Westphal E M, Blackstock W, Feng W, Israel B, Kenney S C
University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA.
Cancer Res. 2000 Oct 15;60(20):5781-8.
The consistent presence of the EBV genome in certain tumors offers the potential for novel EBV-directed therapies. Switching the latent form of EBV infection present in most EBV-positive tumor cells into the cytolytic form may be clinically useful because lytic EBV infection leads to host cell destruction, and very few normal cells contain the EBV genome. It would also be therapeutically advantageous to induce expression of EBV-encoded lytic proteins that convert the nucleoside analogues ganciclovir (GCV) and 3'-azido-3'deoxythymidine (AZT) into their active, cytotoxic forms. In this report, we have explored two different approaches for activating the lytic form of EBV infection in tumors. We show that gamma-irradiation at clinically relevant doses induces lytic EBV infection in lymphoblastoid cell lines in vitro as well as in EBV-positive B-cell tumors in SCID mice. In addition, sodium butyrate (given as a single i.p. dose) is effective for activating lytic viral infection in some EBV tumor types in SCID mice. We also examined whether low-dose gamma-irradiation treatment of EBV-positive lymphoblastoid cells in vitro promotes GCV or AZT susceptibility. The combination of radiation with either GCV or AZT induced significantly more cell killing in vitro than either radiation or prodrug treatment alone. Most importantly, we found that the combination of gamma-irradiation and GCV was much more effective in treating EBV-positive lymphoblastoid tumors in SCID mice than either agent alone. Thus, GCV or AZT treatment could potentially enhance the therapeutic efficacy of radiation therapy for EBV-positive lymphomas in patients.
EBV基因组在某些肿瘤中的持续存在为新型EBV导向疗法提供了潜力。将大多数EBV阳性肿瘤细胞中存在的EBV潜伏感染形式转变为溶细胞形式可能具有临床应用价值，因为EBV溶细胞感染会导致宿主细胞破坏，且很少有正常细胞含有EBV基因组。诱导EBV编码的溶细胞蛋白表达，将核苷类似物更昔洛韦（GCV）和3'-叠氮-3'-脱氧胸苷（AZT）转化为其活性细胞毒性形式，在治疗上也将具有优势。在本报告中，我们探索了两种不同的方法来激活肿瘤中EBV感染的溶细胞形式。我们发现，临床相关剂量的γ射线照射在体外可诱导淋巴母细胞系以及SCID小鼠的EBV阳性B细胞肿瘤发生EBV溶细胞感染。此外，丁酸钠（单次腹腔注射）对激活SCID小鼠某些EBV肿瘤类型中的病毒溶细胞感染有效。我们还研究了体外低剂量γ射线照射处理EBV阳性淋巴母细胞是否会提高其对GCV或AZT的敏感性。与单独的辐射或前药处理相比，辐射与GCV或AZT联合使用在体外诱导的细胞杀伤作用明显更强。最重要的是，我们发现γ射线照射与GCV联合使用在治疗SCID小鼠的EBV阳性淋巴母细胞肿瘤方面比单独使用任何一种药物都有效得多。因此，GCV或AZT治疗可能会提高对EBV阳性淋巴瘤患者放射治疗的疗效。
