耐药相关基因在弥漫性大B细胞淋巴瘤中的表达与其个体化药物治疗方法的探讨

Research on relation of expression of drug resistance-related genes in diffuse large B cell lymphomas and clinical individualized chemotherapy

目的探讨p53、P-gp、GST-π、TopoⅡ基因在弥漫性大B细胞淋巴瘤(DLBCL)中的表达与其个体化药物治疗的方法。方法用免疫组织化学S-P法检测68例DLBCL初治患者、21例难治／复发患者p53、P-gp、GST-π、TopoⅡ蛋白表达,体外进行MTT试验筛选针对DLBCL患者敏感化疗药物,分析其表达与DLBCL难治／复发、化疗药物选择的合理性及其预后相关因素之间的关系。结果难治／复发组患者其p53、P-gp、GST-π表达明显高于初治组患者,二者差异有统计学意义(P<0．01),而TopoⅡ表达差异无统计学意义(P>0．05);初治患者中具有P-gp、GST-π、p53、TopoⅡ呈阳性表达者化疗后发生难治／复发的比例分别为72％、53％、41％、35％;5例p53、P-gp、GST-π均呈阳性表达者化疗后全部出现难治／复发。通过分析相关耐药基因的联合表达及参照MTT药物敏感试验选择相应的化疗药物,发现初治DLBCL患者化疗方案中非适配选择的药物占的比例越多,疗效越差,难治复发病例越多;p53蛋白表达与P-gp、TopoⅡ表达相关外,还与患者结外侵犯部位、临床分期相关。结论p53、P-gp、GST-π、TopoⅡ蛋白表达的联合检测可作为DLBCL患者难治／复发的预测指标,同时,结合体外MTT药物敏感试验选择相应的化疗药物,有利于减少化疗耐药和克服经验性选择化疗方案,从而指导DLBCL患者的个体化治疗。

Objective To investigate the relationship between the expression of drug resistance-related genes including p53,Pglycoprotein（P-gp） ,glutathione-S-transferase-π（GST-π） and DNA topoisomerase Ⅱ（Topo Ⅱ） and the approach of the individualized chemotherapy in diffuse large B cell lymphomas（DLBCL）. Methods Tissue samples from 68 initial patients and 21 relapsed or refractory patients with DLBCL were immunohistochemically stained for p53, P-gp, GST-π and Topo Ⅱ. The sensitive chemical drugs for treatment of DLBCL were detected by MTT assay in vito, in order to explain the relation between the relapsed or refractory evidence,reasonable chemical drug usage and prognosis-related factors and the expression of drug resistance-related genes with DLBCL patients. Resnlts The expression level of p53, P-gp, GST-π,except for Topo Ⅱ in relapsed or refractory patients were significantly higher than that in initial patients with DLBCL （P〈0.01）. The incidence of relapsed or refractory patients with the positive expression of p53, P-gp, GST-π and Topo Ⅱ was 41%, 72%, 53%,52. 9% and 35% respectively. Five initial patients with the simultaneous positive expression of p53, P-gp, Topo Ⅱ and GST-π have all occurred relapsed or refractory situation after receiving chemotherapy. The result showed the incidence of relapsed or refractory patients was relative to inadequate chemical drugs in initial patients with DLBCL,it was verified through our tests. Meanwhile, there were significant relativity between the positive expression of p53 and the positive expression of P-gp, Topo Ⅱ ,extranodule involvment and clinical stage. Conclusion The expressions of p53, P-gp, GST-π and Topo Ⅱ can be used as predictors of the relapsed or refractory occurrence after chemotherapy in DLBCL. Meanwhile, selecting the relevant chemo therapeutic drugs combining with MTT assay in vitro, may be helpful to lower chemothera py resistance,overcome the usage of empirical drugs or protocol,and finally conduct the individualized chemotheranv in DLBCL.