Brown Megan, Bellon Marcia, Nicot Christophe
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, Kansas City 66160, USA.
Blood. 2007 Feb 15;109(4):1653-9. doi: 10.1182/blood-2006-04-015537. Epub 2006 Oct 31.
Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As2O3) has been shown to effectively treat acute promyelocytic leukemia (APL) with greater than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL. The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon alpha (As/IFN-alpha) with emodin and DHA on cell-cycle arrest and cell death of HTLV-I-infected cells. Importantly, we found that clinically achievable doses of DHA and emodin allowed for reduced arsenic concentrations by 100-fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN-alpha with emodin and DHA in patients with ATL refractory to conventional therapy.
成人T细胞白血病（ATL）是一种侵袭性淋巴增殖性疾病，临床预后较差，与人类T细胞白血病病毒I型（HTLV-I）感染有关。三氧化二砷（As2O3）已被证明可有效治疗急性早幼粒细胞白血病（APL），超过80%的患者可实现完全缓解。砷与干扰素联合使用在ATL治疗中也显示出有前景的结果。砷剂量缓慢增加的要求以及患者达到药理活性剂量所需的时间是一个主要障碍，因为ATL患者的中位生存期约为6个月。在本研究中，我们报告了三氧化二砷与干扰素α（As/IFN-α）联合大黄素和二十二碳六烯酸（DHA）对HTLV-I感染细胞的细胞周期阻滞和细胞死亡具有强大的协同作用。重要的是，我们发现临床可达到的DHA和大黄素剂量可使砷浓度降低100倍，同时对肿瘤细胞仍具有高毒性。我们的数据为As/IFN-α与大黄素和DHA联合用于常规治疗难治的ATL患者提供了理论依据。
