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)

Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily. Tandutinib's pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring greater than 1 week of dosing. Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts. Eight patients had FLT3-ITD mutations; 5 of these were evaluable for assessment of tandutinib's antileukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg twice daily, showed evidence of antileukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity.
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PMID:Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. 1690 53

We investigate the role of mutations of receptor tyrosine kinases as well as their downstream scaffold molecules in leukemogenesis of acute myeloid leukemia (AML) in Chinese patients. Genes of interest included FLT3, PDGFRbeta, KDR, CSF2Rbeta, SOCS1, PIAS3 and SHIP. The coding sequence of these genes was analysed by the reverse transcription-polymerase chain reaction to search novel mutations. A novel mutation (A > T, Q1154L) of SHIP (1 of 192, 0.52%) was identified and another novel mutation (C > T, R685C) of PDGFRbeta (2 of 192, 1.04%). In addition, FLT3 mutations were seen in three of five patients with AML following myelodysplastic syndrome (60%) and 39 of 268 (14.6%) de novo AML patients (P < 0.05). No mutations were found in the coding sequence regions of KDR, CSF2Rbeta, SOCS1 or PIAS3.
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PMID:The investigation of mutation and single nucleotide polymorphism of receptor tyrosine kinases and downstream scaffold molecules in acute myeloid leukemia. 1716 6

Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various (111)In, (90)Y, or (177)Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with (111)Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like (90)Y and (177)Lu were developed. Reported anti-tumour effects of [(90)Y-DOTA(0),Tyr(3)]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [(177)Lu-DOTA(0),Tyr(3)]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important.
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PMID:Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. 1765 93

Treatment of myelodysplastic syndromes (MDS) has evolved to encompass a broad spectrum of therapies aiming to inhibit apoptosis, promote hemopoiesis, and reduce proliferation of clonal immature cells. A small but expanding cohort of patients with MDS may be cured, but for the majority the aim of treatment is to prolong survival and to improve quality of life. Patients with low-risk MDS mainly suffer from the effects of severe anemia and an important therapeutic goal is to maintain acceptable hemoglobin levels by optimal transfusion regimens or by erythropoietin+/-granulocyte-colony-stimulating factor, which normalizes hemoglobin levels or abolish transfusion need in around 40% of patients. Lenalidomide has emerged as a drug of choice for patients with low-risk MDS and a 5q deletion, leading to complete erythroid response and cytogenetic remission in 2/3 of patients. A small cohort of younger patients may show excellent responses to anti-thymocyte globulin. Patients with more advanced disease may respond to treatment with the hypomethylating agents azacytidine and decitabine, who both have been shown to prolong time to leukemic transformation / death in MDS. In addition, there are several new agents under clinical investigation targeted to potential mechanisms of disease and progression in MDS. New therapeutic drug include inhibitors of angiogenesis, histone deacetylation, tyrosine kinases and farnesylation, as well as drugs interacting with apoptotic mechanisms. The role of these, alone and in combination with more established therapies will be discussed.
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PMID:Supportive care, growth factors, and new therapies in myelodysplastic syndromes. 1806 81

The IFN consensus sequence-binding protein (ICSBP; also referred to as IFN regulatory factor 8) is a transcription factor which is expressed in myeloid and B cells. In previous studies, we found that ICSBP activated transcription of the gene encoding gp91(PHOX) (the CYBB gene), a rate-limiting component of the phagocyte respiratory burst oxidase expressed exclusively after the promyelocyte stage of myelopoiesis. Previously, we found that CYBB transcription was dependent on phosphorylation of specific ICSBP tyrosine residues. Since ICSBP is tyrosine-phosphorylated during myelopoiesis, this provided a mechanism of differentiation stage-specific CYBB transcription. In the current studies, we found that ICSBP was a substrate for Src homology-containing tyrosine phosphatase 2 (SHP2-PTP) in immature myeloid cells but not during myelopoiesis. Therefore, SHP2-PTP inhibited CYBB transcription and respiratory burst activity in myeloid progenitor cells by dephosphorylating ICSBP. In contrast, we found that ICSBP was a substrate for a leukemia-associated, constitutively active mutant form of SHP2, described previously, throughout differentiation. Consistent with this, constitutive SHP2 activation blocked ICSBP-induced CYBB transcription and respiratory burst activity in differentiating myeloid cells. ICSBP-deficiency and constitutive SHP2 activation have been described in human myelodysplastic syndromes. As these two abnormalities may coexist, our results identified a potential molecular mechanism for impaired phagocyte function in this malignant myeloid disease.
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PMID:Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation. 1808 53

An improved understanding of acute myelogenous leukemia (AML) over the past two decades has led to a characterization of associated recurring cytogenetic abnormalities. AML is often driven by the overexpression or constitutive activation of receptor tyrosine kinases such as Fms-like tyrosine kinase 3 (FLT3), which serves as a good therapeutic target. Millennium Pharmaceuticals Inc's tandutinib (MLN-518) is an orally active inhibitor of FLT3 kinase and family members PDGFR beta and c-Kit. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. The drug exhibited limited activity as a single agent in phase I and II clinical trials in patients with AML and myelodysplastic syndrome, but displayed promising antileukemic activity (90% complete remissions) in a phase I/II trial in patients with newly diagnosed AML when administered in combination with cytarabine and daunorubicin. Phase II clinical trials for tandutinib are ongoing in patients with AML or renal cell carcinoma.
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PMID:Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications. 1817 63

Cancer in a patient usually becomes manifest as a process of excessive cell growth in one or more organs which, if uncontrolled, will ultimately lead to death of the patient. The malignant clinical phenotype of cancer is the reflection of the altered cellular behaviour of individual cancer cells. Cumulative genetic alterations in pathways controlling cellular growth or survival, endow the latter cells with the capacity to grow independently of growth-regulating signals, to resist programmed cell death, to divide endlessly, and to interact differently with non-malignant cellular environment. The discovery of such recurrent genetic aberrations in haematological malignancies has led to new diagnostic tests, but also to a shift towards development of new rational, specific and effective targets for therapy. For instance, protein tyrosine kinases are pivotal switches for growth control, and small molecule inhibitors have profoundly reshaped therapeutic practice in in myeloproliferative disorders or acute lymphoblastic leukemias. New targets however also encompass the detrimental interactions of malignant cells with the normal environment, e.g. the immune system in the myelodysplastic syndromes. Finally, the paradigm of cancer as the result of cumulative genetic damage in normal cells also sheds new light on the vulnerability of congenital bone marrow failure syndromes to develop haematological malignancies. In this paper, we review our recent contributions to this cancer paradigm in malignant or premalignant haematological conditions.
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PMID:Genetic lesions and the malignant phenotype of haematological cancers. 1835 Dec 10

Eosinophilia is a recurrent feature and diagnostic clue in several hematologic malignancies. In stem cell- and myelopoietic neoplasms, eosinophils are derived from the malignant clone, whereas in lymphoid neoplasms and reactive states, eosinophilia is usually triggered by eosinopoietic cytokines. Myeloid neoplasms typically presenting with eosinophilia include chronic myeloid leukemia, chronic eosinophilic leukemia (CEL), other myeloproliferative neoplasms, some acute leukemias, advanced mast cell disorders, and rare forms of myelodysplastic syndromes. Diagnostic evaluations in unexplained eosinophilia have to take these diagnoses into account. In such patients, a thorough hematologic work-up including bone marrow histology and immunohistochemistry, cytogenetics, molecular markers, and a complete staging of potentially affected organ systems has to be initiated. Endomyocardial fibrosis, the most dangerous cardiovascular complication of the hypereosinophilic state, is frequently detected in PDGFR-mutated neoplasms, specifically in FIP1L1/PDGFRA+ CEL, but is usually not seen in other myeloid neoplasms or reactive eosinophilia, even if eosinophilia is recorded for many years. Treatment of hypereosinophilic patients depends on the variant of disease, presence of end organ damage, molecular targets, and the overall situation in each case. In a group of patients, oncogenic tyrosine kinases (TK) such as FIP1L1/PDGFRA, can be employed as therapeutic targets by using imatinib or other TK-blocking agents.
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PMID:Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. 1924 39

Nearly half of the patients with newly diagnosed acute myeloid leukemia have normal cytogenetics (NC-AML) and are classified as intermediate risk, but their 5-year overall survival (OS) ranges from 24 to 42%. Therefore, molecular biomarkers to identify poor-risk patients are needed. Elevated AF1q expression in the absence of specific poor cytogenetics is associated with poor outcomes in pediatric patients with AML and adult patients with myelodysplastic syndrome. We examined AF1q expression in 290 patients with NC-AML. We found that patients with low AF1q (n = 73) expression (AF1q(low)) have better OS (P = 0.026), disease-free survival (P = 0.1), and complete remission rate (P = 0.06) when compared with patients with high AF1q expression (AF1q(high) n = 217). The patients with AF1q(high) had significantly greater incidence of concurrent tyrosine kinase3 internal tandem duplication. A subgroup of the patients with AF1q(high) who received allogeneic stem cell transplantation (SCT) had a significant better relapse-free survival when compared with patients who received chemotherapy/autologous SCT (P = 0.04). This study suggests that high AF1q expression is a poor prognostic marker for adult patients with NC-AML.
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PMID:Elevated AF1q expression is a poor prognostic marker for adult acute myeloid leukemia patients with normal cytogenetics. 1939 56

Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Acalpha, which are coregulators of the G(2)-M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G(2) arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Acalpha gene expression recapitulated del(5q) susceptibility to lenalidomide with induction of G(2) arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Acalpha phosphatases in the selective drug sensitivity of del(5q) MDS.
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PMID:A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. 1947 Apr 55


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