Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis is an essential factor in the growth and progression of hematological malignancies including multiple myeloma (MM). Vascular endothelial growth factor and its receptors have been shown to be targets for treating tumors. This study explores the effect of adenovirus-mediated delivery of soluble vascular endothelial growth factor receptor Fms-like tyrosine kinase-1 (sFLT-1) on the growth of MM cell line KM3 in nude mice. sFLT-1 cDNA was amplified by reverse transcription-polymerase chain reaction from human umbilical vein endothelial cells and was used as a transgene to construct an adenoviral vector carrying sFLT-1 (ADV-sFLT). Cell proliferation and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays were carried out to evaluate the effect of ADV-sFLT on human umbilical vein endothelial cells and KM3 cells in vitro. Eighteen female BALB/c nude mice were inoculated subcutaneously with KM3 cells, and they were randomly divided into three groups and injected intravenously with ADV-sFLT, ADV-LacZ, or phosphate-buffered saline (PBS). The volume of KM3 xenografts was measured twice a week. Three weeks after the initial treatment, the volume of MM xenografts in the mice treated with ADV-sFLT, ADV-LacZ, or PBS was 770.32+/-28.73 mm3, 1983.36+/-43.72 mm3, and 2042.05+/-82.31 mm3, respectively (P<0.01, ADV-sFLT versus ADV-LacZ or PBS). The value of microvessel density was 29.17+/-6.85, 79.17+/-7.35, and 78.83+/-8.54 in the tumors treated with ADV-sFLT, ADV-LacZ, and PBS, respectively (P<0.01, ADV-sFLT versus ADV-LacZ or PBS). This study suggested that the adenovirus-mediated sFLT-1 gene greatly inhibits MM-derived tumor growth and angiogenesis in mouse xenograft, and might serve as a new therapy for MM.
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PMID:Soluble Fms-like tyrosine kinase-1 expression inhibits the growth of multiple myeloma in nude mice. 1762 69

Angiogenesis plays an important role in the progression of tumors. This relationship has been described in several hematologic malignancies. Vascular endothelial growth factor and basic fibroblast growth factor are predictors of poor prognosis in leukemia and non Hodgkin's lymphoma. Bone marrow microvessels were found increased in multiple myeloma, but also in lymphoma and in acute lymphoblastic leukemia. Microvessel density is correlated with decreased survival in myeloma patients and relapse or resistance to chemotherapy in lymphoma. New drugs with antiangiogenic activity such as bevacizumab (binding and inactivation of VEGF) or VEGF-tyrosine kinase inhibitors have shown promising results in phase 1 trials. It will therefore be a future challenge to integrate anti-angiogenesis agents in currently existing treatment protocols to improve the outcome of therapy.
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PMID:[Angiogenesis and hematologic malignancy]. 1784 10

Multiple myeloma (MM) is characterized by devastating bone destruction mainly due to stimulation of osteoclastogenesis. However, whether MM cells can directly influence osteoclast apoptosis, a mechanism that would contribute to increase the number of active osteoclasts, has not been addressed yet. Herein, using authentic mature rabbit osteoclasts, we demonstrated that conditioned media (CM) prepared from U266 and RPMI8226 cells but not from LP-1 and OPM-2 cells, stimulated bone resorption and inhibited osteoclast apoptosis in a dose-dependent manner. The MM cells which exerted an anti-apoptotic effect secreted high amounts of M-CSF and addition of a neutralizing antibody against M-CSF reversed the CM effects. Imatinib mesylate, a tyrosine kinase inhibitor that can target the M-CSF receptor, also prevented the effect of CM. These findings suggest that M-CSF originating from MM cells may play a critical role in MM bone disease by decreasing osteoclast apoptosis.
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PMID:Multiple myeloma cells directly stimulate bone resorption in vitro by down-regulating mature osteoclast apoptosis. 1828 99

Interferon regulatory factor-4 (IRF-4) is a hematopoietic cell-restricted transcription factor important for hematopoietic development and immune response regulation. It was also originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. In contrast to its oncogenic function in late stages of B lymphopoiesis, expression of IRF-4 is down-regulated in certain myeloid and early B-lymphoid malignancies. In this study, we found that the IRF-4 protein levels are increased in lymphoblastic cells transformed by the BCR/ABL oncogene in response to BCR/ABL tyrosine kinase inhibitor imatinib. We further found that IRF-4 deficiency enhances BCR/ABL transformation of B-lymphoid progenitors in vitro and accelerates disease progression of BCR/ABL-induced acute B-lymphoblastic leukemia (B-ALL) in mice, whereas forced expression of IRF-4 potently suppresses BCR/ABL transformation of B-lymphoid progenitors in vitro and BCR/ABL-induced B-ALL in vivo. Further analysis showed that IRF-4 inhibits growth of BCR/ABL+ B lymphoblasts primarily through negative regulation of cell-cycle progression. These results demonstrate that IRF-4 functions as tumor suppressor in early B-cell development and may allow elucidation of new molecular pathways significant to the lymphoid leukemogenesis by BCR/ABL. The context dependent roles of IRF-4 in oncogenesis should be an important consideration in developing cancer therapies targeting IRF-4.
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PMID:IRF-4 functions as a tumor suppressor in early B-cell development. 1871 47

Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
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PMID:Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. 1903 39

Transplantation of hematopoietic stem cells derived from bone marrow or peripheral blood has been used as a therapeutic procedure since the mid-seventies. In recent years, the number of transplants reported annually to the European Group for Blood and Marrow Transplantation (EBMT) Registry is approximately 23,500 including 38% of allogeneic and 62% of autologous procedures. In most developed countries, the incidence of hematopoietic cell transplantations reaches 400/10 million inhabitants per year and 220/10 million per year in Poland. Further advances require both increased funding and improved public health system as a whole. To recommend transplantation, it is necessary to compare the risk associated with the disease itself versus that of the transplantation procedure which depends on the stage of the disease, patient's age, time interval from diagnosis to transplantation, donor type (siblings or unrelated subjects), sex of the donor and individual features. According to the EBMT recommendations, the following categories of indications have been used: "standard procedure" category--S, "clinical option"--CO, indication of "developmental" character--D and "generally not recommended"--NR. The tabular presentation of indications is an approximation since approach to each patient should be individualized. Generally, the most-common indications for auto-transplant treatment are myeloma, malignant lymphoma and acute myeloblastic leukemia while the main indication for bone marrow allotransplantation is acute myeloblastic leukemia (33% of all allotransplantations), lymphoblastic leukemia, dysmyelopoietic syndrome, chronic myeloblastic leukemia refractory to tyrosine kinase inhibitors, then lymphoid malignancies and non-malignant disorders (bone marrow aplasia, severe immunodeficiencies, paroxysmal nocturnal hemoglobinuria, etc.).
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PMID:Indications for hematopoietic stem cell transplantation. 1914 May 70

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer. A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma, prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly: squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary, gastric and mesothelioma. Results of early stage clinical trials, involving recently patented drugs. are included where appropriate. We then outline the current understanding of toxicity related to IGF-1R targeted therapy, and finally outline areas for further research.
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PMID:Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. 1914 88

Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory alphaL-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.
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PMID:Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation. 1922 61

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl was imatinib, which also targets KIT and platelet-derived growth factor receptor kinase and has demonstrated improved outcomes when compared with interferon, the previous standard of care. Imatinib resistance and intolerance have been an issue for patients, and as a result, new therapeutic approaches have been evaluated. Dose-escalated imatinib (800 mg daily) has shown some limited activity in patients with imatinib-resistant CML, but the development of second-generation tyrosine kinase inhibitors has broadened the treatment options. Dasatinib is also an oral kinase inhibitor, but it has increased potency for Brc-Abl compared with imatinib. Dasatinib has demonstrated activity in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the treatment of adults in this setting. Recent phase III data have demonstrated that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally effective, with improved tolerability, compared with the previously approved 70-mg twice-daily dose. Nilotinib, which has been recently approved, has increased potency for Brc-Abl compared with imatinib and has demonstrated activity in patients with imatinib-resistant and -intolerant chronic- and accelerated-phase CML. As experience with these agents continues to mature, we might optimize the treatment efficacy and safety profiles by altering dose regimens.
Clin Lymphoma Myeloma 2008 Mar
PMID:Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules. 1925 84

The tyrosine kinase inhibitor (TKI) imatinib constitutes the current first-line therapeutic approach for patients with chronic myeloid leukemia. The success of imatinib relies on its potent inhibitory activity against the Bcr-Abl kinase that drives the pathogenesis of this disorder. The vast majority of patients treated with imatinib as a single agent will achieve a complete cytogenetic response. However, a subset of patients will develop imatinib resistance, frequently associated with mutations within the Abl kinase domain. In this setting, treatment with the second-generation TKIs nilotinib and dasatinib has proved highly efficacious. While therapy with these Bcr-Abl TKIs is generally well tolerated, adverse events are common and can result in treatment interruptions that compromise clinical responses. Herein, we discuss some of the toxicities characteristically associated with TKI therapy and provide practical approaches to the clinical management of these adverse effects.
Clin Lymphoma Myeloma 2008 Mar
PMID:Practical management of toxicities associated with tyrosine kinase inhibitors in chronic myeloid leukemia. 1925 85


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