Anti-tumor Effect Of Herceptin On Nude Mice Xenografts Of Human Ovarian Cancer SKOV3 Cells And Its Synergistic Effect Of Action With Cisplatin

Objective: 1.To study the anti-tumor effect of anti-HER-2 humanized monoclonal antibodies Herceptin on nude mice xenografts of HER-2-overexpressing human ovarian cancer SKOV3 cells and explore its possible mechanism;2. To study the anti-tumor effect of Herceptin on nude mice xenografts of human ovarian cancer SKOV3 cells by different dose and time;3.To compare the anti-tumor effect of Herceptin with the combination of Herceptin and Cisplatin on nude mice xenografts of human ovarian cancer SKOV3 cells.Methods: An animal model with human ovarian cancer SKOV3 cells involved in nude mice was established and the mice were randomized into 5 groups:①Normal saline group(NS group, negative control),②Low dose Herceptin group,③High dose Herceptin group,④DDP group(Cisplatin group),⑤Combination group of Herceptin(high) and DDP; There are 3 mice in every group.The mice were administrated respectively with Herceptin (20mg/kg),Herceptin (40mg/kg) and Cisplatin(5mg/kg) via caudal vein injection once a week for consecutive 6 weeks, it was observed that the volumetric changes of the xenografts and the survivalship of the mice, then, the tumorous inhibition ratio and survival rate was calculated. Pathological changes of tumor tissues were observed. HE staining and TUNEL staining were used to detect the apoptosis induced by Herceptin in tumor cells. Expression of Ki-67, NF-kB on tumor tissues in the 5 groups was detected by immunohistochemistry.Results: 1.Contrast to negative control(NS group), The growth of xenografts of human ovarian cancer SKOV3 cells in nude mice was significantly inhibited by Herceptin ;Comparison in experiment groups, the tumorous inhibition ratio of high dose Herceptin group was significantly higher than that of low dose Herceptin group(P<0.05), and the tumorous inhibition ratio of the former was significantly raised accompanied with the temporal prolongation of therapy (P<0.05).2.Comparison in experiment groups, the tumorous inhibition ratio of the combination group of Herceptin(high) and DDP was significantly higher than that of high dose Herceptin group on 35 day after therapy (P=0.037), and also significantly higher than DDP group on 21 day after therapy (P=0.030).3. Contrast to negative control(NS group), the survival time of nude mice bearing tumor in 4 experiment groups were all prolonged in different degree, and this effect in high dose Herceptin group was most significantly of all (P<0.01).4.Detected by ICH: Ki-67LI of high dose Herceptin group(44.67±1.53) was significantly lower than that of NS group(55.33±1.53) (P<0.01), and also significantly lower than that of low dose Herceptin group(52.33±1.52) (P<0.01); Ki-67LI of the combination group(Herceptin (high)+DDP) (39.33±2.08)was lower than that of both high dose Herceptin group and DDP group(46.67±1.53) (P<0.01).Minetime, NF-kB labeling index(LI) of high dose Herceptin group(73.50±1.73)was significantly lower than that of NS group (88.00±0.50) (P<0.01), and also lower than that of low dose Herceptin group(83.50±1.73) (P<0.01); NF-kB LI of the combination group(Herceptin(high)+ DDP) (65.83±1.15)was lower than that of both high dose Herceptin group and DDP group(76.50±0.87) (P<0.01).5. Detected by TUNEL:The apoptotic index(AI) of 4 experiment groups were all significantly higher than that of NS group(23.33±5.77) (P<0.05); Comparison in experiment groups ,the AI of the combination group(Herceptin(high)+ DDP) (71.00±2.65) was higher than that of the others(P<0.05); the AI of high dose Herceptin group(56.00±3.61)was higher than that of low dose Herceptin group(47.33±1.53) (P=0.019), but lower than that of DDP group (63.33±1.53) (P=0.032).Conclusion:1. Herceptin can obviously inhibit the growth of xenografts of human ovarian cancer SKOV3 cells in nude mice; Down-regulation of Ki-67,NF -kB expression in SKOV3 cells, and then induction of tumor cell apoptosis might be one of its possible mechanisms. 2. Herceptin can prolong the survival time of nude mice bearing tumor. 3.The anti-tumor effect of Herceptin gradually reinforces accompanied with the increase of drug concentration and the prolongation of action time, So, the drug action is dependent on drug concentration and action time. 4. There are synergistic mechanism of combinative action of Herceptin and carboplatin , and their combination can more effectively inhibit the growth of tumor.