Perrine Susan P, Hermine Olivier, Small Trudy, Suarez Felipe, O'Reilly Richard, Boulad Farid, Fingeroth Joyce, Askin Melissa, Levy Arthur, Mentzer Steven J, Di Nicola Massimo, Gianni Alessandro M, Klein Christoph, Horwitz Steven, Faller Douglas V
Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA.
Blood. 2007 Mar 15;109(6):2571-8. doi: 10.1182/blood-2006-01-024703. Epub 2006 Nov 21.
Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.
与潜伏性爱泼斯坦-巴尔病毒（EBV）相关的恶性肿瘤对核苷类抗病毒药物耐药，因为这些抗病毒药物的病毒酶靶点胸苷激酶（TK）不表达。短链脂肪酸，如丁酸，可在潜伏感染的B细胞中诱导EBV-TK表达。由于丁酸已被证明可使体外EBV（+）淋巴瘤细胞对更昔洛韦诱导的凋亡敏感，因此对15例难治性EBV（+）淋巴恶性肿瘤患者给予精氨酸丁酸联合更昔洛韦，以评估该药物组合的毒性、药代动力学和临床反应。更昔洛韦按标准剂量每日给药两次，精氨酸丁酸通过持续输注给药，在患者耐受的情况下，剂量从500mg/（kg/天）逐步增加至2000mg/（kg/天），为期21天的周期。精氨酸丁酸联合更昔洛韦的最大耐受剂量（MTD）确定为1000mg/（kg/天）。15例患者中有10例显示出显著的抗肿瘤反应，在一个治疗周期内有4例完全缓解（CR）和6例部分缓解（PR）。3例患者出现快速肿瘤溶解并发症。3例患者在精氨酸丁酸剂量大于1000mg/（kg/天）时出现可逆性嗜睡或昏迷。精氨酸丁酸和更昔洛韦的组合耐受性良好，在对其他治疗方案难治的EBV（+）淋巴恶性肿瘤体内似乎具有显著的生物学活性。
