Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusion gene products such as PML-RARalpha and BCR-ABL generated by leukemia-specific chromosomal translocations have been identified as target molecules for the treatment of leukemia. Here we describe one possibility for extending the frontier of mechanism-based medicine for acute myeloid leukemia (AML). FLT3, a receptor tyrosine kinase (RTK) preferentially expressed in hematopoietic progenitor cells, frequently has a gain-of-function mutation in AML. To search for FLT3-targeted compounds, we screened the growth-inhibitory effects of several tyrosine kinase inhibitors (TKIs) on mutant FLT3-transformed 32D cells. Herbimycin A at a concentration of 0.1 microM markedly inhibited the growth of the transfectants but at that concentration was ineffective in parental 32D cells. It suppressed the constitutive tyrosine phosphorylation of the mutant FLT3, but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with transformed 32D cells, the administration of herbimycin A completely prevented leukemia progression. Recent studies have indicated that herbimycin A binds directly with HSP90, a molecular chaperone, and destabilizes HSP90-associated proteins. Another HSP90 inhibitor, radicicol, also induced apoptosis selectively in transformed 32D cells. HSP90 is a promising target for the treatment of AML with mutant FLT3.
 ...
PMID:FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. 1158 62

Angiogenesis in Patients with Hematologic Malignancies The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. Emerging data suggest an involvement of angiogenesis in the pathophysiology of hematologic malignancies as well. Recently, we and others have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when patients achieved a complete remission (CR) after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) and angiopoietins play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data suggest an important role for these mediators in hematologic malignancies as well. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascularization and angiogenic mediators/receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. The immunomodulatory drug thalidomide inhibits angiogenesis in animal models. Moreover, it has significant activity in refractory multiple myeloma. In a current phase II study for patients with primary refractory or relapsed multiple myeloma using a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 evaluable patients (86%). Thus, this combination seems to be very potent. Furthermore, we evaluated the safety and efficacy of thalidomide in patients with AML not qualifying for intensive cytotoxic chemotherapy. 20 patients aged 58-85 (median 69) years were recruited to this phase I/II study and were treated with a dose of 200-400 mg per os daily for a duration of 1-40 (median 6) weeks, dependent on the individual tolerability of the drug. In 4 patients we observed a partial response (PR - defined as more than 50% reduction in leukemic blast infiltration in the bone marrow). This was accompanied by an increase in platelet counts and hemoglobin values. One additional patient showed a significant improvement of peripheral blood counts without fulfilling the criteria of a PR. In parallel, we observed a significant decrease in microvessel density in these 5 patients during treatment with thalidomide. In conclusion, thalidomide seems to have anti-angiogenic as well as anti-leukemic activity in AML. The VEGF/VEGFR-2 pathway seems to play an important role in AML. Therefore, receptor tyrosine kinase inhibitors like SU5416 or SU6668 are currently evaluated in the context of phase II studies in AML. We could recently induce a stable remission in a patient with second relapse of her AML refractory towards chemotherapy by administration of SU5416 (compassionate use), a tyrosine kinase inhibitor of VEGFR-2 and ckit. Current and future studies will clarify the role of anti-angiogenic treatment strategies in AML and other hematologic malignancies.
 ...
PMID:[Angiogenesis in patients with hematologic malignancies]. 1160 Aug 18

Approximately half of children with acute myeloid leukemia (AML) can be cured with contemporary chemotherapy regimens; however, various forms of drug resistance pose considerable obstacles for curing the remaining patients. Recent advances in immunology, cytogenetics, and cellular and molecular biology have provided new insights into fundamental biological differences between leukemic myeloid blasts and their normal counterparts. This article focuses on new technologies involving: (1) antibody- or growth factor-mediated targeting of antigens or growth factor receptors found on AML blasts and restricted sub-groups of normal cells, (2) pharmacologic targeting of the pathologic t(15;17) translocation of acute promyelocytic leukemia with all-trans retinoic acid, (3) pharmacologic and immunologic targeting of mutant RAS oncogenes and related aberrant signaling in AML blasts, and (4) targeting of pathological signaling of the Bcr-Abl oncoprotein and c-kit tyrosine kinase in myeloid leukemias. These advances herald an exciting new era of AML-specific therapies.
 ...
PMID:Targeted therapies for high-risk acute myeloid leukemia. 1167 79

The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.
 ...
PMID:Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. 1178 38

Autologous stem cell transplantation (ASCT) as well as allogeneic stem cell transplantation and conventional chemotherapy (CT) are less effective at treating acute lymphocytic leukemia (ALL) than acute myelocytic leukemia (AML). Chemoresistance and late relapses are hallmarks of ALL. In this context, the question of whether ASCT is superior to CT remains unanswered. In vitro marrow purging using monoclonal antibodies is not routinely used. This review summarizes the results of ASCT for adult and childhood ALL. Statistics from the European Group for Blood and Marrow Transplantation reveal a transplant-related mortality at 5 years of 11% +/- 1%, a relapse incidence of 60% +/- 2%, and a leukemia-free survival (LFS) and overall survival (OS) of 36% +/- 2% and 42% +/- 2%, respectively in 1,366 adults autografted in first remission (CR1). In 269 children, the LFS and OS were 50% +/- 3% and 54% +/- 3%, respectively. There was no evidence in favor of purging the autograft in vitro. In contrast, multicentric and single-institution studies have found better results in adults autografted in CR1, with LFS at 5 years from 46% to 64%, possible efficacy of marrow in vitro purging with mafosfamide (LFS 52%), and improvement in outcome with additional measures post-ASCT, such as maintenance chemotherapy (LFS 57%). Further, as already observed for AML, analyses by risk groups suggest that ASCT may essentially benefit good- but not poor-risk patients. For patients with the Ph1/bcr-abl translocation, the role of STI571 anti-tyrosine kinase for in vivo purging before stem cell harvesting is being investigated.
 ...
PMID:Autologous stem cell transplantation in acute lymphocytic leukemia. 1179 17

Nifedipine (NIF), a calcium channel blocker (CCB) from the first generation of dihydropyridines, induces detrimental effects on patients with cardiovascular diseases. We designed experiments to study, at cellular and molecular level, the mechanisms involved in the induction of deleterious effects by this drug. To this purpose, cultured human smooth muscle cells (HSMC) were used. The effect of NIF and two other CCB (FEL, AML) and inhibitors of intracellular signaling pathways (RR, TG, CAF and GEN) on intracellular calcium [Ca(2+)]I was determined by spectrofluorimetry using Fura 2 AM assay. The results showed that: (i) 10 microM NIF induced the increase of [Ca(2+)]I above the basal values (202.77 +/- 23.98 nM vs. 48.68 +/- 6.45 nM), an effect that was prevented by RR (50.45 +/- 13.9 nM) and was not induced by the two other CCB; (ii) NIF had a thapsigargin-like effect, because it induced the same release of intracellular calcium as TG (212.1 +/- 25.62 nM); (iii) The response to NIF was reduced by 40% after the inhibition of IP3 receptor (121.21 +/- 26.01 nM) and by 50% after the inhibition of tyrosine kinase (101.91 +/- 7.76 nM). Together, these data demonstrate that NIF produces a deregulation of intracellular calcium homeostasis. The abnormal increase of [Ca(2+)]I is due to the activation of store operated channels from the plasma membrane responsible for capacitative calcium entry, a process modulated by the activity of tyrosine kinase and the Ca(2+)-ATPase pump from the sarcoplasmic reticulum.
 ...
PMID:Deleterious effects of nifedipine on smooth muscle cells implies alterations of intracellular calcium signaling. 1186 May 26

The demonstration of the BCR-ABL fusion gene in patients with chronic granulocytic leukaemia and t(9;22)(q34;q11) represents the first recognition, in a human neoplasm, of a translocation leading to formation of an oncogenic fusion gene. Since this initial observation, this leukaemogenic mechanism has been increasingly recognized in chronic myeloid leukaemias. The fusion gene has often incorporated part of a gene encoding a receptor or cytoplasmic tyrosine kinase, particularly ABL, PDGFRB and FGFR1. This contrasts with the frequent involvement of genes encoding transcription factors or other nuclear proteins in acute myeloid leukaemia. Nevertheless, genes encoding tyrosine kinases have also been implicated in some cases of acute leukaemia. With the exception of the BCR-ABL fusion gene in chronic granulocytic leukaemia, all these fusion genes are uncommon or rare among cases of chronic myeloid leukaemia. The molecular mechanisms underlying the great majority of cases of Philadelphia-negative chronic myeloid leukaemia remain to be discovered.
 ...
PMID:An overview of translocation-related oncogenesis in the chronic myeloid leukaemias. 1191 86

The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor-alpha concentration and DNA oxidation and glutathione depletion in malignant CD34+ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics. Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.
 ...
PMID:New approaches to the treatment of myelodysplasia. 1196 Dec 8

We report the transient response of a patient with the ETV6-ABL fusion gene to imatinib mesylate (STI571). A 38-year-old man was referred with an erroneous diagnosis of Philadelphia-positive chronic myeloid leukemia in blastic transformation for treatment with the ABL tyrosine kinase inhibitor, STI571. Further investigation indicated that the patient in fact had acute myeloid leukemia; no evidence of the Philadelphia translocation or BCR-ABL was found using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction. Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript. Because the patient was gravely ill at presentation, treatment was commenced immediately with STI571 monotherapy, resulting in considerable initial improvement. However within 10 days the patient's condition again deteriorated, and he required conventional chemotherapy. This case has implications for the design of future studies using STI571 in leukemias involving ABL-encoded fusion proteins other than BCR-ABL.
 ...
PMID:Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation. 1196 20

Conventional cytotoxic therapy of hematologic malignancies is often associated with significant morbidity. This morbidity is often due to the lack of specificity for hematopoietic cells. Therefore, the concept of targeted therapy for patients with hematologic malignancies has received attention for many years. The goal of monoclonal antibody therapy is to target specific cell surface antigens on malignant hematopoietic cells, while sparing normal cells and tissues. Currently, monoclonal antibodies are being evaluated for their cytotoxic effects as well as their ability to deliver toxic agents or radiation. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with refractory indolent lymphoma. Campath-1H (anti-CD52) has shown encouraging results in patients previously treated for chronic lymphocytic leukemia, with response rates up to 33%, although with significant toxicity. Anti-CD33 antibodies are being used to deliver cytotoxic agents, such as calicheamicin to patients with acute myeloid leukemia with response rates up to 30%. In addition, anti-CD33 and anti-CD45 antibodies have been used to deliver radiation directly to leukemic cells. (131)I-labeled anti-CD45 antibodies are being studied in combination with conventional preparative regimens in patients receiving bone marrow transplantation. Lastly, the therapeutic agent STI571 (signal transduction inhibitor 571) has demonstrated the capability of targeting specific molecular abnormalities seen in hematologic malignancies. STI571 targets the tyrosine kinase activity of the bcr-abl fusion protein seen in chronic myeloid leukemia. STI571 has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials.
 ...
PMID:Cell surface antigen and molecular targeting in the treatment of hematologic malignancies. 1200 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>