上海市器官移植临床医学中心课题(Qy-040101-10),上海市卫生局青年科研基金(局021/05)和上海市青年科技启明星计划(04QMX1417)资助项目.
The work was supported by grants from Shanghai Medical Centre of Organ Transplantation (QY-040101-10), Foundation of Yung Scientists of The Health Bureau of Shanghai (024Y05) and Shanghai Rising-Star Program (04QMX1417).
利用稳定表达绿色荧光蛋白的高度恶性膀胱癌细胞株 BTT-T739-gfp建立皮下肿瘤模型,对比分析在常规免疫抑制剂量下,环孢素、雷帕霉素在肿瘤发展和转移方面的不同效应及其可能的作用机制.24只T739小鼠随机分为对照组、环孢素组、雷帕霉素组.环孢素、雷帕霉素剂量分别为10 mg/(kg·day)、1.5 mg/(kg·day),腹腔注射.观察荷瘤小鼠生存情况,计算荷瘤容积变化,以及肿瘤在肺和肝脏的转移情况,分析其作用的可能机制.结果显示,常规免疫抑制剂量下,与对照组和环孢素组比较,雷帕霉素具有明显的抗肿瘤效应.雷帕霉素可显著提高荷瘤小鼠的生存,观察期末,对照组、环孢素组及雷帕霉素组小鼠荷瘤生存率分别为62.5%、50%、100%,环孢素组与雷帕霉素组差异显著,在观察期内与对照组、环孢素组比较,雷帕霉素可显著抑制负荷肿瘤的容积.雷帕霉素应用后,肿瘤内血管显著减少,肿瘤细胞分泌VEGF的能力明显降低,与肿瘤血管形成有关基因VEGF、HIF-1α的转录活化明显受到抑制.结果证实雷帕霉素具有显著的抗肿瘤效应,这一作用与其抑制肿瘤内血管形成明显相关.抑制VEGF-A、HIF-1α等促进血管形成因子的转录、表达是其主要的作用方式之一.
The different effects of cyclosporine and rapamycin on tumor progress and metastasis and their mechanisms were investigated. BTT-T739-gfp cell line stably expressed green fluorescence protein was intracutaneously inoculated into 24 mice. One week later, the mice were randomly divided into 3 groups and treated intraperitoneally by normal saline (as control), cyclosporine and rapamycin respectively. Survival rate and tumor volume were measured. The tumor metastasis, pathological angiogenesis and expression of angiogenesis-associated genes were analyzed. The metastasis analysis in lung and liver were also accomplished under the fluorescent microscope. Compared with the normal saline and cyclosporine, the general immunosuppressive dosage of rapamycin effectively inhibited the progress and metastasis of the established tumors. It was the rapamycin that improved the survival rate of tumor-beared mice and decreased the developmental velocity of tumor volume, to which was significantly different from the control and cyclosporine groups on the 12th day and 14th day. Experimentally, rapamycin inhibited tumor growth through angiogenesis and metastases repression in the established mouse model. From a mechanistic perspective, rapamycin showed anti-angiogenetic activities related to decrease of VEGF-A production which was a result of the down-regulation on the transcriptional level of VEGF-A and its transcription activator HIF-1α. It implied that conventional immunosuppressants showed different therapeutic roles on established tumors. Rapamycin, not cyclosporine could inhibit the tumor growth and metastasis of which was referred to anti-angiogenesis.
刘永,王丰,袁 琳,胡宏惠,唐孝达.免疫抑制剂对小鼠膀胱癌进程和转移的不同效应[J].生物化学与生物物理进展,2007,34(12):1314-1320
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