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

Angiogenesis, defined as the blood vessel generation from preexisting blood vessels, was found to play an important role in the progression of solid tumors. In addition, bone marrow-derived endothelial precursor cells may contribute to tumor angiogenesis. Recently angiogenesis induction was described in several hematologic neoplasms as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma (MM). Clinical angiogenesis research also termed as angiodiagnosis has established the prognostic relevance of markers of angiogenesis e.g., microvessel density and circulating levels of angiogenic peptides. Development of antiangiogenic treatment for hematologic neoplasms has recently been sparked by the success of Thalidomide (Thal) which has antiangiogenic properties in MM. Antiangiogenic treatment strategies are now being tested in clinical trials on several types of hematologic neoplasms.
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PMID:Angiogenesis in hematologic malignancies. 1179 9

Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.
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PMID:Clinical activity of arsenic trioxide for the treatment of multiple myeloma. 1220 Jul

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. VEGF (vascular endothelial growth factor) is known to be the most important proangiogenic factor, necessary for the development of new tumor vessels. Specific inhibitors of the VEGF receptor tyrosine kinases, like PTK787/ZK222584 (PTK/ZK), have shown antitumoral and antiangiogenic activity in several animal models. Ongoing early clinical trials with antiangiogenic compounds reveal the need for diagnostic methods to detect their biological activity. Pro-angiogenic growth factors like VEGF and bFGF (basic fibroblast growth factor), soluble variants of proangiogenic receptors like sFLT-1 and sTIE-2, as well as endothelial activation markers like sE-Selectin, can be measured in the serum and plasma of patients by the ELISA technique. They were detected in various malignant diseases to assess their use as surrogate markers in tumor angiogenesis. In different clinical Phase I trials with antiangiogenic compounds, these soluble markers were used to detect dose levels for biological activity. Soluble markers of tumor angiogenesis can be used as prognostic markers in various malignancies like colon cancer or multiple myeloma. Furthermore, they correlated with disease activity, prognosis and imaging techniques for the detection of vascular changes. In clinical Phase I trials with specific inhibitors of the VEGF receptor tyrosine kinases, VEGF serum levels increased in patients treated with higher doses, indicating increasing tumor hypoxia. Taking results from imaging techniques such as dynamic enhanced MRI into account, optimal doses for biological activity could be concluded. New biological treatment techniques will need new diagnostic methods to assess their specific biological activity in patients. Soluble markers and imaging techniques are useful tools for the detection of hypoxia under antiangiogenic treatment. Nevertheless, these techniques are still experimental. Therefore, further clinical evaluation is necessary.
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PMID:Soluble markers for the detection of hypoxia under antiangiogenic treatment. 1282 Mar 65

Angiogenesis or new vessel formation is an essential component in the growth and progression of neoplasms and there is growing evidence of its importance in hematological malignancies including multiple myeloma (MM). Vascular endothelial growth factor (VEGF) is believed to play a role in tumor angiogenesis. We studied the expression of VEGF and its receptors (VEGFR1 or Flt-1 and VEGFR2 or Flk-1/KDR) by myeloma cell lines and plasma cells isolated from patients, using different methods. VEGF expression by the plasma cells was demonstrated by immunohistochemistry in 18 of 20 patients with MM. Enzyme-linked immunosorbent assay demonstrated VEGF secretion in all six different myeloma cell lines studied. Five patient marrow samples and seven different myeloma cell lines were then studied for VEGF mRNA expression by reverse-transcriptase polymerase chain reaction (RT-PCR), which was positive in all. We further evaluated the expression of both VEGFR1 and VEGFR2 in different myeloma cell lines and five sorted myeloma bone marrow samples by RT-PCR. All the myeloma cell lines expressed VEGFR1 and three of the cell lines expressed VEGFR2. VEGFR1 expression was detected in all and VEGFR2 in all but one of the sorted marrow samples. Increased expression of VEGF by the myeloma cells taken in the context of the suspected prognostic value of marrow angiogenesis suggests a pathogenetic role for this cytokine and presence of its receptors on myeloma cells points toward an autocrine mechanism. Demonstration of the presence of VEGFR2 in our study provides a potential biological explanation for the preclinical activity observed with VEGFR2 inhibitors.
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PMID:Expression of VEGF and its receptors by myeloma cells. 1451 53

Angiogenesis in solid tumors is important to tumor growth, invasion and metastasis. Recently, it has been suggested that angiogenesis plays a certain role in the development of hematopoietic malignancies, including leukemia and multiple myeloma. We evaluated tumor angiogenesis in the bone marrow (BM) of multiple myeloma (MM) patients by calculating microvessel density (MVD) in needle-biopsy specimens obtained from 51 cases of untreated MM or monoclonal gammopathy of undetermined significance (MGUS). The MVD in the BM of donors for transplantation and patients with non-hematological diseases was calculated as a control. There was an obvious increase in MVD in the BM of MM patients, and the MVD correlated with the grade of myeloma cell invasion of the BM in the untreated MM cases. It was recently reported that thalidomide might be effective for the treatment of MM. We assessed the effect of thalidomide on angiogenesis in BM treatment of 11 patients with refractory MM. The concentration of M-protein in the serum or urine of seven of the 11 patients was reduced by at least 30% after thalidomide treatment, and MVD in the BM decreased in three of these seven cases in response to thalidomide. Increased plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were observed in all 11 cases before thalidomide administration and both levels were reduced after treatment with thalidomide. Augmented angiogenesis in the bone marrow of MM patients was confirmed in the present study. It seems that thalidomide is effective in the treatment of MM through the impairment of angiogenesis by decreasing FGF-2 and VEGF production. This is the first report on pathological evidence in the bone marrow of MM before and after thalidomide treatment, in Japan.
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PMID:Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment. 1508 32

Thalidomide was developed in the 1950s as a sedative drug and withdrawn in 1961 because of its teratogenic effects, but has been rediscovered as an immuno-modifying drug. It has been administered successfully for the treatment of erythema nodosum leprosum, aphthous ulceration in HIV disease, inflammatory bowel diseases, and multiple myeloma. So far, investigations into the mode of action of thalidomide have focused on lymphocytes and vascular endothelial cells and have shown that this agent inhibits the production of tumor necrosis factor (TNF)-alpha and is an inhibitor of tumor angiogenesis. Recently, other immunological effects of this drug have been gaining attention, including attenuation of neutrophil activation and inhibition of myelo-proliferative responses. In autoimmune diseases, inflammation is characterized by an influx of granulocytes, and the association of granulocytes with gastrointestinal ulcer formation or rheumatic arthritis has been well documented. The suppressive effect of thalidomide on the activation of the nuclear transcription factor NF-(kappa)B may explain these effects of thalidomide. NF-(kappa)B is retained in the cytoplasm with I(kappa)B(alpha), and is activated by a wide variety of inflammatory stimuli including TNF, IL-1 and endotoxin followed by its translocation to the nucleus. Constitutive activation of NF-(kappa)B has been detected in various inflammatory diseases, while angiogenesis and organogenesis also require NF-(kappa)B activation. Thalidomide, on the other hand, has been shown to selectively suppress NF-(kappa)B activation induced by inflammatory mediators. NF-(kappa)B is known to be located downstream of proliferative and/or survival signaling induced by growth factors, which regulate anti-apoptotic genes. Myeloid cells in vitro, however, have been found to proceed to apoptosis as the result of the treatment with thalidomide and subsequent inactivation of NF-(kappa)B. These findings are consistent with clinical symptoms that showed the recovery from leukocytosis and/or neutrophilia after the administration of thalidomide. These findings shed new light on the anti-inflammatory properties of thalidomide and suggested that they may inhibit granulocyte-mediated tissue injury.
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PMID:Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. 1572 33

The system involving angiopoietin-2 (Ang-2) and its receptor, Tie-2, appears to play an important role not only in tumor angiogenesis, but also in the biology of haematological and non-haematological malignancies. In the present study we evaluated the serum levels of soluble Ang-2 (sAng-2) and soluble Tie-2 (sTie-2) in patients with haematological malignancies. Measurements were carried out in 15 patients with chronic myeloid leukaemia (CML), 25 with essential thrombocythemia (ET), 24 with multiple myeloma (MM) and six with monoclonal gammopathy of undetermined significance (MGUS). In addition, we correlated the levels of angiopoietins with known prognostic factors. sAng-2 and sTie-2 were quantified with enzyme-linked immunosorbent assay (ELISA). In patients with CML and MM the levels of sAng-2 were significantly higher (1686.53 +/- 936.41 pg/mL and 1917.82 +/- 1427 pg/mL, respectively) than in controls (n = 15; 996.096 +/- 414.65 pg/mL) (P < 0.01). In patients with MM sAng-2 levels were significantly increased with increasing stage of disease, from stage I to stage III (P < 0.03) and presented a trend of correlation with Beta2-microglobulin levels (r = 0.317) and grade of bone involvement. Furthermore, the levels of sAng-2 determined after 6 months of chemotherapy in CML patients were significantly lower than at diagnosis in the patients who achieved haematological remission. Circulating sTie-2 levels were increased in patients with ET (17.5 +/- 9.2 vs 9 +/- 3.5 ng/mL; P < 0.01) and in those with CML (16.29 +/- 8.7 ng/mL; P < 0.04). In conclusion, abnormal levels of sAng-2 and sTie-2 are present in some haematological malignancies. These markers may play a role in the pathophysiology of these conditions and their progression.
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PMID:Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies. 1697 37

Aquaporin-1 (AQP1) is a water channel protein mainly expressed in endothelial and epithelial cells of many tissues, including the vasculature where it serves to increase cell membrane water permeability. Previous studies in active multiple myeloma patients and in AQP1 KO mice indicated an involvement of AQP1 in physiological and tumor angiogenesis. To understand the physiological role of AQP1 in angiogenesis, we used a 21-nucleotide small interfering RNA duplexes (siRNA) to knockdown AQP1 in the chick embryo chorioallantoic membrane (CAM), a commonly used in vivo assay to study both angiogenic and angiostatic molecules. Chicken AQP1 sequence was identified and utilized to synthesize a siRNA directed to the AQP1 sequence. We then tested the efficiency of the siRNA in vitro, using an AQP1 transfected cell line. The level of AQP1 protein reduction obtained using siRNA was 98 % and 92 % after 1 and 2 day transfection respectively. RNA interference experiments were then performed in vivo by using the CAM assay. Results showed that after 4 days of treatment, AQP1 siRNA was able to strongly inhibit angiogenesis. This is the first study showing the in vivo use of RNA interference technique in the CAM assay. Our results strongly support the hypothesis that AQP1 could have a key role in physiological and pathological angiogenesis.
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PMID:In vivo silencing of aquaporin-1 by RNA interference inhibits angiogenesis in the chick embryo chorioallantoic membrane assay. 1754 22

The protein kinase C (PKC) family, the most prominent target of tumor-promoting phorbol esters, is functionally linked to cell differentiation, growth, survival, migration and tumorigenesis and so mediates tumor cell proliferation, survival, multidrug resistance, invasion, metastasis and tumor angiogenesis. Therefore, targeting PKC isozymes may represent an attractive target for novel anticancer therapies. Recent preclinical and clinical studies using the macrocyclic bisindolylmaleimide enzastaurin or the N-benzylstaurosporine midostaurin demonstrate promising activity of PKC inhibitors in a variety of tumors, including diffuse large B-cell lymphoma, multiple myeloma and Waldenstroem's macroglobulinemia. However, our knowledge of PKCs in tumorigenesis is still only partial and each PKC isoform may contribute to tumorigenesis in a distinct way. Specifically, PKC isoforms have vastly different roles, which vary depending on expression levels of organ and tissue distribution, cell type, intracellular localization, protein-protein and lipid-protein interactions and the biologic environment. Although PKC activation generally positively affects tumor cell growth, motility, invasion and metastasis, recent reports show that many PKCs can also have negative effects. Therefore, it is necessary to further dissect the relative contribution of PKC isozymes in the development and progression of specific tumors in order to identify therapeutic opportunities, using either PKC inhibitors or PKC activators.
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PMID:The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. 1792 32

Multiple myeloma (MM) is characterized by the clonal expansion of monoclonal immunoglobulin-secreting plasma cells within the bone marrow (BM). It has become clear that the intimate reciprocal relationship between the tumor cell clone and the niches of the BM microenvironment plays a pivotal pathophysiologic role in MM. We and others have identified several new molecular targets and derived novel therapies which induce cytotoxicity against MM cells in the BM milieu, including thalidomide, bortezomib, and lenalidomide. Importantly, these agents induce tumor-cell death, as well as inhibit MM-cell-BM-stromal-cell (BMSC) adhesion and related tumor-cell growth, survival, and migration. Moreover, they block both constitutive and MM-cell binding-induced growth factor and cytokine secretion in BMSCs. Further, they also block tumor angiogenesis and can augment anti-MM immunity. Although all three of these agents are now FDA-approved to treat MM, patients inevitably relapse, and further improvements remain urgently needed. Here we review our current knowledge of the MM cell clone, as well as the impact of the BM microenvironment on tumor-cell growth, survival, migration and drug resistance. Delineating the mechanisms and sequelae of the reciprocal relationship between the MM cell clone, distinct BM extracellular matrix proteins, and accessory cell compartments may provide the basis for new effective therapeutic strategies to re-establish BM homeostasis and thereby improve MM patient outcome.
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PMID:The malignant clone and the bone-marrow environment. 1807 Jul 8


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