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)

Many cancers are associated with hypercoagulability, including multiple myeloma. At least four possible reasons for hypercoagulability have been described in myeloma patients: interference of immunoglobulins on fibrin structure, procoagulant autoantibody production, effects of inflammatory cytokines on endothelium, and acquired activated protein C (APC) resistance. Moreover, injury to endothelium, either by tumor cells or by chemotherapy, may predispose to thrombosis by causing upregulation of adhesion molecules, allowing adhesion of blood cellular elements (platelets, lymphocyte, neutrophils, and tumor cells, which secrete thrombogenic as well as angiogenic substances). In most cases, the pathogenesis of a thrombotic complication in myeloma patients remains unexplained. Administration of chemotherapy may play a larger role in the thrombotic process than a specific abnormality does because thrombotic complications become more prominent after the start of treatment. The recently reported evidence of a non-factor V Leiden APC resistance has increased our understanding of the pathophysiology of this hypercoagulable state.
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PMID:The blood coagulation mechanism in multiple myeloma. 1288 31

We investigated the rare case of a patient with IgGlambda multiple myeloma for whom both prothrombin time and APTT were significantly prolonged. The IgG inhibited coagulation reactions upstream from prothrombin when coagulation was initiated by mRVVT, but not by FXa, as indicated by a chromogenic substrate for FXa. The mPT and the mAPTT showed inhibition of FXa generation in both the intrinsic and extrinsic pathways. The IgG inhibited both protein C (indicated by APTT) and FX (indicated by RVV) but not amidolysis for either activated protein C or FXa. The addition of excess phospholipid significantly shortened the prolonged RVVT of the patient. It inhibited the coagulation reactions of normal plasma and was dependent on decreasing the PS concentration in the APTT reagent. It was suggested that the IgG showed lupus anticoagulant (LA)-like activity that inhibited phospholipid-dependent coagulation reactions in the intrinsic, extrinsic, and common pathways. However, the IgG did not bind cardiolipin-beta2GPI complex, beta2GPI, or prothrombin in ELISA assays. The IgG did not bind to either PS or phospholipid complexes in the presence or absence of prothrombin, FX, or FXa. Interestingly, the IgG lost its LA like-activity when it was degraded to F(ab')2 and Fc fragments by pepsin. We suspected that the IgG might inhibit the interaction between coagulation factors and acid phospholipid non-immunologically and that this process requires an intact IgG conformation, although the reaction mode is still not clear.
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PMID:A non-immunological phospholipid-dependent coagulation inhibitor associated with IgGlambda-type multiple myeloma. 1469 30

Monoclonal gammopathies (MG) may be associated with unique monoclonal immunoglobulin (MIg)-induced disturbances of either primary hemostasis or plasma coagulation. We have investigated the possible interference of MIg with antithrombotic systems in 49 patients with MG. Although an increase of tissue-type plasminogen activator (t-PA) activity was the most frequent abnormality in our group, defect of anticoagulation factors was found in 26.5% of patients. The relationship between MIg type and concentration and frequency of antithrombotic factor abnormalities was not found. The risk of venous thrombosis was higher in patients with the defect in comparison with the unaffected group (46% vs. 22%), but the difference was not statistically significant. Bleeding complications were markedly less frequent in the group of patients with defect of anticoagulation mechanisms (0% vs. 17%). In conclusion, we have found abnormalities in anticoagulation and/or fibrinolytic system, analogous to well-known disturbances of hemostatic mechanisms, in more than a quarter of patients with MG. The interference of M-protein with antithrombotic pathways is supposed to be another mechanism of secondary deficiencies of antithrombin III (AT III), protein C (PC), protein S (PS), plasminogen and APC resistance. Together with other factors, it could contribute to higher risk of thromboembolism in myeloma patients.
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PMID:Disturbances of anticoagulation and fibrinolytic systems in monoclonal gammopathies-another mechanism of M-protein interference with hemostasis. 1504 Dec 73

We have established a large-scale manufacturing system to produce recombinant human alpha-thrombin. In this system, a high yield of alpha-thrombin is prepared from prethrombin-2 activated by recombinant ecarin. We produced human prethrombin-2 using mouse myeloma cells and an expression plasmid carrying the chicken beta-actin promoter and mutant dihydrofolate reductase gene for gene amplification. To increase prethrombin-2 expression further, we performed fed-batch cultivation with the addition of vegetable peptone in 50 liters of suspension culture. After five feedings of vegetable peptone, the expression level of the recombinant prethrombin-2 reached 200 micro g/ml. Subsequently, the recombinant prethrombin-2 could be activated to alpha-thrombin by recombinant ecarin expressed in a similar manner. Finally, recombinant alpha-thrombin was purified to homogeneity by affinity chromatography using a benzamidine-Sepharose gel. The yield from prethrombin-2 in culture medium was approximately 70%. The activity of the purified recombinant alpha-thrombin, including hydrolysis of a chromogenic substrate, release of fibrinopeptide A, and activation of protein C, was indistinguishable from that of plasma-derived alpha-thrombin. Our system is suitable for the large-scale production of recombinant alpha-thrombin, which can be used in place of clinically available alpha-thrombin derived from human or bovine plasma.
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PMID:Preparation of recombinant alpha-thrombin: high-level expression of recombinant human prethrombin-2 and its activation by recombinant ecarin. 1517 95

Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells in the bone marrow and peripheral blood. PCL is also characterized by a fulminant course and poor prognosis. Diagnosis of PCL is established based on Kyle's criteria which include an absolute plasma cell number comprising greater than 20% of peripheral blood cells. PCL has two variants: the primary form presents de novo in patients with no previous history of multiple myeloma (MM) and the secondary form consists of a leukemic transformation in a previously recognized MM. In this paper, we report ten cases of PCL occurring since 1994 to 2005 in a Mexican health institution. Median age at presentation in our study was 58 years, most of them were female (70%). Primary PCL (PPCL) represented 80% and secondary PCL (SPCL) 20%. We describe clinical characteristics, stage, and response to treatment. Interestingly, we report a patient who presented a secondary PCL and acquired activated protein C resistance (APC-R). Additionally, we found an incidence of 20% of venous thrombosis events in two patients with PPCL. Mean survival was 5.9 months (range 2-17) for both PPCL and SPCL. Mean survival for PPCL was 6.75 months and for SPCL 2.0 months, similar to previous literature reports.
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PMID:Plasma cell leukemia: a rare condition. 1641 15

Deep vein thrombosis and its lethal complication pulmonary embolism are manifestations of venous thromboembolism (VTE), which is typically associated with cancer and recent major surgery. Certain solid tumors and hematologic malignancies impose an inherently elevated risk of VTE that is compounded by chemotherapy and other risk factors. Multiple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their multiple hemostatic effects, including elevated interleukin-6 levels, pro-coagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance, and endothelial damage. The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported. Various VTE prophylaxis strategies with thalidomide- and lenalidomide-containing combinations have been investigated in clinical studies. This review discusses emerging results on the use of VTE prophylaxis to minimize VTE risks associated with MM treatment regimens containing thalidomide and lenalidomide.
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PMID:Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. 1673 69

Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE). APCR was determined in 1178 myeloma patients using an activated partial thromboplastin time-based resistance assay in the presence of excess of factor V-deficient plasma; polymerase chain reaction amplification of genomic DNA was used to detect factor V Leiden mutation. A total of 109 patients were found to have abnormal APCR and one-third of them were carriers for the mutation. With a median follow-up of 40 months, the presence of aAPCR was associated with a significantly increased risk of thrombosis (P < or = 0.001). APCR was measured again after treatment in 31 patients with abnormal baseline values and had normalised in 30 of them. This study indicates that aAPCR is the most common single transitory baseline coagulation abnormality associated with VTE in myeloma patients.
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PMID:Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. 1688 32

Multiple myeloma, as with other malignancies, has been associated with the development of venous thromboembolic events. Chemotherapy or steroids in combination with antiangiogenic agents can further enhance this risk. The identification of measurable factors associated with this prothrombotic state could help in the selection of patients who need antithrombotic prophylaxis. Malignancy-associated thrombophilic state, paraprotein-specific mechanisms and treatment-induced changes can explain the high rate of thrombosis in this cancer population. While the release of inflammatory cytokines induces high levels of factor VIII, von Willebrand factor and downregulate the protein C system, elevated plasma immunoglobulin can impair fibrinolysis. Strategies of thromboprophylaxis with low molecular weight heparin, warfarin or aspirin in patients treated with thalidomide/chemotherapy or lenalidomide and dexamethasone have shown efficacy. Early data indicate that the effect of low molecular weight heparin on multiple myeloma is not confined to the anticoagulant effect but could extend to survival; a similar positive trend in overall survival has also been reported in patients treated with aspirin.
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PMID:Thrombosis in multiple myeloma. 1733 51

Ligation of CD40 induces maturation of dendritic cells (DC) and could be a useful target for vaccines. In this study, we have constructed two types of Ab-based vaccine constructs that target mouse CD40. One type is a recombinant Ab with V regions specific for CD40 and has defined T cell epitopes inserted into its C region. The other type is a homodimer, each chain of which is composed of a targeting unit (single-chain fragment variable targeting CD40), a dimerization motif, and an antigenic unit. Such proteins bound CD40, stimulated maturation of DC, and enhanced primary and memory T cell responses. When delivered i.m. as naked DNA followed by electroporation, the vaccines induced T cell responses against MHC class II-restricted epitopes, Ab responses, and protection in two tumor models (myeloma and lymphoma). Two factors apparently contributed to these results: 1) agonistic ligation of CD40 and induction of DC maturation, and 2) delivery of Ag to APC and presentation on MHC class II molecules. These results highlight the importance of agonistic targeting of Ag to CD40 for induction of long-lasting and protective immune responses.
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PMID:Delivery of antigen to CD40 induces protective immune responses against tumors. 1737 73

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
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PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76


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