贝伐单抗对荷耐顺铂人肺腺癌A549/DDP裸鼠皮下移植瘤生长的影响

Effects of bevacizumab and cisplatin on human lung adenocarcinoma A549/DDP xenografts in nude mice

目的探讨贝伐单抗联合或不联合顺铂对耐顺铂肺腺癌A549/DDP移植瘤生长的抑制作用。方法建立裸鼠移植瘤模型,随机分成空白对照组(A组)、单药贝伐单抗组(B组)、单药顺铂组(C组)、联合用药组(D组)和联合半剂量组(E组)5组,连续用药4周。观察肿瘤生长情况,计算抑瘤率;免疫组化法检测肿瘤组织微血管密度(MVD);RT-PCR分析各组经治疗后凋亡基因bcl-2及耐药基因(LRP、GST-π)mRNA表达情况。结果与空白对照组比较,经贝伐单抗治疗组(B、D、E组)抑瘤率分别为20.96%、51.67%、50.95%,联合用药组(D、E组)效果最佳。经贝伐单抗治疗组微血管密度分别为18.6±1.14、13.6±1.14、14.4±0.55,联合用药组最为显著,而单药顺铂组与对照组在抑瘤率和微血管密度表达上均无差异(P=0.632)。经贝伐单抗治疗组bcl-2mRNA表达较对照组有显著差异(P<0.001),但三组之间无差异(P>0.05);五组之间在LRP、GST-πmRNA表达上无明显差异(P>0.05)。结论贝伐单抗对荷A549/DDP裸鼠移植瘤有抑制作用,联合顺铂用药有显著协同作用,同时提高A549/DDP耐药细胞对顺铂的敏感性,其作用机制可能与抑制肿瘤微血管形成、诱导细胞凋亡增加有关。

Objective To explore the effects of bevacizumab with or without cisplatin （DDP） on the growth of lung adenocarcinoma A549/DDP cell xenografts in mice. Methods Human lung cancer A549/DDP cells was subcutaneously transplanted in to 25 nude mice, which were randomly divided into control group （group A）, bevacizumab group （group B）, DDP group （group C）, combined treatment group （group D） and half-dose combined treatment group （group E）. After corresponding treatments for 4 consecutive weeks, the tumor inhibition rate was evaluated, tumor microvessel density （MVD） measured with immunohistochemistry, and the mRNA expression of apoptosis-associated gene （bcl-2） and multidrug resistance genes （LRP and GST-π） assessed by RT-PCR. Results The tumor growth inhibition rates in groups B, D, and E with bevacizumab treatment were 20.96%, 51.67% and 50.95%, respectively, and the two combined treatment groups showed better effects. MVD in these 3 groups were 18.6~1.14, 13.6~1.14, and 14.4~0.55, respectively, and no significant difference was found in MVD between DDP group and the control group. Compared with the control group, the 3 bevacizumab-treated groups showed decreased expression of bcl-2 genes in A549/DDP tumors at a comparable amplitude, and LRP and GST-π mRNA expression showed no significant differences between the 5 groups. Conclusion Bevacizumab has synergetic inhibitory effect with conventional chemotherapy against lung adencarcinoma A549/DDP cell xenografts in mice by inhibiting angiogenesis of the tumor, and may enhance the sensitivity of A549/DDP cells to DDP by inducing cell apoptosis.