α (1.5 × 10 ~ 7 U / kg body weight / d) was administered subcutaneously on the second day after the tumor inoculation for 20 days. The treatment groups A and B nude mice were sacrificed on days 1 and 21 Were given the same dose of IFN-α (1.5 × 10 ~ 7 U / kg body weight / d) combined with Gleevec (100mg / kg body weight / d, Gavage) for 20 days. Control groups E ~ G were sacrificed on the 28th, 48th and 68th days after the tumor inoculation. The body weight, tumor size, volume, serum VEGF concentration and tumor microvessel density were observed. Extract total RNA from groups A, D, E, and G to do SuperArray microarray on angiogenesis. Results The size of tumors in groups A to G were 0.27, 1.54, 3.22, 2.23, 0.68, 1.93 and 3.98 g, respectively, in which group A and group E, group D and group The difference in tumor size was statistically significant (P <0.05). There was significant difference between peripheral blood VEGF concentration group A and group E, group C, D and group G (P <0.05). Chips results suggest that in the course of IFN-α, VEGF mRNA in liver cancer tissue and VEGF in the serum of nude mice remain low, while PDGF-AA mRNA expression levels gradually increased. Microvessel density in group A was significantly lower than that in group E, but there was no significant difference between group C and group G. Hematoxylin and eosin staining showed that the number of abnormal mitosis, the thinning of the peritumoral envelope and the decrease of fiber content in the treatment group compared with the control group. Conclusions Hepatocarcinoma is resistant to IFN-α therapy. The possible mechanism is that hepatic cancer angiogenesis is converted from VEGF-dependent to PDGF-dependent.