卡波希氏瘤皰疹病毒 (Kaposi's sarcoma herpesvirus ,；簡稱 KSHV)是一種可以感染人類的病毒，而且還可能因?yàn)楦腥径葑兂蔀榭úㄏＪ先饬?，以及初期積水型淋巴癌 (primary effusion lymphoma,；簡稱 PEL),，不過最近由赫爾辛基大學(xué) (University of Helsinki)發(fā)表的一份研究結(jié)果顯示，利用活化p53訊息調(diào)控路徑,，可以有效的治療KSHV 所引發(fā)的淋巴瘤,。
就先前相關(guān)的研究所了解， p53這個屬于轉(zhuǎn)錄因子(transcription factor) 的蛋白質(zhì),，是由一個稱為TP53 的基因所負(fù)責(zé)的,，研究人員發(fā)現(xiàn)正常的細(xì)胞會適時的活化TP53 基因，利用像細(xì)胞自裁(apoptosis) 的手段,，用來保護(hù)細(xì)胞,，避免癌化的發(fā)生，而臨床上也證實(shí),，約有一半的惡性腫瘤檢體,，都找得到 TP53基因失效的證據(jù),，而最近針對p53 分子的研究,，還發(fā)現(xiàn)它會和一個稱為MDM2 的逆向調(diào)節(jié)分子(negative regulator) 相互作用,，因此使得像是一個稱為Nutlin -3a的小分子抑制物,，就成了p53 基因正常,，細(xì)胞卻仍然發(fā)生癌化的潛在治療藥物,。
這次研究人員所鎖定 KSHV病毒所引發(fā)的PEL( 初期積水型淋巴癌) ,，就是屬于TP53基因并沒有發(fā)生異常，但細(xì)胞組織仍然發(fā)生癌化的例子,，參與的研究人員,，就利用 Nutlin-3a抑制物 (inhibitor)，成功的阻斷 p53與MDM 以及KSHV 病毒的相關(guān)抗原，啟動了PEL細(xì)胞群的死亡現(xiàn)象,，因而使得原本沒有治療方法的初期積水型淋巴癌,，出現(xiàn)了成功防治的希望,。
(資料來源 : Bio.com)
英文原文：
03/16/07 -- Kaposi's sarcoma herpesvirus (KSHV) is a human tumor virus and an etiological agent for Kaposi's sarcoma and primary effusion lymphoma (PEL). PELs are aggressive lymphomas with reported median survival time shorter than six months after diagnosis. Researchers at the University of Helsinki have discovered that activation of the p53 pathway offers a novel effective treatment modality for KSHV-infected lymphomas.
The findings by the research group of Dr. P?ivi Ojala (University of Helsinki) in collaboration with the groups of Professor Marikki Laiho (University of Helsinki), Dr. Pirjo Laakkonen (University of Helsinki), and Dr. J?rgen Haas (Max von Pettenkofer Institute, Munich & University of Edinburgh) open new options for exploiting reactivation of p53 as a novel and highly selective treatment modality for this virally-induced lymphoma. The project involves scientists from two Academy of Finland National Centre of Excellence Programs, the Translational Genome-Scale Biology and Cancer Biology. The study will be published 15.3.2007 in the Journal of Clinical Investigation.
TP53 gene encodes a transcription factor (p53) that plays a central role in protecting cells from tumor development by inducing cell-cycle arrest or apoptosis via a complex signal transduction network referred to as the p53 pathway. TP53 gene is mutated or deleted in 50% of all malignant tumors. A recently discovered strategy for p53 activation targets the interaction of p53 with its negative regulator MDM2. This is based on a potent and selective small-molecule inhibitor of the p53--MDM2 interaction, the Nutlin-3a, originally discovered by Dr Lyubomir T Vassilev (Roche Research Center, Nutley, NJ., USA). Nutlin-3a has been suggested to be a potential treatment option for cancers with wt p53.
PEL is a non-Hodgkin type lymphoma latently infected with KSHV, and it manifests as an effusion malignancy in Kaposi's sarcoma patients. There are no current therapies effective against the aggressive KSHV-induced PEL. KSHV displays two patterns of infection: latent and lytic phase. During latency, only a restricted set of viral genes is expressed. The KSHV genome encodes several homologues of cellular proteins, which engage cellular signaling pathways, govern cell proliferation and modulate apoptosis.
Majority of the PELs appear to have an intact TP53 gene suggesting that genetic alterations are not selected for during PEL tumorigenesis. The results of this study demonstrate binding of the KSHV latency associated antigen LANA to both p53 and MDM2, and that the MDM2 inhibitor Nutlin-3a disrupts the p53-MDM2-LANA complex and selectively induces massive apoptosis in PEL cells. The cytotoxic effect of Nutlin-3a was specific for the KSHV-infected cells since Nutlin-3a did not induce apoptosis in lymphoblastoid cell lines transformed with another human tumor virus, the Epstein-Barr virus, despite of their wt p53 status.
Moreover, the researchers show that Nutlin-3a has striking anti-tumor activity in vivo in a mouse xenograft model for the PEL. Nutlin-3a treatment resulted in a marked regression of all tumors in the treated animals in two weeks. These results demonstrate that p53 reactivation via Nutlin-3a is an efficient treatment for KSHV-lymphomas in mice and suggest a novel therapeutic strategy for treatment of these fatal virus-induced malignancies also in humans.
Source: University of Helsinki
