Sehgal S N
Wyeth-Ayerst Research, Princeton, New Jersey 08540, USA.
Ther Drug Monit. 1995 Dec;17(6):660-5. doi: 10.1097/00007691-199512000-00019.
Rapamycin (Sirolimus, Rapamune), a potent immunosuppressive agent, has been demonstrated to have remarkable activity in inhibiting allograft rejection in animal models of transplantation. It is currently in phase II clinical trials. Rapamycin belongs to the class of macrocyclic immunosuppressive drugs that are bioactive only when bound to immunophilins. Cyclosporin A and FK506, two other members of this class, selectively block the transcriptional activation of several cytokine genes, thereby inhibiting cytokine production. Although rapamycin and its structural analog FK506 bind to the same immunophilin (FKBP), rapamycin acts at a later stage in T-cell cycle progression by blocking cytokine-mediated signal transduction pathways. This inhibition is the consequence of modulation of activity of a target protein by the rapamycin: FKBP complex [sirolimus effector protein (SEP)]. Although the identification of SEP has recently been reported, its function in cell-cycle progression is not known. The biochemical events that rapamycin has been shown to inhibit are (a) activation of p70S6 kinase, (b) activation of cdk2/cyclin E complex, (c) phosphorylation of retinoblastoma protein, and (d) suppression of cdc2 and cyclin A transcription.
雷帕霉素（西罗莫司，Rapamune）是一种强效免疫抑制剂，已证实在移植动物模型中对抑制同种异体移植排斥反应具有显著活性。它目前正处于II期临床试验阶段。雷帕霉素属于大环免疫抑制药物类别，只有与亲免素结合时才具有生物活性。该类别中的另外两个成员环孢素A和FK506，选择性地阻断几种细胞因子基因的转录激活，从而抑制细胞因子的产生。尽管雷帕霉素及其结构类似物FK506与相同的亲免素（FKBP）结合，但雷帕霉素通过阻断细胞因子介导的信号转导途径在T细胞周期进程的后期发挥作用。这种抑制作用是雷帕霉素：FKBP复合物[西罗莫司效应蛋白（SEP）]对靶蛋白活性进行调节的结果。尽管最近已报道了SEP的鉴定，但它在细胞周期进程中的功能尚不清楚。雷帕霉素已被证明能抑制的生化事件包括：（a）p70S6激酶的激活；（b）cdk2/细胞周期蛋白E复合物的激活；（c）视网膜母细胞瘤蛋白的磷酸化；以及（d）cdc2和细胞周期蛋白A转录的抑制。
