Luan Fu L, Ding Ruchuang, Sharma Vijay K, Chon W James, Lagman Milagros, Suthanthiran Manikkam
Department of Medicine, Weill Medical College of Cornell University, New York-Presbyterian Hospital New York, New York, USA.
Kidney Int. 2003 Mar;63(3):917-26. doi: 10.1046/j.1523-1755.2003.00805.x.
Rapamycin is an effective inhibitor of human renal cancer metastasis.
Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value.
We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor beta1 (TGF-beta1) were also investigated.
Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-beta1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice.
Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-beta1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as well, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.
雷帕霉素是人类肾癌转移的有效抑制剂。
人类肾细胞癌（RCC）很常见，在终末期肾病（ESRD）患者和肾移植候选者中，其发病率要高出10至100倍。转移性RCC的治疗大多无效，而移植受者的免疫抑制治疗会进一步削弱疗效。一种既能预防移植排斥又能抑制RCC进展的治疗方案将具有很高的价值。
我们建立了一种人类RCC肺转移模型，使用人类RCC 786 - O作为肿瘤激发物，严重联合免疫缺陷（SCID）米色小鼠作为宿主。我们探究了雷帕霉素、环孢素或雷帕霉素加环孢素对肺转移发生及生存的影响。还研究了这些药物对肿瘤细胞生长、凋亡以及血管内皮生长因子（VEGF - A）和转化生长因子β1（TGF - β1）表达的影响。
雷帕霉素减少了肺转移灶数量，而环孢素增加了肺转移灶数量。雷帕霉素对环孢素治疗的小鼠有效，雷帕霉素或雷帕霉素加环孢素可延长生存期。雷帕霉素使RCC 786 - O细胞生长停滞于G1期并降低VEGF - A表达。与未治疗或环孢素治疗的小鼠相比，雷帕霉素治疗的小鼠肺组织中血管性血友病因子的免疫染色最少，且VEGF - A和TGF - β1的循环水平较低。
我们的研究结果支持雷帕霉素可能对RCC患者有价值这一观点，其抗肿瘤疗效是通过细胞周期停滞以及靶向降低VEGF - A和TGF - β1来实现的。已证明雷帕霉素和环孢素方案在减少肾移植急性排斥方面有效，它也可能预防RCC进展，并且有潜力预防接受肾移植的ESRD患者因RCC导致的死亡。
