Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas
Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas
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DOI：
10.1128/jvi.78.4.1893-1902.2004
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发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Kenney, SC
中科院分区：
文献类型：
--
作者：
Feng, WH;Hong, G;Kenney, SC
EB病毒（EBV）阳性肿瘤的一种新疗法涉及有意诱导裂解形式的EBV感染联合更昔洛韦（GCV）治疗。病毒编码的激酶（胸苷激酶和BGLF 4）仅在感染的裂解形式期间表达，将GCV（一种核苷类似物）转化为其活性的细胞毒性形式。然而，由于B细胞中的EB病毒感染具有高度潜伏性，因此很难找到可在临床上用于诱导B细胞淋巴瘤中溶解性病毒感染的药物。在这里，我们证明，吉西他滨和阿霉素（而不是5-氮杂胞苷，顺铂，或5-氟尿嘧啶）诱导裂解EBV感染EBV转化的B细胞在体外和体内。吉西他滨和多柔比星都激活了EBV阴性B细胞中两个病毒立即早期基因BZLF 1和BRLF 1启动子的转录。这种效应需要BRLF 1启动子中的EGR-1基序和BZLF 1启动子中的CRE（ZII）和MEF-2D（ZI）结合位点。在野生型EBV转化的淋巴母细胞中，GCV增强了吉西他滨或多柔比星对细胞的杀伤作用，但在不能进入裂解型感染的突变病毒（BZLF 1立即早期基因缺失）转化的淋巴母细胞中则没有。最重要的是，吉西他滨或多柔比星和GCV的组合对于抑制SCID小鼠中EBV驱动的淋巴增生性疾病比单独化疗显著更有效。相比之下，齐多夫定和吉西他滨的组合并不比单独的吉西他滨更有效。这些结果表明，无论是吉西他滨或阿霉素的化疗方案中加入GCV可能会提高这些药物对EBV驱动的淋巴组织增生性疾病的患者的治疗效果。
A novel therapy for Epstein-Barr virus (EBV)-positive tumors involves the intentional induction of the lytic form of EBV infection combined with ganciclovir (GCV) treatment. Virally encoded kinases (thymidine kinase and BGLF4) which are expressed only during the lytic form of infection convert GCV (a nucleoside analogue) into its active, cytotoxic form. However, tightly latent EBV infection in B cells has made it difficult to identify drugs that can be used clinically to induce lytic viral infection in B-cell lymphomas. Here we demonstrate that gemcitabine and doxorubicin (but not 5-azacytidine, cis-platinum, or 5-fluorouracil) induce lytic EBV infection in EBV-transformed B cells in vitro and in vivo. Gemcitabine and doxorubicin both activated transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBV-negative B cells. This effect required the EGR-1 motif in the BRLF1 promoter and the CRE (ZII) and MEF-2D (ZI) binding sites in the BZLF1 promoter. GCV enhanced cell killing by gemcitabine or doxorubicin in lymphoblastoid cells transformed with wild-type EBV, but not in lymphoblastoid cells transformed by a mutant virus (with a deletion in the BZLF1 immediate-early gene) that is unable to enter the lytic form of infection. Most importantly, the combination of gemcitabine or doxorubicin and GCV was significantly more effective for the inhibition of EBV-driven lymphoproliferative disease in SCID mice than chemotherapy alone. In contrast, the combination of zidovudine and gemcitabine was no more effective than gemcitabine alone. These results suggest that the addition of GCV to either gemcitabine- or doxorubicin-containing chemotherapy regimens may enhance the therapeutic efficacy of these drugs for EBV-driven lymphoproliferative disease in patients.