阿霉素对裸小鼠人肝癌原位移植瘤多药耐药性的影响

目的　探讨阿霉素对裸小鼠原位移植人肝癌多药耐药性的影响 ,并研究其耐药机制。方法　人肝癌 (BEL 740 2 )裸小鼠原位移植 ,用阿霉素腹腔注射诱导耐药 ,经MTT法检测原代培养的耐药细胞对抗癌药的敏感性 ,以流式细胞仪检测癌细胞表面mdr1基因产物P170的表达及功能。以裸小鼠原位移植人肝癌模型观察阿霉素对耐药组的疗效。结果　移植瘤组织形态及生物学方面符合人肝癌特征 ,耐药细胞表面P170表达为 75 45 %± 5 6 7% ,而对照组表达仅 4 2 5 %± 1 2 8% (P <0 0 1) ,对阿霉素的耐药倍数提高了 16 7倍 ,对羟基喜树碱和表阿霉素具有交叉耐受性(13 7倍和 7 5倍 )。耐药细胞表面P170有较强的药物外排功能。诱导后的肝癌在体内对阿霉素获得了明显的抗性。结论　阿霉素较易诱导原位移植于裸小鼠的人肝癌多药耐药性的产生 ,耐药机制主要与P170的过度表达有关

Adriamycin induced overexpession of mdrl gene-coded p-glycoportein in human hepatocelluar carcinoma orthotopic transplanted into nude mice

AIM To explore the effect of adriamycin(ADM) on expressions of mdr1 gene coded p glycoportein(p170) in human hepatocellular carcinoma(HCC) orthotopic transplanted into nude mice(BALB/C nu/nu) and observe its multidrug resistance mechanism. METHODS Four to six week old nude mice were orthotopic transplanted with HCC tissue (BEL 7402) and treated by injection of adriamycin(ADM 1 5 mg·kg -1 ,once a week for 8 weeks) into the abdomen. The primary culture of nude mice liver tumor was taken after eight weeks. The cytotoxicity to cancer cells was determined by MTT assay. The pump efflux activity and the expression of p170 were examined by flow cytometric assay and by rhodamine 123(R 123) test. RESULTS The most typical behaviour of HCC were observed in nude mice liver tumor. The results showed that p170 level of ADM group was 75 45%±5 67%, but those of that in control group was 4 25%±1 28%( P< 0 01). Hepatocellular carcinoma cells with positive mdr1 gene expression showed cross drug resistance to ADM , hydroxycamptothecin and Epirubicin. IC 50 is 16 7,13 7 and 7 5 times that of the cells with negative mdr1 gene expression. The drug pump efflux function of P glycoportein on the cytomembrane of hepatocellular carcinoma cells with positive mdr1 gene expression was markedly enhanced. Hepatocellular carcinoma with positive mdr1 gene expression was resistant to adriamycin in vivo . CONCLUSION Adriamycin can easily induce the mdr1 gene coded p glycoportein overexpression which leads to acquired multidrug resistance of human HCC in vivo .