Chinese Medical Journal 2012;125(19):3556-3560
Arsenic trioxide: an ancient drug revived

ZHOU Jin

ZHOU Jin (Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China)

Correspondence to:ZHOU Jin,Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China (Tel: 86-451-85555120. Fax:86-451-53670428. E-mail:zhoujin1111@ 126.com)
Keywords
acute promyelocytic leukemia; arsenic trioxide; treatment; mechanism
Abstract
Objective  To summarize the clinical applications of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), as well as non-APL malignancies and to discuss the mechanisms and adverse effects involved in ATO administration.
Data sources  The data in this article were collected from PubMed and CHKD database with relevant English and Chinese articles published from 1957 to 2011, with key words including acute promyelocytic leukemia, arsenic trioxide, treatment, and mechanism.
Study selection  Articles including any information about ATO in the treatment of APL were selected.
Results  APL is a rare subtype of acute myeloid leukemia, with dismal prognosis under treatment with traditional chemotherapy. ATO impressively increases the complete remission rate and prolongs survival of patients with APL, with only mild and transient adverse effects. The advances in the understanding of multiple mechanisms involved in ATO treatment will benefit more cancers in future.
Conclusion  Deeper understanding of mechanisms involved in ATO treatment may provide rationales for future clinical applications in a number of human malignancies.
Arsenic has been used in medicine for more than 2400 years for a variety of ailments including ulcers, the plague, and malaria.1,2 In the 19th century, arsenic, in the form of Fowler’s solution, was introduced in clinics as an anti-leukemic remedy until it was replaced by radiation and cytotoxic chemotherapy in the early 20th century.3 In 1971, clinicians in the First Affiliated Hospital of Harbin Medical University (HMU) firstly applied arsenic compound (Ai-Lin 1) to treat cancers. Their attempts initiated the following studies on arsenic trioxide (ATO), making ATO a milestone in the treatment of acute promyelocytic leukemia (APL).4
 
ATO IN TREATMENT OF APL
 
APL is a rare subtype of acute myeloid leukemia (AML), accounting for 5%–8% of AML.5,6 In the 1950s, APL was first described as a special entity by Hillestad, as the most malignant form of acute leukemia, characterized by an accumulation of abnormal promyelocytes and a tendency of severe bleeding.7 In the 1970s, Rowley et al8 identified chromosomes 15 and 17 translocation in APL, which resulted in the formation of PML-RARA fusion transcript. At the same time, anthracycline-based chemotherapy shed light on the clinical outcome of APL. However, only 35%–45% of APL patients could be cured as defined by the assessment of 5-year disease-free survival (DFS).9 In 1985, WANG Zhen-yi’s group at the Shanghai Rui Jin Hospital demonstrated the efficacy of all-trans-retinoic acid (ATRA) in APL, raising the complete remission (CR) rate up to 90%–95% and 6-year DFS up to 86%.10 ATO (Ai-Lin 1) was first successfully applied in the treatment of adult APL in the First Affiliated Hospital of HMU since the 1980s.11-13 Since the 1990s, the clinical outcome of de novo and relapsed/refractory APL was largely improved by administration of ATO, as demonstrated by several studies in China. In 1992, Sun et al12 found that the Ai-Lin 1 induced CR in 21 of 32 (66%) patients with APL and the 10-year overall survival (OS) rate reached 30%. Subsequently, it was reported that with intravenous administration of ATO, the CR rates were 73% (22/30) in newly diagnosed APL and 52% (22/42) in relapsed APL.13 In 1997, Shen and coworkers evaluated the clinical efficacy of ATO in 15 relapsed APL patients.14 Ninety percent (9/10) of the patients achieved CR with treatment of ATO alone.
 
ATO in treatment of relapsed APL
Based on the impressive results from China, a pilot study was performed in relapsed APL patients after failure in treatment with ATRA and chemotherapy and this result was reported in the New England Journal of Medicine.15 Of the 12 relapsed patients who were refractory to ATRA, 11 patients achieved CR with a single-agent ATO. Among those responders, eight patients achieved molecular remission, which was defined by the undetectable level of PML-RARA fusion gene expression. Later, a large multi-center clinical trial was conducted.16 Eighty-five percent of patients (34/40) who relapsed after ATRA treatment achieved CR after administration of ATO. Furthermore, the PML-RARA fusion gene was negative in all those responders. The 2-year OS rate was 77% and the relapse-free survival (RFS) rate was 58% for patients in the first relapse. Supported by the above clinical trials, ATO (Trisenox) was approved by the Food and Drug Administration (FDA) in patients with relapsed/refractory APL after treatment with ATRA/anthracycline therapy.
 
ATO in treatment of de novo APL
ATO as induction therapy
The clinical efficacy of ATO has been demonstrated in relapsed/refractory APL as a re-induction agent. Recent studies supported that ATO was an effective drug in de novo APL patients. The CR rates reach up to 83%–86%, and 3-year OS rates were 79%–86%.17,18 In China, Shen et al19 evaluated the efficacy and safety of three induction regimens including ATRA, ATO, and ATRA+ATO. CR rates were similar between different treatment groups. However, incorporation of ATO in the treatment could largely reduce the relapse rate and improve the 3-year DFS.20 Those studies supported the efficacy if ATO alone in adult patients with newly diagnosed APL. However, in pediatric APL patients, the optimal dosage, the route of administration during remission induction, and post-remission therapy remained unclear. Most importantly, the toxicity and long-term safety of ATO treatment should be further evaluated in children. In 2010, ZHOU Jin and his group first evaluated the clinical outcome of ATO in 19 pediatric APL patients.21 Single-agent ATO solution (10 mg/10 ml) was supplied by the Harbin Yida Pharmaceutical Company. Intravenous ATO infusion prepared in 5% dextrose, was administered daily at the dose of 0.20 mg/kg for children 4–6 years of age and 0.16 mg/kg for those older than 6 years of age, with a maximum daily dose of 10 mg. The total daily dose was infused intravenously over the course of 2–4 hours. ATO infusion was given daily until achievement of hematological CR or to a maximum of 60 doses. Seventeen (89.5%) patients achieved hematological CR. Two early deaths occurred due to intracranial hemorrhage in the early phase of the treatment. ATO-induced leukocytosis was observed in 13 (68.4%) patients. No other severe toxicities were identified. The 5-year OS and event-free survival (EFS) were 83.9% and 72.7% respectively. This study showed that single-agent ATO was highly effective and safe in the treatment of pediatric APL, without significant risk of chronic arsenic toxicity or secondary malignancies. This regimen can replace chemotherapy in children, without inducing drug resistance.
 
ATO as consolidation therapy
In a phase 3 clinical trial (North American Leukemia Intergroup Study C9710), 481 patients with untreated APL were randomized to either a standard induction and consolidation chemotherapy regimen (tretinoin, cytarabine, and daunorubicin, followed by two courses of consolidation therapy with tretinoin plus daunorubicin), or to the same regimen plus two 25-day courses of ATO consolidation immediately after induction.22 EFS and DFS were significantly better in the ATO arm (EFS: 80% vs. 63%, P=0.0007; DFS: 90% vs. 70%, P <0.0001). This study demonstrated that the addition of ATO consolidation significantly improved EFS and DFS in adults with untreated APL. Gore et al23 evaluated the efficacy of a single cycle of ATO-based consolidation therapy (0.15 mg×kg−1×d−1, Monday–Friday, beginning on day 8, for 30 doses) in a phase 2 trial. Survival outcomes (EFS, DFS, and OS) were comparable to the ATO treatment arm of the C9710 phase 3 trial. Furthermore, this study showed that addition of ATO may reduce toxicities related to chemotherapy.
 
Those studies strongly supported the routine incorporation of ATO into the first-line consolidation therapy of de novo APL.
 
ATO as maintenance therapy
To date there is no published randomized clinical trial with regard to the effect of ATO in maintenance therapy in APL. However, the maintenance regimen including ATRA and 6-mercaptopurine and methotrexate is recommended.2 It is of note that oral ATO is under evaluation because of inconvenience existing when giving intravenous ATO daily for weeks. In a recent study, 76 patients with APL in first CR after induction and consolidation by daunorubicin and cytosine arabinoside received oral ATO-based maintenance.24 Oral ATO was demonstrated to be feasible and safe with favorable clinical outcomes.
 
MECHANISMS OF ATO
 
ATO has multiple functions via different molecular targets. The mechanisms of ATO mainly include promoting differentiation, inducing apoptosis, accumulating reactive oxygen species (ROS), and eliminating leukemic stem cells (LSC).
 
Promotion of differentiation
It has been shown in in vitro studies that ATO partially promoted myeloid differentiation of primary and NB4 APL cells at low concentrations (0.1–0.5 mmol/L).25 Morphologically, myelocyte-like cells can be observed in peripheral blood after treatment with ATO for 2–3 weeks. Meanwhile, ATO can modulate expression of cell surface differentiation markers, by down-regulating CD33 and up-regulating CD11b.15 CD11b is one of the cell surface markers of more mature myeloid cells.26 In APL, normal differentiation was blocked by PML-RARA fusion protein, through recruitment of co-repressors and histone deacetylases onto RARA target genes.27 As recently demonstrated, ATO-induced SUMOylation and degradation of PML-RARA fusion protein accounted for the main mechanism of differentiation promotion.28 Futhermore, ATO promoted differentiation via inducing histone acetylation and alteration in gene transcription.29
 
Induction of apoptosis
It has been verified that ATO induced apoptosis at high concentrations (1–2 mmol/L).22 Caspases are key components in apoptosis. Those intracellular cysteine proteases resulted in cleavage of key cellular proteins, in response to pro-apoptotic signalings.30 ATO can induce apoptosis in APL cells, non-APL hematological cells, as well as non-malignant cell lines.31,32 The activation of the caspase cascade, the decrease of the mitochondrial membrane potential (Dy),and the production of ROS all played important roles in ATO-induced apoptosis.2 Recent studies proved that ATO induced apoptosis at the gene and protein levels, including histone H3 phosphoacetylation, activation of JNK signaling pathway, suppression of human telomerase reverse transcriptase gene, inhibition of nuclear factor kB (NF-kB), downregulation of Wt1 gene, etc.3,33
 
Accumulation of cellular ROS
ROS include free radicals such as OH, O2, and molecules such as H2O2, which can damage DNA, RNA, proteins, and lipids. ROS play key roles in cellular signaling transduction, transcriptional activation, regulation of cell proliferation and apoptosis. ATO accumulates cellular ROS via different mechanisms. ATO increased ROS level through inhibiting glutathione peroxidase that can eliminate ROS.34 Using gene expression profiling and RNA interference, Chou et al35 demonstrated that NADPH oxidase was a major target of ATO-induced ROS production.
 
Elimination of LSCs
LSCs, which are initiating cells of myeloid and lymphoid leukemia, are self-renewing, pluripotent and quiescent. The majority of LSCs reside in G0 cell cycle, conferring to the resistance to traditional chemotherapy and targeted therapy.36 ATO resulted in clearance of APL LSC through degradation of PML-RARA fusion proteins.37 By using the Sca1+/lin− murine stem cells retroviral transduced by PML-RARA, Zheng et al38 found that ATO could overcome the aberrant LSCs capacities. However, ATRA cannot target the primitive APL LSCs. Furthermore, ATRA induced proliferation of LSCs, whereas ATO inhibited proliferation. This study indicated that ATO could cure APL via targeting the primitive LSCs. In non-APL diseases, ATO eliminated LSCs through inhibiting stem cell signaling transduction pathways, such as Notch, NF-kB, b-catenin, etc.39,40
 
ATO IN TREATMENT OF HEMATOLOGICAL MALIGNANCIES OTHER THAN APL
 
Chronic myeloid leukemia
Chronic myeloid leukemia (CML) is a pluripotent stem cell disorder, characterized by chromosomes 9 and 22 translocation, resulting in formation of BCR-ABL fusion protein.41 Tyrosine kinase inhibitors imatinib and dasatinib significantly improved the clinical outcome of CML by inhibiting BCR-ABL.42 Unfortunately, neither of the inhibitors can target LSC, which causes relapse of the leukemia. In the 19th century, Fowler’s solution (potassium bicarbonate-based solution of arsenic) has been applied in treatment of CML.43 Recently, ATO was shown to be able to eradicate quiescent LSCs in CML.36 ATO attenuated and degraded BCR-ABL fusion protein by inhibiting translation of BCR-ABL mRNA and making post-translational modifications of the fusion protein. Furthermore, ATO can synergize with imatinib, inducing apoptosis and blocking cell cycle in CML cells.36 Combination of ATO and imatinib might be a promising strategy in treatment of CML.
 
Multiple myeloma
Multiple myeloma (MM) is a B-cell neoplasm, characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, producing monoclonal immunoglobulin and damaging the organs. Even in patients aged less than 60 years, treated by high-dose chemotherapy plus autologous stem cell transplantation, the 10-year OS rate remains below 30%.44 The clinical efficacy of ATO in MM has recently been discovered. In vitro, ATO inhibited growth and induced apoptosis of MM cells, partially related with the inhibitory effects of ATO on potassium channel.45 Berenson et al46 evaluated the efficacy and safety of ATO combined with ascorbic acid and melphalan (MAC) in treatment of relapsed or refractory MM. Thirty-one (48%) patients achieved clinical responses. The median EFS and OS were 7 and 19 months separately. Also, ATO combined with ascorbic acid and dexamethasone or bortezomib were efficient in treatment of MM.47,48
 
Myelodysplastic syndrome (MDS)
MDS is a group of heterogeneous myeloid disorders, with the characterizations of cytopenia in peripheral blood and risk of transformation to AML.49 No current treatment can cure this disease effectively, especially the high-risk MDS. Schiller et al50 studied single-agent ATO in treatment of MDS. In low-risk and intermediate-risk 1 groups, 34% and 39% patients achieved hematological improvements, and for patients in intermediate-risk 2 and high-risk groups, only 6% and 9% did. In a phase 2 clinical trial in France, ATO was administrated at a loading dose at 0.3 mg×kg−1×d−1 for 5 days, followed by a maintenance dose at 0.25 mg×kg−1×d−1 for twice weekly and 15 weeks in total.51 The hematological responses in low-risk and high-risk patients were 26% and 17% separately. Those studies provide rationales for a clinical trial to test ATO treatment in MDS. It is also under investigation of ATO treatment in lymphoid malignant and solid tumor, such as lung cancer, colorectal cancer, renal cell carcinoma, etc.36
 
ADVERSE EFFECTS OF ATO
 
Although ATO is toxic, the toxicity is transient and mild at a therapeutic dosage, which can be effectively managed in clinic. No severe bone marrow depression and ATO-related secondary malignancies have been observed.21,36 ATO-induced leukocytosis occurred during remission induction.21 Other adverse effects, such as asymptomatic QTc prolongation, headache, skin rash, facial edema, peripheral neuropathy, musculoskeletal pain, hepatic toxicity, and dryness of the mouth were observed. Those toxicities were mild and resolved when ATO was discontinued. No long-term toxicities were observed. The arsenic concentrations in urine, nail, and hair were below the safe limits on discontinuation of ATO for 2 years. Leukocytosis commonly occurred during ATO induction, due to ATO or ATRA-induced chemokine.52 Continuously intravenous administration of ATO could maintain an effective arsenic concentration to induce apoptosis and inhibit differentiation of leukemic blasts.53 Using this administrative method, leukocytosis during remission induction can be significantly reduced and organ damage can be alleviated as well.
 
CONCLUSIONS AND PERSPECTIVES
 
As a milestone in treatment of APL, ATO impressively improved the clinical outcomes of both de novo and relapsed/refractory patients with APL and prolonged survival of those patients. Mechanisms of ATO involved inducing apoptosis, promoting differentiation, accumulating ROS, and eliminating LSCs. Recent studies showed clinical efficacy of ATO in non-APL hematological malignancies and solid tumors. Combination with ATO and other tyrosine kinase inhibitors, e.g. imatinib in CML, is expected to further improve the outcomes of those diseases.
 
REFERENCES
 
1.  Waxman S, Anderson KC. History of the development of arsenic derivatives in cancer therapy. Oncologist 2001; 6: 3-10.
2.  Emadi A, Gore SD. Arsenic trioxide, an old drug rediscovered. Blood Rev 2010; 24: 191-199.
3.  Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111: 2505-2515.
4.  Zhou J, Meng R. Mechanisms and adverse effects of arsenic trioxide in the treatment of acute promyelocytic leukemia. J Clin Hematol 2003; 16: 280-282.
5.  Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937-951.
6.  Han LN, Zhou J, Schuringa JJ, Vellenga E. Treatment strategies in acute myeloid leukemia. Chin Med J 2011; 124: 1409-1421.
7.  Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand 1957; 159: 189-194.
8.  Rowley JD, Golomb HM, Dougherty. 15/17 Translocation: a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1977; 1: 549-550.
9.  Warrell RP Jr, de Thé H, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-189.
10.  Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhao L, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567-572.
11.  Zhang T, Li Y. Clinical analysis and research on Ai-lin 1 treatment in acute myeloid leukemia. Chin J Integrat Chin West Med 1984; 4: 19-20.
12.  Sun HD, Ma L, Hu XC, Zhang TD. Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin West Med 1992; 12: 170-171.
13.  Zhang P, Wang SY, Hu XH. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol (Chin) 1996; 17: 58-62.
14.  Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997; 89: 3354-3360.
15.  Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339: 1341-1348.
16.  Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 3852-3860.
17.  Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107: 2627-2632.
18.  Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R, et al. Treatment of new cases of acute promyelocytic leukemia by arsenic trioxide without ATRA +/− chemotherapy and long term follow up of patients. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 140.
19.  Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2004; 101: 5328-5335.
20.  Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2009; 106: 3342-3347.
21.  Zhou J, Zhang Y, Li J, Li X, Hou J, Zhao Y, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood 2010; 115: 1697-1702.
22.  Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116: 3751-3757.
23.  Gore SD, Gojo I, Sekeres MA, Morris L, Devetten M, Jamieson K, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol 2010; 28: 1047-1053.
24.  Au WY, Kumana CR, Lee HK, Lin SY, Liu H, Yeung DY, et al. Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study. Blood 2011; 118: 6535-6543.
25.  Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), I: As2O3 exerts dose-dependent dual effects on APL cells. Blood 1997; 89: 3345-3353.
26.  Terstappen LW, Hollander Z, Meiners H, Loken MR. Quantitative comparison of myeloid antigens on five lineages of mature peripheral blood cells. J Leukoc Biol 1990; 48: 138-148.
27.  de The H, Chen Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer 2010; 10: 775-783.
28.  Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010; 328: 240-243.
29.  List A, Beran M, DiPersio J, Slack J, Vey N, Rosenfeld CS, et al. Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia 2003; 17: 1499-1507.
30.  Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281: 1312-1316.
31.  Rojewski MT, Baldus C, Knauf W, Thiel E, Schrezenmeier H. Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation. Br J Haematol 2002; 116: 555-563.
32.  Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 2003; 63: 2103-2108.
33.  Zhang Y, Zhou J, Li D. The role of c-un N-terminal kinase (JNK) signaling pathway in the treatment of arsenide for leukemia. Bull Chin Cancer 2004; 13: 264-266.
34.  Park MJ, Lee JY, Kwak HJ, Park CM, Lee HC, Woo SH, et al. Arsenic trioxide (As2O3) inhibits invasion of HT1080 human fibrosarcoma cells: role of nuclear factor-kappaB and reactive oxygen species. J Cell Biochem 2005; 95: 955-969.
35.  Chou WC, Jie C, Kenedy AA, Jones RJ, Trush MA, Dang CV. Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A 2004; 101: 4578-4583.
36.  Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005; 5: 311-321.
37.  Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, et al. Eradication of acute promyelocytic leukemia- initiating cells through PML-RARA degradation. Nat Med 2008; 14: 1333-1342.
38.  Zheng X, Seshire A, Ruster B, Bug G, Beissert T, Puccetti E, et al. Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RAR{alpha}-positive leukemic stem cells. Haematologica 2007; 92: 323-331.
39.  Chen SJ, Zhou GB, Zhang XW, Mao JH, de Thé H, Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood 2011; 117: 6425-6437.
40.  Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072-1078.
41.  Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005; 5: 172-183.
42.  Jabbour E, Fava C, Kantarjian H. Advances in the biology and therapy of patients with chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009; 22: 395-407.
43.  O’Dwyer M. Multifaceted approach to the treatment of bcr-abl-positive leukemias. Oncologist 2002; 7: 30-38.
44.  Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011; 364: 1046-1060.
45.  Zhou J, Wang W, Wei QF, Feng TM, Tan LJ, Yang BF. Effects of arsenic trioxide on voltage-dependent potassium channels and on cell proliferation of human multiple myeloma cells. Chin Med J 2007; 120: 1266-1269.
46.  Berenson JR, Boccia R, Siegel D, Bozdech M, Bessudo A, Stadtmauer E, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol 2006; 135: 174-183.
47.  Wu KL, Beksac M, van Droogenbroeck J, Amadori S, Zweegman S, Sonneveld P. Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. Haematologica 2006; 91: 1722-1723.
48.  Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS. A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 2007; 13: 1762-1768.
49.  Garcia-Manero G. Myelodysplastic syndromes: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86: 490-498.
50.  Schiller GJ, Slack J, Hainsworth JD, Mason J, Saleh M, Rizzieri D, et al. Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 2006; 24: 2456-2464.
51.  Vey N, Bosly A, Guerci A, Feremans W, Dombret H, Dreyfus F, et al. Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol 2006; 24: 2465-2471.
52.  Luesink M, Pennings JL, Wissink WM, Linssen PC, Muus P, Pfundt R, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome. Blood 2009; 114: 5512-5521.
53.  Zhou J, Meng R, Yang BF. Comparing two arsenic trioxide administration methods in APL therapy. Chin Med J 2004; 117: 1411-1413.
  1. National Natural Science Foundation of China,No. 81070439;