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)

Angiogenesis has been implicated in the growth, dissemination and metastasis of solid tumours. Several recent studies have shown increased bone marrow vasculature in acute and chronic leukaemia as well as in myelofibrosis and myelodysplastic syndromes. Increased serum and/or cellular levels of vascular endothelial growth factor (VEGF) as the most potent and specific angiogenic factor were reported in acute and chronic leukaemia and multiple myeloma and also predict poor prognosis in these haematological malignancies. Little is known about angiogenesis and VEGF levels in polycythemia. Thus, the serum levels of VEGF (pg/ml) and erythropoietin (U/l) were determined using ultra-sensitive ELISA assays in 16 polycythemia patients (10 with polycythemia vera (PV) and 6 with secondary polycythemia) and correlated with their clinical and laboratory features. The serum levels of VEGF were significantly higher in 90% of PV cases and 60% of secondary polycythemia compared to healthy controls. The median VEGF levels (pg/ml) were 622 (range, 272-4760), 306 (range, 111-408) and 143 (range, 91-282) in PV, secondary polycythemia and healthy controls, respectively. Since serum VEGF reflects both plasma VEGF and platelet released VEGF, the concentration of VEGF per platelet (VEGF/PLT) as pg per 10(6) platelet was used as a more standardised measure. Splenomegaly emerged as the main factor associated with a marked increase in serum VEGF/PLT levels. On the other hand, the serum erythropoietin levels (U/l) were significantly reduced in PV (range, 1.2-14.3) raised in secondary polycythemia (range, 26-104) compared with normal controls (range, 9.7-31.1), P<0.01. In conclusion, the present study shows increased VEGF levels in most polycythemia patients, and splenomegaly is associated with a profound increase in VEGF serum levels in these patients. Also, patients with PV have significantly reduced serum levels of erythropoietin compared with secondary polycythemia. Also, serum VEGF/PLT was higher in PV patients treated with phlebotomy alone rather than oral chemotherapy, suggesting a possible advantage for chemotherapy over phlebotomy alone in suppressing the disease progression. Further studies with large number of polycythemia cases are warranted to explore the role of these cytokines in the pathogenesis, diagnosis and/or therapy of polycythemia.
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PMID:Increased serum levels of vascular endothelial growth factor correlate with splenomegaly in polycythemia vera. 1236 69

Angiogenesis is defined as the formation of new capillaries from preexisting blood vessels and plays an important role in the progression of solid tumors. Recently a similar relationship has been described in several hematologic malignancies. Expression of the angiogenic peptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor correlates with clinical characteristics in leukemia and non-Hodgkin's-lymphoma and the serum/plasma concentrations serve as predictors of poor prognosis. Increased bone marrow microvessels in multiple myeloma (MM) are correlated with decreased overall survival. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in MM, myelodysplastic syndrome and acute myeloid leukemia (AML). Preliminary data indicate activity of VEGF-tyrosine kinase inhibitors in AML. Clinical research is now aimed at testing antiangiogenic treatment strategies in several hematologic neoplasms as well as identifying the best candidate patients for specific approaches.
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PMID:Angiogenesis in hematologic malignancies. 1263 37

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.
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PMID:SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. 1264 63

Thalidomide the first commercially available immune modulatory drug (IMiD), has activity in the treatment of Waldenstrom's macroglobulinemia (WM), as well as multiple myeloma, myelodysplastic syndrome, myelofibrosis with myeloid metaplasia, chronic lymphocytic leukemia (CLL), and B-cell lymphomas. Although its molecular mechanisms of action have not yet been elucidated, thalidomide and the IMiDs affect a variety of cytokines and inflammatory mediators including tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, interferon gamma (IFNgamma), IL-6, IL-10, IL-12, and COX-2 and angiogenesis factors such as vascular endothelial growth factor (VEGF) and its receptor. The IMiDs also affect adhesion molecules such as ICAM-1, ICAM-2, and L-CAM, in addition to preferentially stimulating CD8 cells and expanding natural killer (NK) cell populations. Since most IMiDs share these properties, it would be expected that the second-generation IMiDs (REVIMID, ACTIMID) would have activity similar to thalidomide in WM with an improved safety profile. TNFalpha and angiogenesis most likely play a role in promoting the growth and development of WM. The selective cytokine inhibitory drugs (SelCIDs) are potent phosphodiesterase 4 (PDE-4) inhibitors that inhibit TNFalpha production and are highly antiangiogenic. In addition, inhibition of PDE-4 induces apoptosis in human CLL lymphocytes. It is therefore expected that the SelCIDs might have activity in Waldenstrom's tumors. Jun N-terminal kinase (JNK) is a component of signaling cascades that modulate apoptosis, the induction of an inflammatory response via the AP-1 pathway, and modulation of cellular proliferation. In a variety of tumors, including multiple myeloma, JNK is induced as part of a protective mechanism. It is hypothesized that inhibition of JNK activity might allow other chemotherapeutic agents to be more effective in a similar manner to corticosteroids. Work is in progress to evaluate this. Inhibitors of the E3 subunit of ubiquitin ligase may also selectively modulate the expression of receptors, growth factors, and transcription factors essential to the growth, survival, and spread of tumors. We hypothesize that the IMiDs, SelCIDs, JNK inhibitors, and ligase inhibitors will be the basis for a new nonchemotherapeutic approach to the treatment of WM and other related diseases.
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PMID:Potential new therapeutics for Waldenstrom's macroglobulinemia. 1272 Jan 52

Chronic myelomonocytic leukemia (CMML) is a myeloproliferative disorder with unique characteristics. Dysplasia is usually present in the bone marrow, thus CMML has usually been classified as a myelodysplastic syndrome. The recent World Health Organization classification of myeloid malignancies proposes to classify CMML into a new category of myelodysplastic syndromes and myeloproliferative disorders. A new prognostic score has also been developed exclusively for patients with CMML that recognizes four groups with distinct prognoses. Significant biologic findings in the recent months include the recognition of the importance of angiogenesis in CMML with a possible autocrine role for vascular endothelial growth factor, and the further understanding of the role of tyrosine kinase fusion genes and activation in some patients with CMML Therapeutic discoveries have been hampered by the paucity of studies looking specifically at CMML Among agents with potential significant activity are imatinib mesylate (for patients with platelet-derived growth factor beta receptor-associated fusion genes), hypomethylating agents, antiangiogenic agents, farnesyltransferase inhibitors, and topoisomerase I inhibitors. Future studies should consider CMML as a separate entity to promote a better understanding and identify more effective therapy for patients with this disease.
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PMID:CMML: a biologically distinct myeloproliferative disease. 1290 41

Thalidomide is a putative anti-angiogenesis agent that has significant anti-tumour activity in haematological malignancies with increased bone marrow angiogenesis, including multiple myeloma (MM) and myelodysplastic syndromes (MDS). Increased levels of the mitogen for angiogenesis, vascular endothelial growth factor (VEGF), correlate with worse survival in acute myeloid leukaemia (AML). A phase II trial of thalidomide was conducted in patients with relapsed- or refractory-AML previously treated with cytarabine-containing regimens. A total of 16 patients with refractory- or relapsed-AML were treated with thalidomide 200-800 mg orally daily (median dose 400 mg daily) for a median of 27 d (range, 3-94 d). Overall, one patient (6%) achieved complete remission (CR) lasting for 36 months, and two patients had a transient reduction in marrow blasts from 8% and 7% to less than 5% in both cases. There was no correlation between reduction in levels of angiogenesis markers and response. Toxicities related to thalidomide were significant, and precluded dose escalation beyond 400 mg orally daily in most patients. Although there appears to be some evidence of biological activity, single agent thalidomide is not an optimal choice of therapy for salvaging patients with relapsed- or refractory-AML. Thalidomide analogues with more potent immunomodulatory activities and more favourable toxicity profiles may offer more promise as anti-AML therapy.
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PMID:Single agent thalidomide in patients with relapsed or refractory acute myeloid leukaemia. 1461 2

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by peripheral cytopenias in the setting of a normocellular or hypercellular bone marrow that morphologically shows trilineage dysplasia. Mechanisms of disease include pluripotent stem cell damage, abnormalities in proliferation, differentiation, and apoptosis leading to an ineffective hematopoiesis. A growing body of evidence support angiogenesis as having a key role in the pathophysiology of hematologic malignancies, including MDS. Knowledge and interest in angiogenesis and its interactions with proliferation and apoptosis have provided the rationale for the use of antiangiogenic drugs, such as thalidomide and its analogue CC5013, with hematologic improvement. Although the results are modest, other drugs with somewhat novel antiangiogenic mechanisms of action are under development, such as the vascular endothelial growth factor-receptor blocker SU5416, the antivascular endothelial growth factor antibody bevacizumab, arsenic trioxide, metalloproteinase inhibitors, such as AG3340, and farnesyl transferase inhibitor R115777. This review attempts to provide an overview of the evidence of increased angiogenesis and the status of drug development targeting angiogenesis in patients with MDS.
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PMID:The role of angiogenesis in the biology and therapy of myelodysplastic syndromes. 1508 66

This meeting was convened by Richard T. Silver, M.D. and co-chaired by Jerry L. Spivak, M.D. It was held from 16 to 18 October 2003 in New York City, New York, USA. Thirty-nine invited speakers from nine different countries participated in the conference. There were more than 350 attendees. There were formal presentations and discussions on biology, clinical aspects, and management of patients with these diverse bone marrow stem cell disorders linked by a variable progression to acute myeloid leukemia. Of considerable interest, a clinical symposium exclusively for patients was held the day preceding the meeting at which John Bennett, Tiziano Barbui, Richard Silver, Jerry Spivak, and Ayalew Tefferi spoke on various topics pertaining to these diseases. This proved to be highly informative to the patients who reported that they enjoyed the program immensely. This was sponsored by the Cancer Research & Treatment Fund, Inc. Representatives of the Myelodysplasia Foundation were also present. This meeting report provides a summary of five different sections prepared by one or more of the session chairs. The keynote address was given by Shahin Rafii (Cornell Medical Center). Most appropriately, this talk focused on the expression and activation of angiogenic factors which play a crucial role in the progression of both myeloproliferative disorders and myelodysplastic syndromes (MDS). Among the known factors, vascular endothelial growth tyrosine kinase receptors (VEGF-R1, R2, and R3) support proliferation, survival, and mobility. Rafii's team has demonstrated that these receptors are expressed on subsets of primary hematopoietic cells as well as leukemic cells. Some leukemic cells express both VEGF-A and VEGF-R2, resulting in the generation of an autocrine loop that supports survival and within the osteoblastic zone translocating these cells to the vascular enriched niche for receipt of molecular instructions required for proliferation and differentiation. A pathologic correlation can be seen in some patients with the identification of abnormal localization of immature precursors (ALIP) in the central portions of the medullary cavity. Misplaced megakaryocytes can release pro-fibrotic factors, including platelet derived growth factors and transforming growth factor-beta. Collectively, these data suggest that chronic disregulation of angiogenic factors alter the microenvironment dislocating marrow stem cells that force both proliferation and differentiation in varying degrees, contributing to these hematological disorders.
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PMID:The second international congress on myeloproliferative and myelodysplastic syndromes. 1523 76

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. Therapeutic interventions for MDS other than allogeneic bone marrow transplantation have been palliative. Because most of the patients are elderly and may not be candidates for ablative transplant conditioning regimens, treatment has focused on supportive care. Recently, several novel biological and chemotherapeutic agents have demonstrated activity in MDS and are being incorporated into the treatment paradigm. These agents are based on specific mechanisms aimed at angiogenesis in the bone marrow, secretion of growth factors and/or their receptors, and modulators in their intracellular pathways. Several agents are in the initial stages of clinical trial, including anti-vascular endothelial growth factor, bevacizumab, receptor tyrosine kinase inhibitors, farnesyl transferase inhibitors, protein kinase C inhibitors, matrix metalloproteinase inhibitors and other agents such as thalidomide and arsenic trioxide. Novel chemotherapeutic agents include topoisomerase inhibitors such as topotecan and rubitecan, and deoxyadenosine analogues such as troxacitabine, tezacitabine, and clofarabine. Prognostic factors predicting response in MDS patients treated with intensive chemotherapy have been identified and include younger age and favorable cytogenetics.
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PMID:Nucleoside analogs and antimetabolite therapies for myelodysplastic syndrome. 1549 95

Current investigations have revealed that angiogenesis plays a role in the pathogenesis of high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia, and in the mechanisms of disease progression. Secretion of cytokines and growth factors modulates angiogenesis in the marrow leading to increased vascularity and sustenance of the clonal population. For high-risk MDS patients older than 60 years who are not eligible for aggressive chemotherapy or stem cell transplant, there are few therapeutic options other than supportive treatment. Recent delineation of the pathobiology of MDS has resulted in the development of new agents and treatment modalities that impact on these mechanisms. One of the features of bone marrow pathology is the presence of new vessels, which appear to sustain growth and the hypercellularity of the marrow. Blocking angiogenesis may reduce the microvessel density of the marrow, cellularity, and disease progression. Angiogenesis can be targeted by inhibition of vascular endothelial growth factor (VEGF), which modulates new vessel growth, by the use of antibodies aimed at VEGF and its receptors, as well as receptor tyrosine kinases that block VEGF signaling. Other agents include inhibitors of farnesyl transferase and protein kinase C, which affect upstream modulators of growth factors and their receptor interactions; matrix metalloproteinases, which disrupt matrices and adhesion function promoting vessel growth; and other inhibitors with broader function, such as endostatin, thalidomide, and related analogues.
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PMID:Modulation of angiogenesis in patients with myelodysplastic syndrome. 1549 99


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