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The present treatment and mechanism progress of arsenic trioxide in hematological malignancies

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      Abstract

      Highlights:This paper reviewed the development history of arsenic trioxide (ATO), and summarized its mechanisms and clinical application in the treatment of hematologic malignancies. ATO can induce tumor cell apoptosis, tumor cell differentiation and play a role in the treatment of malignant tumor of the blood system.AbstractArsenic trioide (ATO) is a kind of highly toxic substances and the main effective components of arsenic. ATO has been used medicinally for over 2400 years. Recent years, many studies have found that ATO has a significant efficacy on the acute promyelocytic leukemia (APL). To further explore the latest findings of research on the treatment of hematologic malignanies of ATO, this paper reviewed the development history of ATO, and summarized its mechanisms and clinical application in the treatment of hematologic malignancies. In addition, we want to provide new ideas for researches on the treatment of cancer of ATO.

      Translated abstract

      三氧化二砷(ATO)是一种剧毒物质,又是中药砒霜的主要成分,人类用它作为药物治疗疾病已有2400多年的历史。近年来发现ATO对急性早幼粒细胞性白血病(APL)具有显著的疗效。为进一步了解ATO治疗血液系统恶性肿瘤作用的研究近况,本文回顾ATO的研发历史,并总结其在治疗血液恶性肿瘤中的作用机制及临床应用,以期为ATO治疗肿瘤方面的研究提供新的思路。

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      Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.

      All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
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        From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia.

        Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.
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          Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia.

          The long-term follow-up results of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy show high cure rates. Several studies have shown high efficacy of single-agent arsenic trioxide in newly diagnosed APL. However, long-term follow-up results are needed. One hundred ninety-seven patients with newly diagnosed APL were treated with arsenic trioxide 0.15 mg/kg daily intravenous infusion until complete remission (CR). After achieving CR, the patients received one to four more courses of therapy with arsenic trioxide as consolidation and were observed with reverse-transcriptase polymerase chain reaction studies from peripheral blood (to detect of minimal residual disease) every 3 months or until relapse or death. The morphologic CR rate was 85.8%. The most common cause of remission failure was early death owing to APL differentiation syndrome (13.2%). The most important prognostic factor for early mortality was a high WBC count at presentation. The 5-year disease-free survival (DFS) rate was 66.7% ± 4% (SE). Relapse after 5 years in CR was rare. The 5-year overall survival (OS) rate by intention-to-treat analysis was 64.4% ± 4%. In patients who achieved CR, OS and DFS were identical. The long-term follow-up of newly diagnosed patients with APL treated with single-agent arsenic trioxide shows high rates of DFS and OS.
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            Author and article information

            Affiliations
            1Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
            Author notes
            Corresponding to: Zhi-Gang Zhao, Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Email: zhaodor001@ 123456hotmail.com .
            Submitted: 11 April 2016

            Executive Editor: Xiao-Dong Wang, Zong-Shi Qin, Yi-Cheng Shi, Xiao-Hua Zhang, Lin Li

            Contributors
            Journal
            Traditional Medicine Research
            Traditional Medicine Research
            TMR Editorial Board (Jintang road, 99, Hedong district Tianjin,China, 300170. )
            2413-3973
            January 2016
            5 January 2016
            : 1
            : 3
            : 115-121
            2413-3973-1-3-115

            This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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            Orginal Article
            Medicine
            Traditional Medicine

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