Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice

Rousselot, Philippe; Larghero, Jérôme; Labaume, S.; Poupon, Joël; Chopin, Martine; Dosquet, Christine; Marolleau, Jean‐Pierre; Janin, Anne; Brouet, Jean‐Claude; Fermand, Jean‐Paul

doi:10.1046/j.0902-4441.2003.00194.x

Cited by 44 publications

(30 citation statements)

References 13 publications

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“…The result is similar to the findings of Yasmin et al (2011); but contradicts that of Rousselot et al (2004) where they found decreased WBC level and constant Hb level when mice were given higher dose of arsenic and that might be due to apoptotic effect of arsenic on plasma cells. It is possible that since arsenicosis is not an infectious condition, there was no mobilization of the physiologic system to increase the production of white blood cells or lymphocytes.…”

Section: Hemoglobin Concentration (Hb)supporting

confidence: 76%

Effectiveness of combined treatment using Spirulina and vitamin A against chronic arsenicosis in rats

Do¹

2013

Afr. J. Pharm. Pharmacol.

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Chronic arsenicosis remains a condition of public health concerns in many countries of the world and has been linked to many other diseases. This condition has been managed in humans using a combination of therapy with differing outcomes. We conducted a controlled experiment to assess the effect of chronic arsenicosis on hematological and biochemical changes in Long-Evans rats and to assess the protective role of Spirulina combined with vitamin A following experimental arsenicosis, using daily oral doses of sodium arsenite for 63 days. The values of SGOT (Serum glutamate oxaloacetate transaminase) and SC (Serum creatinine) increased significantly (P<0.01) in all the treated groups of rats (T 1 , T 2 , T 3 and T 4 ) compared to the control (T 0 ) group, but Spirulina combined with Vitamin A produced values significantly comparable to the untreated control group. Whereas SGPT (Serum glutamate pyruvate transaminase) showed slight significance differences among the treatment groups, Spirulina combined with Vitamin A appeared most effective in managing arsenic treatment. Spirulina + Vitamin A increased the values of TEC, TLC and Hb (Total erythrocyte count, Total leukocyte count and Hemoglobin) against arsenic toxicity in rats but showed no significance differences. In conclusion, the combination of Spirulina and vitamin A were found more effective in the prevention of chronic arsenicosis in rat than using these substances (Spirulina or Vitamin A) alone.

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Section: Hemoglobin Concentration (Hb)supporting

confidence: 76%

Effectiveness of combined treatment using Spirulina and vitamin A against chronic arsenicosis in rats

Do¹

2013

Afr. J. Pharm. Pharmacol.

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“…6 Yet, we have also noted, in our SCID-MM model, that effective bone marrow concentrations may be difficult to achieve. 10 Two other phase II trials have recently been reported in advanced-phase MM patients. In the study of Munshi et al, 12 14 patients were treated with a similar ATO continuous protocol (0.15 mg/kg up to 60 days).…”

Section: Discussionmentioning

confidence: 99%

“…10 After these encouraging results, we decided to evaluate the efficacy and the safety of ATO administration in patients with refractory MM.…”

Section: Introductionmentioning

confidence: 99%

A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients

et al. 2004

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We previously showed that arsenic trioxide (ATO) and melarsoprol may inhibit the growth of multiple myeloma (MM) cells in vitro and in vivo. We report here the administration of arsenic derivatives in 12 relapsing or refractory secretory MM patients. A total of 10 patients received ATO (eight in a continuous schedule, two discontinuously) and two received melarsoprol. The melarsoprol arm was prematurely closed due to toxicity. In the ATO arm, median duration of treatment was 38 days (9-54). Hepatic toxicity was grade 3 and 2 in one and eight patients, respectively. Other toxicities included neuropathy (n ¼ 2, grade 2), encephalitis (n ¼ 1, grade 3) and leuconeutropenia (n ¼ 4, grade 3). At 2 weeks after treatment initiation, mean serum concentration of arsenic was 1.1170.16 lmol/l. No complete or partial remission was observed. A minor response (25-49% reduction of M protein in serum) and a stabilization of the Mprotein level were observed in three and four patients, respectively. After ATO discontinuation, these responses were of short duration in all cases. ATO as a single agent did not produce any significant response in advanced MM patients despite sufficient arsenic exposure. Strategies to improve biodistribution, pharmacokinetic and efficacy of the drug as well as treatment combinations are needed.

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“…Despite treatment with alkylating agents, anthracyclines, corticosteroids, 1,2 and bortezomib 3 as well as high-dose therapy and stem cell transplantation, 4-6 MM remains an incurable disease because of the high resistance to apoptosis and both intrinsic and acquired drug resistance. [7][8][9][10][11][12] Therefore, new therapeutic strategies are needed to improve patient outcome.Preclinical in vitro and in vivo studies showed that arsenic trioxide (ATO) has antimyeloma effects both as a single agent [13][14][15][16] and in combination with glutathione-depleting agents [17][18][19] and/or other antimyeloma agents. 15,20,21 Moreover, the combined results of 3 phase 2 studies in patients with relapsed MM refractory to conventional chemotherapy showed only modest efficacy of ATO as single agent, [22][23][24][25][26][27][28] but combination therapies with ascorbic acid, melphalan, steroids, thalidomide, and bortezomib have shown promising results.…”

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confidence: 99%

Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways

Lunghi

Giuliani

Mazzera

et al. 2008

Blood

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IntroductionMultiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow (BM). Despite treatment with alkylating agents, anthracyclines, corticosteroids, 1,2 and bortezomib 3 as well as high-dose therapy and stem cell transplantation, 4-6 MM remains an incurable disease because of the high resistance to apoptosis and both intrinsic and acquired drug resistance. [7][8][9][10][11][12] Therefore, new therapeutic strategies are needed to improve patient outcome.Preclinical in vitro and in vivo studies showed that arsenic trioxide (ATO) has antimyeloma effects both as a single agent [13][14][15][16] and in combination with glutathione-depleting agents [17][18][19] and/or other antimyeloma agents. 15,20,21 Moreover, the combined results of 3 phase 2 studies in patients with relapsed MM refractory to conventional chemotherapy showed only modest efficacy of ATO as single agent, [22][23][24][25][26][27][28] but combination therapies with ascorbic acid, melphalan, steroids, thalidomide, and bortezomib have shown promising results. [29][30][31][32][33][34] We have previously demonstrated that PD184352 (PD), a highly selective inhibitor of MEK phosphorylation and activation, strikingly enhances ATO-mediated apoptosis in acute myelogenous leukemia (AML) via multiple intrinsic apoptotic pathways activation. [35][36][37] MEK blockade efficiently and selectively sensitizes tumor cells to suboptimal doses of other apoptotic stimuli, including classic cytotoxic treatment (nucleoside analogs, microtubule-targeted drugs, ␥-irradiation), 38-43 biologicals (retinoids, interferons), 44,45 steroids, [46][47][48] and other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists, Bcl-2 antisense oligonucleotides). [49][50][51][52][53] In this study, we tested the apoptotic activity of ATO combined with MEK inhibitors in MM cells, and we were able to demonstrate that PD enhances ATO-induced cytotoxicity both in vitro and in vivo in a human plasmacytoma xenograft model, through a multiple modulation of apoptotic regulatory proteins, including p53 family proteins, TRAIL receptors, several Bcl-2 family proteins, and caspases, that depend on the functionality of the p53 pathway. MethodsApproval for the study was obtained from the Institutional Review Board of the Department of Clinical Sciences, University of Parma (Parma, Italy). ReagentsATO was purchased from Sigma-Aldrich (St Louis, MO). A 1 mM stock solution was obtained by dissolving ATO in phosphate-buffered saline.Submitted October 3, 2007; accepted June 12, 2008. Prepublished online as Blood First Edition paper, June 26, 2008; DOI 10.1182 DOI 10. /blood-2007 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on April 27, 2019. by guest www.bloodj...

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Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice

Cited by 44 publications

References 13 publications

Effectiveness of combined treatment using Spirulina and vitamin A against chronic arsenicosis in rats

Effectiveness of combined treatment using Spirulina and vitamin A against chronic arsenicosis in rats

A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients

Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways

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