卡波希氏瘤疱疹病毒 (Kaposi's sarcoma herpesvirus ；简称 KSHV)是一种可以感染人类的病毒，而且还可能因为感染而演变成为卡波希氏肉瘤，以及初期积水型淋巴癌 (primary effusion lymphoma；简称 PEL)，不过最近由赫尔辛基大学 (University of Helsinki)发表的一份研究结果显示，利用活化p53讯息调控路径，可以有效的治疗KSHV 所引发的淋巴瘤。
就先前相关的研究所了解， p53这个属于转录因子(transcription factor) 的蛋白质，是由一个称为TP53 的基因所负责的，研究人员发现正常的细胞会适时的活化TP53 基因，利用像细胞自裁(apoptosis) 的手段，用来保护细胞，避免癌化的发生，而临床上也证实，约有一半的恶性肿瘤检体，都找得到 TP53基因失效的证据，而最近针对p53 分子的研究，还发现它会和一个称为MDM2 的逆向调节分子(negative regulator) 相互作用，因此使得像是一个称为Nutlin -3a的小分子抑制物，就成了p53 基因正常，细胞却仍然发生癌化的潜在治疗药物。
这次研究人员所锁定 KSHV病毒所引发的PEL( 初期积水型淋巴癌) ，就是属于TP53基因并没有发生异常，但细胞组织仍然发生癌化的例子，参与的研究人员，就利用 Nutlin-3a抑制物 (inhibitor)，成功的阻断 p53与MDM 以及KSHV 病毒的相关抗原，启动了PEL细胞群的死亡现象，因而使得原本没有治疗方法的初期积水型淋巴癌，出现了成功防治的希望。
(资料来源 : 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
