Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The (3;21)(q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the alpha subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the beta subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression prevented tumor growth. These results suggest that expression of AML1/EAP and AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line.
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PMID:The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. 857 11

The pathogenesis of the anemia of cancer involves the combination of a shortened erythrocyte survival in circulation with the failure of bone marrow to increase red cell production in compensation. Inappropriate red cell production is itself related to a conjunction of factors, including impaired availability of reticuloendothelial storage iron, inadequate erythropoietin (Epo) response to anemia, and overproduction of cytokines which are capable of inhibiting erythropoiesis. Many of these cytokines may interfere with erythropoietin production by the kidney. Consequently inadequate serum erythropoietin levels are often encountered in cancer patients, though more frequently in those with solid tumors or multiple myeloma than in those with other hematologic malignancies. There is little evidence supporting a negative impact of chemotherapy, including cisplatin, on erythropoietin production. Rather, chemotherapy usually causes a transient elevation of serum Epo. Red cell transfusions are often administered to cancer patients, possibly resulting, among other deleterious effects, in enhancement of tumor growth. Recombinant human erythropoietin (rHuEpo) has thus been proposed as an alternative. RHuEpo has been shown to be safe and effective in correcting the anemia of cancer and reducing the need for transfusions. The response rate is as good in hematologic malignancies as in solid tumors, but it is extremely poor in those with myelodysplastic syndromes. The effect of rHuEpo does not differ among patients receiving or not receiving chemotherapy, including cisplatin. The probability of response is also similar in patients with adequate or inappropriate erythropoietin production before therapy, although the doses used are usually 2 to 3 times higher than in renal failure patients.
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PMID:Erythropoietin and the anemia of cancer. 866 61

In the past several years, interest in the immunophysiological role of the pineal gland and melatonin has grown to the extent that now their immunoregulatory role is widely recognized. Melatonin has immunoenhancing properties and it is able to counteract the immunodepression induced by acute stress, drug treatment (i.e., anticancer drugs), and viral infections. Here we review the therapeutic efficacy of melatonin alone or in combination with interleukin-2 (IL-2) in cancer patients who did not respond to standard anticancer chemotherapies and/or refused any aggressive treatment. In this review, we summarize a series of reports from 1986 through 1994 in which patients affected by metastatic solid tumors, metastatic non-small-cell lung cancer, advanced solid neoplasms, myelodysplastic syndrome, hepatocellular carcinoma, and advanced endocrine tumors were studied. The conclusion drawn from these studies is that melatonin protects against IL-2 and synergizes with the IL-2 anticancer action. This combined strategy represents a well tolerated intervention to control tumor growth. In most cases performance status and quality of life seem improved.
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PMID:The clinical neuroimmunotherapeutic role of melatonin in oncology. 875 Mar 42

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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PMID:Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. 1097 72

Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders. Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes. In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes. In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance. In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD). One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor. The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy. Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines. Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT. To this end, graft manipulation to reduce the presence of Fas Ligand (FasL)-expressing cells or interleukin (IL)10 and tumor growth factor (TGF)beta production has been proposed. In contrast to autologous transplantation, graft manipulation during allogeneic transplantation is used extensively. This includes limiting the infusion of T cells within the product or as a donor leukocyte infusion (DLI), resulting in a reduction in GVHD and the induction of long-term survivors. Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia. The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch. Allergy Immunol. 102 (1993) 309, J. Exp. Med. 183 (1996) 589]. The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease. Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation). In contrast to autologous transplantation, control of GVHD following allogeneic SCT focuses on immune suppression and the induction of tolerance. Here too, graft manipulation is appropriate, and there are numerous studies of T-cell depletion to reduce GVHD, with or without the isolation and infusion of T cells as DLI. Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance. Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different. In this review, we emphasize using graft manipulation to regulate immune tolerance and anergy in association with SCT. Although this paper focuses on hematopoietic SCT, it should be noted that these strategies are relevant to conditions other than neoplastic and congenital diseases, including solid organ transplants, and autoimmune and inflammatory diseases.
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PMID:Hematopoietic stem cell graft manipulation as a mechanism of immunotherapy. 1286 Jan 68

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Myeloid malignancies are appropriate disease targets, in that they express relevant biologic targets, such as Ras, Mitogen-Activated Protein Kinase (MAPK), AKT, and others that may depend upon farnesyl protein transferase (FTase) activity to promote proliferation and survival. Phase I trials in acute leukemias and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in a variety of hematologic malignancies and disease settings, in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
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PMID:Farnesyltransferase inhibitors (FTIs) in myeloid malignancies. 1512 88

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectivly inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Acute myeloid leukemias (AMLs) are appropriate disease targets in that they express relevant biologic targets such as Ras, MEK, AKT, and others that may depend upon farnesyl protein transferase activity to promote cell proliferation and survival. Indeed, different intracellular proteins are substrates for prenylation. Interruption of prenylation may prevent substrates from undergoing maturation which may result in the inhibition of cellular events that depend on the function of those substrates. Phase I trials in AML and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with these hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
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PMID:[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia]. 1582 Sep 17

Tumor-specific immunotherapy with a Wilms' tumor 1 (WT1) peptide has been on clinical trial for leukemia, myelodysplastic syndrome, breast and lung cancers and is producing promising results. In this study, we treated three patients with renal cell carcinoma with an anchor modified, HLA-A*2402 binding WT1 peptide which was emulsified in Freund's incomplete adjuvant. In two patients tumor growth was suppressed and clinical response was evaluated as stable disease by the RECIST criteria after 3 months of weekly immunizations. Notably, development of new metastases has stopped in these patients for a prolonged period. No deleterious side effects were observed. Peptide-specific T cells were expanded in PBMCs of the patients and a substantial fraction of them bore the surface phenotype consistent with a CD8+ cytotoxic effector population. Although established tumors did not regress further, considering the component of the vaccine, i.e. peptide alone, the stabilization effect suggested the potential of WT1 peptide to develop into a more effective vaccine. To our knowledge, this is the first report of WT1 immunotherapy for renal cell carcinoma. Hopefully, the results will stimulate more extensive clinical studies.
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PMID:WT1 (Wilms' tumor 1) peptide immunotherapy for renal cell carcinoma. 1757 61

The aim of this study was to investigate the tumor suppression efficacy of a histone deacetylase inhibitor, sodium valproate combined with adriamycin in the treatment of myelodysplastic syndrome cell line MUTZ-1. After treated with different concentrations of sodium valproate alone, adriamycin alone or combination of them, growth curve of MUTZ-1 cell line were detected; growth of the tumor cells were analyzed by flow cytometry and morphology method. The results indicated that when the myelodysplastic syndrome cell line MUTZ-1 was treated with adriamycin (0.039 microg/ml, 0.078 microg/ml, 0.156 microg/ml, 0.312 microg/ml, 0.4 microg/ml), the tumor growth inhibition rates were 5.08 +/- 0.79%, 12.32 +/- 2.39%, 23.65 +/- 1.34%, 43.33 +/- 2.38% and 47.85 +/- 1.46% (p < 0.05), 0.25 mmol/L sodium valproate did not show apoptosis effect, but could synergize adriamycin to promote apoptosis. When the myelodysplastic syndrome cell line MUTZ-1 treated with two drug combination, the tumor growth inhibition rates were 23.46 +/- 1.12%, 49.87 +/- 0.84%, 52.37 +/- 1.05%, 78.43 +/- 4.34% and 82.47 +/- 1.04% (p < 0.05), and displayed concentration-dependent manner. All the data above were significantly different from those in control (p < 0.05). Sodium valproate showed obvious effect at concentration of 0.078 microg/ml adriamycin. After treated with 0.25 mmol/L sodium valproate and 0.078 microg/ml adriamycin for 72 hours, MUTZ-1 cell line showed typical apoptosis morphological character. It is concluded that sodium valproate may enhance the efficacy of adriamycin on MUTZ-1 cell line.
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PMID:[Sodium valproate synergizes adriamycin to inhibit proliferation and induce apoptosis in myelodysplastic syndrome cell line]. 1854 28

Methionine (Met) deprivation stress (MDS) is proposed in association with chemotherapy in the treatment of some cancers. A synergistic effect of this combination is generally acknowledged. However, little is known on the mechanism of the response to this therapeutic strategy. A model of B16 melanoma tumor in vivo was treated by MDS alone and in combination with chloroethylnitrosourea (CENU). It was applied recent developments in proton-NMR spectroscopy-based metabolomics for providing information on the metabolic response of tumors to MDS and combination with chemotherapy. MDS inhibited tumor growth during the deprivation period and growth resumption thereafter. The combination of MDS with CENU induced an effective time-dependent synergy on growth inhibition. Metabolite profiling during MDS showed a decreased Met content (P < 0.01) despite the preservation of the protein content, disorders in sulfur-containing amino acids, glutamine/proline, and phospholipid metabolism [increase of glycerophosphorylcholine (P < 0.01), decrease in phosphocholine (P < 0.05)]. The metabolic profile of MDS combined with CENU and ANOVA analysis revealed the implication of Met and phospholipid metabolism in the observed synergy, which may be interpreted as a Met-sparing metabolic reprogramming of tumors. It follows that combination therapy of MDS with CENU seems to intensify adaptive processes, which may set limitations to this therapeutic strategy.
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PMID:Combined methionine deprivation and chloroethylnitrosourea have time-dependent therapeutic synergy on melanoma tumors that NMR spectroscopy-based metabolomics explains by methionine and phospholipid metabolism reprogramming. 1983 24


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