Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalidomide acts on the microenvironment of myelodysplastic syndromes (MDS) by influencing cytokine networks, and growing evidence supports thalidomide's usefulness in the management of haematological malignancies, such as MDS. The European Collaboration Group on Myelofibrosis with Myeloid Metaplasia reviewed patients who received at least four weeks' thalidomide treatment, in doses ranging from 50 mg/day to 400 mg/day. The results showed that 30% of patients had increases in haemoglobin, and, of these, almost 40% became transfusion independent. Platelets were increased in a significant proportion of patients, and approximately 40% of patients had a reduction in their spleen size. Data on thalidomide and acute myeloblastic leukaemia (AML) are conflicting: a recently published study indicated that thalidomide does not have a role in the management of acute myeloblastic leukaemia (AML), while other studies suggest some patients may respond because of thalidomide's ability to activate natural killer cells and cytotoxic T-lymphocytes. Partial responses to thalidomide treatment have been recorded in patients with lymphoma. In a phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinaemia, a partial response was seen in 25% of patients who received a starting dose of 200 mg, which was escalated in 200 mg increments every 14 days as tolerated to a maximum of 600 mg. Although further study is required, thalidomide shows promise in the treatment of a number of haematological malignancies, many of which currently have limited treatment options and poor prognosis.
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PMID:Future directions in haematology: beyond multiple myeloma. 1616 70

To investigate the purging effect of CD3AK/iNOS on primary leukemic cells from chronic myeloid leukemia patients in vitro, amphotropic packaging cell line PA317 transfected with the whole length of iNOS gene was cultivated, amplified and screened by G418. The viral titer was determined by the NIH3T3 cells. Human peripheral blood mononuclear cells were isolated and activated by anti-CD3 monoclonal antibody in vitro. CD3AK cells were incubated with viral supernatant and selected by G418. Resistant clones were assayed for iNOS gene expression by RT-RCR. The content of nitric oxide and the activity of iNOS in the culture supernatant of CD3AK/iNOS were evaluated by the method of Griess. After BMMNC or PBMNC from CML patients were co-cultured with CD3AK/iNOS, CD3AK/Neo and CD3AK/iNOS respectively, the expression of bcr/abl fusion gene was detected by serial dilution semi-quantitative net RT-PCR assay. The results showed that anti-G418 positive packaging cell line PA317 transfected with the whole length of iNOS gene clones could stably synthesize and excrete recombinant retroviral vectors. The titer of recombinant retroviral vectors was 1.0 x 10(5) CFU/ml. After being transfected by recombinant retroviral supernatant, the iNOS cDNA was expressed in CD3AK/iNOS. The content of NO and activity of iNOS that synthesized and excreted by CD3AK/iNOS were notably increased, compared with those of CD3AK. There were statistically significant differences in NO content and iNOS activity between two groups. After BMMNC or PBMNC from CML patients were co-cultured with CD3AK/iNOS, CD3AK/Neo and CD3AK/iNOS respectively, the expression of bcr/abl fusion gene in all of them was down-regulated by serial dilution semi-quantitative RT-PCR assay. It is concluded that construction of CD3AK/iNOS can markedly increase the content of NO and the activity of iNOS, which can be more efficient in in vitro purging leukemia cells for autologous hematopoietic stem cell transplantation.
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PMID:[Purging effects of CD3AK/iNOS in vitro on primary leukemic cells from chronic myeloid leukemia patients]. 1640 54

Today several monoclonal antibodies, including the anti-CD20 antibody (rituximab), the anti-CD52 antibody (alemtuzumab) and the anti-CD33 antibody (gemtuzumab ozogamacin) are all integrated in the therapeutic armamentarium of patients with malignant lymphoma, chronic lymphocytic leukaemia and acute myelogenous leukaemia, respectively. Rituximab has also been shown to be highly effective in the treatment of refractory autoimmune haemolytic anemias, idiopathic thrombocytopenia, and relapsing thrombotic thrombocytopenic purpura. New signal transduction inhibitors, dasatinib and nilotinib, are being used in patients with chronic myelogeneous leukaemia who develop resistance to imatinib. Thalidomide, lenalidomide and bortezomib have all been shown to be highly effective in multiple myeloma, and JAK2-inhibitors have entered phase II studies of patients with JAK2-positive primary myelofibrosis and related diseases.
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PMID:[Novel medical treatment modalities in hematology]. 1856 91

Thalidomide has been shown to exert its antitumor activity through the significant effects on microenvironment and immunomodulatory properties. In this study, 10 microM thalidomide treatment markedly increased the expression of the early growth response gene 1 (Egr-1) at both mRNA and protein levels in HL-60 leukemic cells. Thalidomide treatment significantly decreased the invasive cells number through Matrigel and human umbilical vein endothelial cells when compared with the controls. Moreover, the inhibitory effects could be markedly abolished by Egr-1 gene silencing with siRNA technology. Our data indicated thalidomide could suppress leukemia cell invasion and migration by upregulation of Egr-1, suggesting a novel mechanism of thalidomide in the treatment of leukemia. Further investigations are needed to explore the detailed mechanism of Egr-1 induction by thalidomide and the downstream pathways involved in the regulation of leukemia cell invasion.
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PMID:Thalidomide inhibits leukemia cell invasion and migration by upregulation of early growth response gene 1. 1915 68

The treatment of multiple myeloma (MM), a largely incurable B-cell hematologic malignancy, is changing dramatically. Autologous stem cell transplantation (SCT) and the approval of two new classes of drugs, immunomodulators and proteosome inhibitors, have resulted in improved response rates and increased overall survivals. Thalidomide, bortezomib and lenalidomide have been combined with corticosteroids, alkylators and anthracyclines in front-line MM treatment. Phase 2 and preliminary phase 3 studies have reported very high response rates and complete response rates formerly seen only with SCT. When patients with MM who have received these new drugs then proceed to transplant, major response rates are further increased. Owing to limited follow-up, it is unclear whether these higher response rates translate into increased survival. Despite these improvements, the disease remains incurable for all but a small fraction of patients. Allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect but is limited by mortality. Mortality can be reduced through the use of lower intensity conditioning regimens but this comes at a cost of higher rates of disease progression and relapse. Strategies to improve outcomes of allogeneic transplants include more intensive, yet non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering, post-transplant maintenance and targeted conditioning therapies.
Leukemia 2009 Mar
PMID:Role of autologous and allogeneic stem cell transplantation in myeloma. 1927 49

Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. We treated patients with chronic lymphocytic leukemia (CLL) with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in vivo before fludarabine treatment. Thalidomide was given daily (100 mg p.o. per day) and fludarabine was administered on days 7-11 (25 mg/m(2) i.v. per day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first-line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (del17p, del11q). The overall response rate was 80 and 25% for untreated and previously treated patients, respectively. Although thalidomide reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Tregs) was significantly decreased. Gene expression profiling revealed a thalidomide-induced signature containing both targets known to have a function in immunomodulatory drug action as well as novel candidate genes. Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk patients with CLL. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell-dependent antitumor effect.
Leukemia 2009 Oct
PMID:Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia. 1944 Feb 14

This multicenter, open-label, non-comparative phase II trial evaluated the safety and efficacy of salvage therapy with lenalidomide, melphalan, prednisone and thalidomide (RMPT) in patients with relapsed/refractory multiple myeloma (MM). Oral lenalidomide (10 mg/day) was administered on days 1-21, and oral melphalan (0.18 mg/kg) and oral prednisone (2 mg/kg) on days 1-4 of each 28-day cycle. Thalidomide was administered at 50 mg/day or 100 mg/day on days 1-28; six cycles were administered in total. Maintenance included lenalidomide 10 mg/day on days 1-21, until unacceptable adverse events or disease progression. Aspirin (100 mg/day) was given as thromboprophylaxis. A total of 44 patients with relapsed/refractory MM were enrolled and 75% achieved at least a partial response (PR), including 32% very good PR (VGPR) and 2% complete response (CR). The 1-year progression-free survival (PFS) was 51% and the 1-year overall survival (OS) from study entry was 72%. Grade 4 hematologic adverse events included neutropenia (18%), thrombocytopenia (7%) and anemia (2%). Grade 3 non-hematologic adverse events were infections (14%), neurological toxicity (4.5%) and fatigue (7%). No grade 3/4 thromboembolic events or peripheral neuropathy were reported. In conclusion, RMPT is an active salvage therapy with good efficacy and manageable side effects. This study represents the basis for larger phase III randomized trials.
Leukemia 2010 May
PMID:Lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma. 2037 79

This study was aimed to investigate the effect of CD44 gene silence on the drug resistance and biologic activity of human multidrug resistant leukemia cell line K562/A02. The oligonucleotides of CD44 gene were designed according to related data of GenBank, double-stranded DNA was produced by annealing, and was inserted into pGCsilencerU6/Neo/GFP vector. The resultant recombinant plasmid pGCsiRNA-CD44 was transfected into K562/A02 cell line. Expressions of CD44, mdr-1 and blc-2 mRNA were assayed by real time RT-PCR. The 50% inhibitory concentration (IC50) of doxorubicin (ADM) for K562/A02 cell line was determined by MTT method. Cell cycle was determined by flow cytometry. The morphology of apoptotic cells was examined by Hochst 33258 staining. The results indicated that the siRNA eukaryotic plasmid directing at CD44 gene could effectively silence the CD44 gene of K562/A02 cells; as compared with control group, the CD44 expression in K562/A02 cells transfected with 4 pGCsiRNA-CD44 plasmids was obviously inhibited, while the inhibition of CD44 expression in cells transfected with siCD44-1 was strongest. After being transfected with pGCsiRNA-CD44, the expression of CD44 mRNA in K562/A02 cells reduced by 64.1% (p<0.05), at the same time the expression of mdr-1 and bcl-2 mRNA in pGCsiRNA-CD44-transfected K562/A02 cells reduced by 25.6% and 50.8% respectively. IC50 of K562/A02 cells after transfection decreased to (8.77+/-1.63) microg/ml and was obviously lower than that of control (17.97+/-1.61) microg/ml (p<0.01). After transfection for 48 hours, the ratio of K562/A02 cells in G0/G1 increased by 10.7%, and the cells displayed karyopyknosis, nuclear margination and apoptotic bodies. It is concluded that the siRNA plasmid specifically targeting CD44 gene can remarkably down-regulate the expression of CD44 gene, inhibit K562/A02 cell proliferation, induce its apoptosis and effectively reverse the multidrug resistance of K562/A02 cells.
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PMID:[Effect of CD44 gene silence on multi-drug resistance reversal and biologic activity in K562/A02 cells]. 2041 63

This study investigated the intracellular localization of asparagine synthetase (ASNS) in the relation with chemoresistance in leukemia. pIRES-GFP-ASNS-Flag/Neo expression vector was transiently tansfected into SK-N-MC cells and 297T cells respectively. Immunofluorescence and Western blot analysis were performed for cellular localization of ASNS respectively. U937 cells were treated with L-asparaginase for 48 h and examined for endogenous ASNS expression on plasma membrane by immunofluorescence staining. Immunofluorescence staining showed that the transiently expressed ASNS was partly localized on transfected-SK-N-MC cell surface. Moreover, Western blotting exhibited that ASNS expressed both in cytosol and on plasma membrane of transfected-293T cells. Immunofluorescence staining with anti-ASNS-specific monoclonal antibody revealed that endogenous ASNS was localized on the plasma membrane of U937 cells, except for its distribution in the cytosol. In addition, ASNS exhibited a higher expression on plasma membrane after treatment with L-asparaginase as compared with the untreated cells. It was concluded that the subcellular translocation of ASNS may play an important role in L-asparaginase resistance in leukemia cells.
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PMID:Asparagine synthetase is partially localized to the plasma membrane and upregulated by L-asparaginase in U937 cells. 2150 76

Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
Leukemia 2012 Nov
PMID:Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. 2255 8


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