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)

Multiple myelomas often occur in elderly people with complications due to aging. A 54-year-old man was first admitted with cerebral infarction, and multiple myeloma (IgG kappa, stage IIIA) occurred in November 1989 that was followed by partial remission after chemotherapy. The karyotype of the bone marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single-strand conformation polymorphism analysis. Chemotherapy (melphalan 10 mg, vindesine 3 mg, ranimustine 150 mg, prednisolone 60 mg for 4 days) was performed in February 1999 because of aggravation of the myeloma. After daily subcutaneous injection of 50 micrograms of nartograstim for six days to treat neutropenia, soft tissues around the right eye were swelled gradually without redness, accompanied by elevation of the serum creatine-kinase concentration. The swelling disappeared, and the enzyme level normalized after discontinuation of nartograstim. In July, on the sixth day of daily subcutaneous injection of 75 micrograms of filgrastim after the same chemotherapy, similar swelling of the soft tissues around the left eye became evident, and again this proved reversible. In July 2000, 40 mg of dexamethasone was infused, and after 5-day subcutaneous-injection of 75 micrograms of filgrastim daily, the right subclavicular soft tissue became swollen. He died of myocardial infarction, and autopsy revealed infiltration of myeloma cells into the right subclavicular muscle and bone marrow packed with myeloma cells. This case suggests that myeloma cells can proliferate and infiltrate into soft tissues on exposure to granulocyte-colony stimulating factors.
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PMID:[A case of multiple myeloma with infiltration into skeletal muscle after injections of a granulocyte-colony stimulating-factor]. 1218 9

Interleukin-6 (IL-6) is a 4-helical protein that binds to a specific IL-6 receptor on target cells and to two molecules of the promiscuous signal transducing protein, glycoprotein 130 (gp130). Structure-function analysis has led to the definition of molecular contacts between IL-6 and its receptor subunits. This knowledge has led to the design of competitive antagonistic proteins that retain their receptor binding capability, but fail to stimulate one or both gp130 proteins; the properties of such recombinant antagonistic proteins are compared with traditional neutralising monoclonal antibodies targeted at IL-6 or receptor subunits. Furthermore, several strategies have been employed to construct molecules with increased bioactivity. Possible therapeutic applications in putative IL-6 dependent haematologic disorders, e.g., Castleman's disease (CD), POEMS syndrome, multiple myeloma, and bone diseases, e.g., Paget's disease, osteoporosis, are outlined. IL-6 antagonists could also, in theory, suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. This principle may prove advantageous in myocardial infarction (MI) and unstable angina pectoris. More generally, IL-6 antagonists could improve the wasting and microcytic anaemia of chronic diseases. IL-6 antagonists might slow down development of mesangio-proliferative glomerulonephritis (MPGN). Hyperagonistic variants of IL-6 have a potential use in the ex vivo expansion of haematopoietic progenitor cells and as thrombopoietic agents. They might well be the first drugs to aid liver regeneration in vivo.
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PMID:The therapeutic potential of interleukin-6 hyperagonists and antagonists. 1598 26

Interleukin-6 (IL-6) is a four-helical protein which, on target cells, binds to a specific IL-6-receptor and two molecules of the promiscuous signal transducing protein gp130. Structure-function analysis defined three molecular contact sites between IL-6 and its receptor subunits. Using this information, competitive antagonistic proteins as well as hyperagonistic proteins were developed. Possible therapeutic applications of IL-6 antagonists are in IL-6 dependent haematological disorders (Castleman's disease, POEMS syndrome, multiple myeloma) and bone diseases (Paget's disease, osteoporosis). Designer IL-6 antagonists could suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. IL-6 antagonists could also prove advantageous in myocardial infarction and unstable angina pectoris. IL-6 antagonists might slow down development of (mesangioproliferative) glomerulonephritis. On the other hand, hyperagonistic variants of IL-6 have a potential in ex vivo expansion of bone marrow stem cells and as thrombopoietic agents. They might also be developed into drugs to support liver regeneration in vivo and to treat stress-induced cardiac insufficiency.
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PMID:New developments in IL-6 dependent biology and therapy: where do we stand and what are the options? 1599 52

Apoptosis of cardiomyocytes plays an important role in reperfusion injury following myocardial infarction. Conversely, interleukin-6 (IL-6)--a potent cytokine--inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor (IL-6R). We hypothesized that the IL-6/soluble IL-6R complex can inhibit myocardial apoptosis, and limit infarct size in reperfused acute myocardial infarction. Anesthetized rats were randomly divided into five groups: sham, coronary occlusion and reperfusion rats administered IL-6/soluble IL-6R complex, IL-6 alone, soluble IL-6R (sIL-6R) alone, or a control vehicle. Rats were subjected to 30 min occlusion of the left coronary artery followed by 3 h reperfusion. After reperfusion, the hearts were excised. For detection and quantification of apoptosis, gel electrophoresis of extracted genomic DNA and TUNEL method of paraffin sections were performed. The percentage of the infarct area was measured using tetrazolium chloride staining. The cardiomyocyte apoptosis analysis revealed that apoptosis in the reperfused myocardium was inhibited only in the complex group. Furthermore, the percentage of the infarct area out of the area at risk was remarkably reduced in the complex group (23.8+/-1.8%), compared with that in the vehicle (37.9+/-3.7%), the IL-6 (40.7+/-1.0%), or the sIL-6R (37.5+/-2.4%) groups (P=0.0002). No significant differences were observed among the vehicle, IL-6, and sIL-6R groups. The IL-6/soluble IL-6 receptor complex inhibits cardiomyocyte apoptosis in reperfused acute myocardial infarction. It possibly reduces irreversible reperfusion injury.
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PMID:Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis. 1605 42

The bicyclam AMD3100 (originally called JM3100), in which the two cyclam rings are tethered by an aromatic bridge, emanated from JM2763, where the two cyclam moieties are tethered by an aliphatic linker - JM2763 in turn originated from JM1657, where the cyclam rings are directly linked to one another via a C-C bridge, and which was identified as an impurity, showing anti-HIV activity, in a commercial cyclam preparation. AMD3100 proved very effective against HIV-1 and HIV-2, inhibiting virus replication within the nM range, without toxicity for the host cells at concentrations that were > 100,000-fold higher than those required to inhibit HIV replication. The anti-HIV activity of AMD3100 appeared to be confined to the T-lymphotropic (X4) HIV strains, i.e. those strains that use the CXCR4 receptor to enter their target cells, and AMD3100 as of today still stands as one of the most potent and selective CXCR4 antagonists ever discovered. Hence, AMD3100 was found to interfere with a number of (patho)physiological processes which depend on the interaction of CXCR4 with its natural ligand, stromal derived factor (SDF-1) and which play an important role in rheumatoid, allergic and malignant diseases. AMD3100 has been shown to mobilize CD34+ stem cells from the bone marrow into the bloodstream and has also been shown to augment migration of bone marrow-derived endothelial progenitor cells into sites of neovascularization after myocardial infarction. Currently, AMD3100 is actively pursued as a stem cell mobilizer for transplantation in patients with multiple myeloma and non-Hodgkin's lymphoma.
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PMID:Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. 1617 23

The antiangiogenic and immunomodulatory properties of thalidomide have led to its use and evaluation in refractory or relapsed multiple myeloma (MM). However, thalidomide use is associated with several side effects, although deep vein thrombosis and peripheral neuropathy are the most serious. The incidence of thrombosis after treatment with thalidomide ranges from 2% to 23%, but is higher among patients who also receive chemotherapy. Thromboembolic episodes are usually venous and may cause pulmonary embolism or even myocardial infarction and cerebral venous thrombosis. Arterial occlusion is rare, and the association between arterial thrombotic events and thalidomide is infrequent with only a few patients reported who developed arterial strokes on thalidomide. We describe a case of nonfatal thrombotic stroke occurring in a patient with relapsed MM treated with thalidomide.
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PMID:Stroke in a multiple myeloma patient treated with thalidomide. 1790 89

Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non-ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart disease.
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PMID:The therapeutic potential of stem cells in heart disease. 1818 53

The ubiquitin-proteasome system (UPS) displays an important cellular quality control function, by removing abnormal proteins from the cytosol, the nucleus and the endoplasmic reticulum. It controls the intracellular levels of short-lived and regulatory proteins, which are important for a variety of basic cellular processes. The pathway involves an enzymatic cascade through which multiple 76-amino acid ubiquitin monomers are covalently attached via a three-step process to the protein substrate, which is then degraded by the 26S proteasome complex. The proteasome is a cylindrical organelle that recognizes ubiquitinated proteins, degrades a large proportion of intracellular proteins, and recycles ubiquitin. Alterations in the proteasome proteolytic pathway have been thought to contribute to protein alterations associated with aging and, in fact, dysregulation of the UPS has been linked to several disease states including neurodegenerative diseases, malignancies, and inflammatory-related disorders. Strong preclinical data now exist supporting the use of reversible proteasome inhibitors to treat a variety of disease states including cancer, autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury. Bortezomib (Velcade) has recently been licensed for the treatment of patients with multiple myeloma and is also undergoing further evaluation for the treatment of chronic lymphocytic leukemia (CLL) and a variety of solid tumors. MLN-519 is a small-molecular-weight lactacystin analogue and is being studied for the potential treatment of inflammatory disease and acute stroke. MLN-519 has demonstrated a neuroprotective effect in rat models of middle cerebral artery occlusion by reducing infarct volume, brain oedema and improving neurological outcome with a therapeutic window of up to 6-hrs. This review article focuses on the recent progress in the use of proteasome inhibitors in nervous system diseases with emphasis on the bench-to-bedside research effort which provided the foundation for clinical development of proteasome inhibitors in the treatment of neurological disorders.
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PMID:The ubiquitin-proteasome system and proteasome inhibitors in central nervous system diseases. 1822 Jul 25

Coronary heart disease and chronic heart failure are common diseases and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impair quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies carried out in the past few years have demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non-ischemic cardiomyopathy (dilatative cardiomyopathy) and heart failure due to hypertensive heart disease.
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PMID:Therapeutic potentials of stem cells in cardiac diseases. 1927 33

Few studies have evaluated prognostic factors among patients with multiple myeloma (MM) since new therapies have become available. Monthly zoledronic acid (ZOL) has been incorporated into many treatment regimens to reduce skeletal-related events (SREs), but outcomes among patients receiving this bisphosphonate have not been well-defined. The aim of this retrospective study was to determine baseline and on-treatment prognostic factors in these patients. Data were collected from the date of diagnosis on 300 consecutive MM patients treated with ZOL. Median duration of ZOL was 18 months (range 1-121 months). The skeletal morbidity rate was 0.116 events per patient year. Five-year overall survival (OS) was 69%. Risk factors for shortened OS included SREs, increased serum creatinine, and International Staging System (ISS) Stage II or III. Thirty-four (11%) patients showed worsening renal function. In 28 of these patients, ZOL was discontinued and restarted in half of these patients following a brief delay. Only 5 of the 34 patients showed worsening of their renal function. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ). All patients with ONJ are in remission or with stable disease except one patient who died of a myocardial infarction while in remission. Only two patients showed some worsening of ONJ despite of ongoing monthly ZOL. Overall, these results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ and renal deterioration may infrequently occur with ZOL, most patients do not experience worsening of these conditions with ongoing treatment with this bisphosphonate.
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PMID:Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. 2112 Aug 61


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