Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression

Raza, Azra; Buonamici, Silvia; Lisak, Laurie; Tahir, Sarah; Li, Donglan; Imran, Mehnaz; Chaudary, Nusrat Ijaz; Pervaiz, Hassan; Gallegos, J.Alejandro; Alvi, Madiha; Mumtaz, Muhammad Ali; Gezer, Sefer; Venugopal, Parameswaran; Reddy, Poluru L.; Galili, Naomi; Candoni, Anna; Singer, Jack W.; Nucifora, Giuseppina

doi:10.1016/j.leukres.2003.11.018

Cited by 76 publications

(44 citation statements)

References 31 publications

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“…Increased surface expressions of CD44 and CD18 by splenic neutophils would increase their ability to remain in the periphery, which might contribute to the increased numbers and percentages of neutrophils in the spleen even at the 24-h time point after the last Thd treatment in the 28-day Thd-treated mice. This finding is consistent with the report that MDS patients treated with Thd usually have a delayed response in increasing blood neutrophil counts (Raza et al, 2004;Invernizzi et al, 2005). Increased CD44 expression by peripheral neutrophils would also increase their cytotoxic function (Pericle et al, 1996).…”

Section: Discussionsupporting

confidence: 91%

“…Patients with MDS often develop neutropenia and are associated with a high mortality rate due to recurrent bacterial infections (Mufti et al, 1985;Kouides and Bennett, 1997). It is currently unknown how Thd treatment in MDS patients has improved the patient's overall health, although it was hypothesized that an increased neutrophil function may be responsible (Musto, 2004;Raza et al, 2004;Lubbert et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In clinical studies, patients take Thd for several weeks or months. There is evidence that a prolonged treatment rather than a short trial is necessary to produce a positive response in MDS patients (Raza et al, 2004). Our previous reports have shown that treatment with Thd at 30-150 mg/ kg (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

Auttachoat¹,

Zheng²,

P.³

et al. 2007

Toxicology and Applied Pharmacology

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Previously, we have reported that thalidomide (Thd) can enhance neutrophil function in female B6C3F1 mice. The present study was intended to evaluate the mechanisms underlying the enhanced neutrophil responses following Thd treatment intraperitoneally (100 mg/kg) for 14 or 28 days. Treatment with Thd increased the numbers of neutrophils in the spleen, peripheral blood, bone marrow, peritoneal cavity and lung of female B6C3F1 mice when compared to the vehicle control mice. Thd treatment for 14 days increased the percentages and the number of neutrophils in the spleen in the first eight hours (peaking at 2 h) after the last Thd treatment, and it returned to the baseline after 24 h. However, Thd treatment for 28 days increased the percentages and number of neutrophils in the spleen even at the 24-h time point after the last Thd treatment. These neutrophils were demonstrated to be functional by the myeloperoxidase activity assay. Further studies have ruled out the possibility of an increased bone marrow granulopoiesis following Thd treatment. Flow cytometric analysis of the surface expression of adhesion molecules suggested that Thd treatment for either 14 or 28 days decreased the surface expression of either CD18 or CD44 by bone marrow neutrophils. On the other hand, the surface expression of both CD18 and CD44 by splenic neutrophils was increased following Thd treatment for 28 days but not for 14 days. No effect was produced for other cell surface molecules such as CD62L and CD11a. It was possible that decreased surface expressions of CD18 and CD44 facilitated neutrophils' release from the bone marrow; increased surface expressions of CD44 and CD18 by splenic neutrophils after 28 days of Thd treatment increased their ability to remain in the periphery. Taken together, Thd treatment increased neutrophils in female B6C3F1 mice, at least partially, through differentially modulating the surface expression of CD18 and CD44 by the neutrophils in the bone marrow and spleen.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

Auttachoat¹,

Zheng²,

P.³

et al. 2007

Toxicology and Applied Pharmacology

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“…Recent reports indicate that patients with high EVI1 mRNA levels before treatment respond well to the combination of arsenic trioxide and thalidomide. 12 This finding is consistent with the observation that forced EVI1 expression in murine bone marrow progenitors results in increased sensitivity to the growth inhibitory effects of arsenic trioxide. 8 In our case, another approach might have been to target the Ph þ clone with ABL1 tyrosine kinase inhibitors.…”

supporting

confidence: 89%

Association of 3q21q26 syndrome and late-appearing Philadelphia chromosome in acute myeloid leukemia

et al. 2007

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“…More recently, the discovery of its profound efficacy in acute promyelocytic leukemia (APL) has renewed interest in ATO as an antineoplastic agent (6,25). Clinical studies have demonstrated the utility of ATO in other hematologic malignancies including multiple myeloma (3) and myelodysplastic syndrome (20). ATO has also shown promise in the treatment of solid tumors including neuroblastoma, head and neck cancer, gastric cancer, prostate and ovarian cancers, and renal cell carcinoma (1,12,23,27,31).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism

Bowling

Doudican

Manga

et al. 2008

Cancer Chemother Pharmacol

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Purpose-Current standard chemotherapeutic regimens for malignant melanoma are unsatisfactory. Although in vitro studies of arsenic trioxide (ATO) have demonstrated promise against melanoma, recent phase II clinical trials have failed to show any significant clinical benefit when used as a single agent. To enhance the efficacy of ATO in the treatment of melanoma, we sought to identify compounds that potentiate the cytotoxic effects of ATO in melanoma cells. Through a screen of 2000 marketed drugs and naturally occurring compounds, a variety of antibiotic inhibitors of mitochondrial protein translation were identified.Methods-The mechanism of action for the most effective agent identified, thiostrepton, was examined in a panel of melanoma cells. Effects of combinatorial ATO and thiostrepton treatment on cytotoxicity, apoptosis, mitochondrial protein content, and reactive oxygen species (ROS) were assessed.Results-Thiostrepton (1μM) sensitized 3 out of 5 melanoma cell lines to ATO-mediated growth inhibition. Treatment with thiostrepton resulted in reduced levels of the mitochondrial-encoded protein cytochrome oxidase I (COX1). Exposure to thiostrepton in combination with ATO resulted in increased levels of cleaved poly (ADP-ribose) polymerase and cellular ROS. The growth inhibitory and pro-apototic effects of addition of the ATO/thiostrepton combination were reversed by the free radical scavenger N-acetyl-l-cysteine.Conculsions-Our data suggest that thiostrepton enhances the cytotoxic effects of ATO through a ROS-dependent mechanism. Co-administration of oxidative stress-inducing drugs such as thiostrepton in order to enhance the efficacy of ATO in the treatment of melanoma warrants further investigation.

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Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression

Cited by 76 publications

References 31 publications

Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

Association of 3q21q26 syndrome and late-appearing Philadelphia chromosome in acute myeloid leukemia

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism

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