新型阿霉素前体药PDOX对人胃癌原位移植瘤模型的分子靶向治疗研究

Studies of Molecular Targeted Therapy on New Adriamycin Prodrug PDOX in Treating Nude Mice Model of Orthotopically Transplanted Human Gastric Carcinoma with Peritoneal Carcinomatosis

目的:比较PDOX与DOX对裸鼠人胃癌原位移植瘤模型的疗效和毒副作用方法:建立MGC-803人胃癌原位移植瘤模型35只,随机分为PDOX组(n=12)、DOX组(n=12)和Control组(n=11),接种后第10、17、24天按体质量给药,每周进行两次详细全面记录。末次给药后1周终止实验,取血行常规、生化检查;解剖裸鼠,详细记录胃部肿瘤及腹腔播散情况,对肿瘤进行称重,计算抑瘤率;进行组织病理学检查,分析肿瘤细胞增殖、凋亡,肿瘤血管生成、侵袭转移等指标,行统计学分析。结果:至研究终点时,Control组和PDOX组全部存活,DOX组6只死亡。在肿瘤局部控制指标中,PDOX组和DOX组的胃肿瘤质量、体积均显著低于Control组(P<0.05),PDOX组和DOX组抑瘤率分别为26.4%和24.9%,两组疗效相当(P>0.05)。在血常规指标中,PDOX组血小板计数高于Control组(P<0.05),淋巴细胞比例低于Control组(P<0.05),而红细胞计数和血红蛋白在三组间差异无统计学意义(P>0.05)。在心功能指标中,PDOX组CK-MB水平高于Control组(P<0.01)。CK、LDH、肝功能及肾功能指标三组间差异均无统计学意义(P>0.05)。PDOX组和DOX组淋巴管癌栓发生率显著低于Control组(P<0.05)。免疫组织化学结果显示PDOX组Ki-67水平显著低于DOX与Controll组,三组间两两比较差异均有统计学意义(P<0.01);Bcl-2、Bcl-6、Tunel、VEGF差异均无统计学意义(P>0.05),CD34、D2-40有明显下降趋势。结论:PDOX治疗人胃癌原位移植瘤模型的整体疗效优于DOX,毒副作用低于DOX。

Objective：This project aimed to compare the efficacy and toxicity of anti-tumor drugs, PDOX and DOX, on orthotop -ic nude mice model of human gastric carcinoma （GC）. Methods：The orthotopic nude mice model of human GC was established with human GC cell line MGC- 803. The animals were randomized into PDOX （ n=12）, DOX （ n=12）, and Control （ n=11 ） groups, and were treated with PDOX （ 28.8 mg/Kg, i.p）, DOX （DOX4.0 mg/kg, i.p）, and the control （ 10.0 ml/kg, i.p）, respectively, on days10, 17, and 24. Detailed records of the general status were made on all animals twice a week. The experiments were terminated when the nude mice of any group died of tumor progression, and all the remaining nude mice were euthanized. Peripheral blood was collected for hematolo-gy and biochemistry. At autopsy, detailed records were made on the weight and size of GC, ascites, abdominal lymph nodes metastasis, and tumor-host body weight ratio. Histo-pathological studies were performed to identify any suspected sites. All data were subjected to statistical analysis. Results： Compared with the Control group, both the PDOX and DOX groups showed significant reduction in tumor weight and volume （P〈0.05）, and both treatments resulted in weight reduction of gastric tumor by 26.4% and 24.9% , respectively. There were no statistical differences between the PDOX and DOX treatments （P〉0.05）. Based on peripheral blood routine, there was a significantly higher level of platelets in the PDOX than in the Control group and （P〈0.05）, while lymphocyte ratio was lower in the PDOX than in the Control group （P〈0.05）. There were no significant differences in red blood cells and hemoglobin levels among the three groups （ P〉0.05）. There were also no significant differences in the liver and kidney functions among the three groups （ P〉0.05）. Cardiac function showed that PDOX had a significantly higher level of CK-MB compared with the Control group （P〈0.01）, and both the DOX and PDOX groups had no significant differences in creatine kinase （CK） and lactate dehydrogenase （LDH）. Immunohisto -chemistry showed that PDOX had a significantly lower level of Ki-67compared with the DOX and Control groups （P〈0.01）. There were no statistically significant differences among Bcl- 2, Bcl- 6, Tunel, and VEGF of the groups （ P〉0.05）. The values of CD 34and D2-40decreased in the PDOX group compared with DOX and Control groups. Conclusion：Compared with DOX, PDOX may have a better overall efficacy in this GC model, particularly in terms of inhibiting distant metastases and reducing toxicities.