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Relapsed acute promyelocytic leukemia in a hemodialysis-dependent patient treated with arsenic trioxide: a case report  [cached]
Emmons Gregory S,Steingart Richard H,Stewart James A,Mertens Wilson C
Journal of Medical Case Reports , 2012, DOI: 10.1186/1752-1947-6-355
Abstract: Introduction In the relapsed setting, arsenic trioxide remains the backbone of treatment. Scant literature exists regarding treatment of relapsed acute promyelocytic leukemia in patients with renal failure. To the best of our knowledge we are the first to report a safe and effective means of treatment for relapsed acute promyelocytic leukemia in the setting of advanced renal failure, employing titration of arsenic trioxide based on clinical parameters rather than arsenic trioxide levels. Case presentation A 33-year-old Caucasian man with a history of acute promyelocytic leukemia in remission for 3 years, as well as dialysis-dependent chronic renal failure secondary to a solitary kidney and focal segmental glomerulosclerosis and human immunodeficiency virus infection, receiving highly active antiretroviral therapy presented to our hospital with bone marrow biopsy-confirmed relapsed acute promyelocytic leukemia. Arsenic trioxide was begun at a low dose with dose escalation based only on side effect profile monitoring and not laboratory testing for induction as well as maintenance without undue toxicity. Our patient achieved and remains in complete hematologic and molecular remission as of this writing. Conclusion Arsenic trioxide can be used safely and effectively to treat acute promyelocytic leukemia in patients with advanced renal failure using careful monitoring of side effects rather than blood levels of arsenic to guide therapeutic dosing.
TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA WITH SINGLE-AGENT ARSENIC TRIOXIDE  [cached]
Vikram Mathews,Ezhilarasi Chendamarai,Biju George,Auro Viswabandya
Mediterranean Journal of Hematology and Infectious Diseases , 2011, DOI: 10.4084/mjhid.2011.
Abstract: It is well recognized that arsenic trioxide (ATO) is an efficacious agent for the treatment of acute promyelocytic leukemia (APL). Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other agents to improve the clinical outcome with reduction of dose intensity of chemotherapy and remains an option for patients who would not tolerate conventional therapy. In this review we focus on the use of single agent ATO for the treatment of APL and summarize our experience and review the literature.
Successful Control of Disseminated Intravascular Coagulation by Recombinant Thrombomodulin during Arsenic Trioxide Treatment in Relapsed Patient with Acute Promyelocytic Leukemia
Motohiro Shindo,Katsuya Ikuta,Lynda Addo,Satoshi Ito,Mikihiro Fujiya,Yoshihiro Torimoto,Yutaka Kohgo
Case Reports in Hematology , 2012, DOI: 10.1155/2012/908196
Abstract: Disseminated intravascular coagulation (DIC) frequently occurs in patients with acute promyelocytic leukemia (APL). With the induction of therapy in APL using all-trans retinoic acid (ATRA), DIC can be controlled in most cases as ATRA usually shows immediate improvement of the APL. However, arsenic trioxide (ATO) which has been used for the treatment of relapse in APL patients has shown to take time to suppress APL cells, therefore the control of DIC in APL with ATO treatment is a major problem. Recently, the recombinant soluble thrombomodulin fragment has received a lot of attention as the novel drug for the treatment of DIC with high efficacy. Here, we present a relapsed patient with APL in whom DIC was successfully and safely controlled by rTM during treatment with ATO.
Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide  [PDF]
Serkan Sertel, Margaret Tome, Margaret M. Briehl, Judith Bauer, Kai Hock, Peter K. Plinkert, Thomas Efferth
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035584
Abstract: Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC50 values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.
Successful Control of Disseminated Intravascular Coagulation by Recombinant Thrombomodulin during Arsenic Trioxide Treatment in Relapsed Patient with Acute Promyelocytic Leukemia  [PDF]
Motohiro Shindo,Katsuya Ikuta,Lynda Addo,Satoshi Ito,Mikihiro Fujiya,Yoshihiro Torimoto,Yutaka Kohgo
Case Reports in Hematology , 2012, DOI: 10.1155/2012/908196
Abstract: Disseminated intravascular coagulation (DIC) frequently occurs in patients with acute promyelocytic leukemia (APL). With the induction of therapy in APL using all-trans retinoic acid (ATRA), DIC can be controlled in most cases as ATRA usually shows immediate improvement of the APL. However, arsenic trioxide (ATO) which has been used for the treatment of relapse in APL patients has shown to take time to suppress APL cells, therefore the control of DIC in APL with ATO treatment is a major problem. Recently, the recombinant soluble thrombomodulin fragment has received a lot of attention as the novel drug for the treatment of DIC with high efficacy. Here, we present a relapsed patient with APL in whom DIC was successfully and safely controlled by rTM during treatment with ATO. 1. Brief Communication Disseminated intravascular coagulation (DIC) frequently occurs in patients with acute promyelocytic leukemia (APL), contributing to bleeding complications, especially during treatment. With the induction of therapy in APL using all-trans retinoic acid (ATRA), DIC can be controlled in most cases as ATRA usually shows immediate improvement of the APL. However, arsenic trioxide (ATO) which has recently been used for the treatment of relapse in APL patients has shown to take time to suppress APL cells, therefore the control of DIC in APL with ATO treatment is a major problem. Recently, the recombinant soluble thrombomodulin fragment (rTM, Recomodulin; Asahi Kasei Pharm, Tokyo, Japan) has received a lot of attention as the novel drug for the treatment of DIC with high efficacy [1]. DIC may however occur as a result of various diseases, such as severe infection and malignant tumors, therefore more clinical experiences using rTM for various situations are needed to know the precise indications of rTM. Here, we present a relapsed patient with APL in whom DIC was successfully and safely controlled by rTM during treatment with ATO. A 38-year-old Japanese man was diagnosed with APL in 2007. At the time of first onset of the disease, no finding indicating DIC was observed. Chemotherapy combined with ATRA was performed as induction therapy. ATRA syndrome occurred, but that was successfully improved with the administration of steroid. After consolidation therapy, molecular CR was achieved. ATRA administration was continued intermittently for 2 years as maintenance therapy; this involved eight sequential courses of the daily administration of ATRA for 2 weeks followed by a 10-week follow-up period without the use of ATRA. In 2011, however, PML-RARα fusion transcript was
Dose- and Time-Dependent Response of Human Leukemia (HL-60) Cells to Arsenic Trioxide Treatment  [PDF]
Clement G. Yedjou,Pamela Moore,Paul B. Tchounwou
International Journal of Environmental Research and Public Health , 2006, DOI: 10.3390/ijerph2006030017
Abstract: The treatment of acute promyelocytic leukemia (APL) has been based on the administration of all-trans retinoic acid plus anthracycline chemotherapy, which is very effective as first line therapy; however 25 to 30% of patients will relapse with their disease becoming refractory to conventional therapy. Recently, studies have shown arsenic trioxide to be effective in the treatment of acute promyelocytic leukemia. In this study, we used the human leukemia (HL-60) cell line as a model to evaluate the cytoxicity of arsenic trioxide based on the MTT assay. Data obtained from this assay indicated that arsenic trioxide significantly reduced the viability of HL-60 cells, showing LD50 values of 14.26 + 0.5μg/mL, 12.54 + 0.3μg/mL, and 6.4 + 0.6μg/mL upon 6, 12, and 24 hours of exposure, respectively; indicating a dose- and time-dependent response relationship. Findings from the present study indicate that arsenic trioxide is highly cytotoxic to human leukemia (HL-60) cells, supporting its use as an effective therapeutic agent in the management of acute promyelocytic leukemia.
Arsenic trioxide induce apoptosis independent of TNFR-I and CD30 pathways in Acute promyelocytic leukemia patient with t(15;17) translocation.
Ardjmand.AR,Alimoghadam. K,Kaviani S,Ghavamzadeh A
International Journal of Hematology-Oncology and Stem Cell Research , 2005,
Abstract: Arsenic trioxide (ATO) has been reported to induce apoptosis in Leukemic cells of Acute Promyelo-cytic Leukemia (APL) patients through different pathways. However, the exact mechanism of ATO-induced apoptosis is not yet clear. Co stimulation of death receptors CD30 and tumor necrosis factor receptor type one (TNFR-I) is one of the postulated mechanisms.In the present study we aimed to evaluate their involvement in fresh Promyelocytic cells separated from bone marrow of APL patients. Immunomagnetic separated cells were treated up to 48 hr at clinically tolerable concentrations of ATO (0.5-2.0 μmol/l) and expression of TNFR-I and CD30 were evaluated within the apoptotic and live populations using a sensitive triple color flow cytometric method for measuring apoptosis in combina tion with dual color immunofluorescence."nOur results suggest that the expression of TNFR-I and CD30 might not be related to ATO-induced apoptotic cell death.
Efficacy of arsenic trioxide for acute promyelocytic leukemia: a systematic review and meta-analysis
Shuang-nian XU,Jian-ping LIU
Zhong Xi Yi Jie He Xue Bao , 2009,
Abstract: Objective: To systematically review the efficacy and safety of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL). Methods: The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), China National Knowledge Infrastructure (CNKI, from 1994 to December 2008), and China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of controlled trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The related journals in the library of Third Military Medical University were hand-searched. The randomized controlled trials (RCTs) of ATO in treatment of APL were included. We adopted complete remission, overall survival rate, disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions as outcome indicators. Data were entered and analyzed with the Cochrane review manager software 5.0 (RevMan 5.0).Results: After merger of the included trials, five eligible RCTs with 328 cases were included. All the RCTs focused on the comparison of all-trans retinoic acid (ATRA) plus ATO regimen with ATRA monotherapy. Meta-analysis showed that the effect indexes for time to complete remission, two-year disease free survival rate, relapse rate, incidence of edema and incidence rate of QT interval prolongation were -1.20 [-1.68, -0.72], 8.64 [1.66,45.00], 0.21 [0.09,0.47], 4.16 [1.46,11.79] and 22.10 [2.75,177.49], respectively. The influences on other outcome indicators such as complete remission and leukocytosis were statistically non-significant.Conclusion: ATO can prolong disease free survival and reduce the time to complete remission and relapse rate of newly diagnosed APL patients, and increase the incidence of edema and prolongation of corrected QT interval during the treatment. Due to limitation of the included trials, this conclusion needs to be validated by further studies.
Toxicity Mechanisms and Metabolic Pathways of Arsenic Trioxide
三氧化二砷的代谢途径及毒理机制综述

Niu Yimin,Sakurai Tetsurou,Sun Hui,Wang Xijun,
牛一民
,樱井徹郎,孙 晖,王喜军

世界科学技术-中医药现代化 , 2011,
Abstract: Arsenic trioxide is well known as a deadly poison.However,arsenous acid injection,which is originated from white arsenic in traditional Chinese medicine(TCM),has great efficacy in the treatment of acute promyelocytic leukemia(APL).This medication is still accompanied with some severe adverse drug reactions(ADR).This paper tried to discuss metabolic pathways,as well as acute and chronic mechanisms of arsenic trioxide.The hypothetic ADR mechanism of arsenous acid injection was proposed to provide basis for new drug discovery in order to eliminate ADR.
Treatment of new cases of Acute Promyelocytic Leukemia With Arsenic Trioxide
Ardeshir Ghavamzadeh1,Kamran Alimoghaddam Hamidolah Ghafari Shahrbano Rostami Yousef Mortazavi Mohamad Jahani Roholah Hoss
International Journal of Hematology-Oncology and Stem Cell Research , 2005,
Abstract: Introduction: Arsenic Trioxide is effective and approved for treatment of relapsed or refractory APL cases to ATRA but its effects in new cases of APL is not clear and needs long term follow up to dis close the role of this drug in treatment of APL in combination with chemotherapy/ATRA or alone. Material and methods: we studied 111cases of APL (94 new case and 17 relapsed) diagnosed by mor phological criteria and confirmed by cytogenetic and/or RT-PCR for the presence of PML/RARA fu sion gene."nArsenic Trioxide was infused as 0.15mg/kg/day doses, until complete remission by morphological cri teria or till 60 days. In case of complete remission, after 28 days do rest, 0.15mg/kg/days Arsenic Tri-oxide was infused for an additional 28 days as consolidation. Also, we studied minimal residual disease by semi-sensitive RT- PCR on peripheral blood samples up to a year after complete remission. Results: Complete remission was observed in 95 patients (85.6%) and median time to complete remis sion was 30 days. There was no significant difference between remission rate in new and relapsed cases."nDuring the induction phase, the most common cause of toxicity and mortality was APL differentiation syndrome (23 cases or 20.7%). Other toxicities were serosistis (7.2%) and hepatotoxicity (19.8%). With a median follow up of 16.5(1-57) months for patients in complete remission, one and two year disease free survival (DFS) was 88.3% and 63.7%, respectively. We observed 24 relapses and 19 of them achieved second complete remission, again by Arsenic Trioxide. Median time to relapse was 17 months (4-33) and median time of second DFS after re-treatment with Arsenic Trioxide was 18 months. We observed a third and fourth remission for some patients, who relapsed, again by Arsenic Trioxide."nFor patients in complete remission, one and three years survival was 95.5% and 87.6%, respectively. Minimal residual disease was positive in 4 (8.3%) out of 48 cases up to a year after remission induction and 3 of these patients clinically relapsed."nConclusion: Arsenic Trioxide is effective as a first line treatment of APL. Results of Arsenic Trioxide combination with chemotherapy/ATRA needs further study. Also it seems that Arsenic Trioxide is ap plicable for relapsed patients again and drug resistance is an unusual event
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