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)

Hyperphosphatemia, in patients with multiple myeloma, is usually associated with severely reduced renal function. Paraproteins can interfere with the measurement of serum inorganic phosphate when certain types of automatic methods are employed. We present the case of a 44-year-old male admitted to our hospital with severe back pain and an osteolytic lesion of the first lumbar vertebra. He was diagnosed with multiple myeloma based on serum protein electrophoresis and bone marrow biopsy results. An initial serum phosphate level of 12.5 mg/dl, (normal 2.5-5 mg/dl), in the setting of normal kidney function, did not improve after treatment with oral phosphate binders. The inorganic phosphate determinations were repeated on sulfosalicylic acid deproteinized serum samples, yielding normal range phosphate levels. This case reiterates the importance of using deproteinized serum samples for phosphate measurements in patients with multiple myeloma, normal renal function and elevated phosphate levels, before initiating therapy with phosphate binders.
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PMID:Pseudohyperphosphatemia in a patient with multiple myeloma. 1500 69

We present a new antibody-directed enzyme prodrug therapy strategy (ADEPT) based on a post-proline cleaving endopeptidase and prodrugs, in which cytotoxic moieties are linked to a proline-containing peptide. Human prolyl endopeptidase was expressed in Escherichia coli and purified to homogeneity. The enzyme was active in buffer and in human serum but was rapidly thermally inactivated by incubation at 37 degrees C, thus preventing applications in vivo. While prolyl endopeptidase display on filamentous phage abolished viral infectivity and prevented directed evolution strategies based on phage display, we robotically screened 10752 individual colonies of mutant enzymes using a fluorogenic assay to improve enzyme stability. A single amino acid mutation (Glu289 --> Gly) improved protein stability, resulting in a half-life of 16 h at 37 degrees C in phosphate buffer. Two prodrugs were synthesized, in which an N-protected glycine-proline dipeptide was covalently coupled to doxorubicin and melphalan. (Benzyloxycarbonyl)glycylprolylmelphalan, but not the more sterically hindered doxorubicin prodrug, could be efficiently activated by prolyl endopeptidase [specific activity = 813.3 nmol min(-1) (mg of enzyme)(-1) at 25 degrees C]. The melphalan prodrug was essentially nontoxic to CHO, F9 teratocarcinoma, MCF7 breast adenocarcinoma, and p3U1 mouse myeloma cells up to millimolar concentrations, while prodrug incubation with the engineered prolyl endopeptidase mutant led to a cell killing profile superimposable to the one of melphalan. The prolyl endopeptidase mutant was then chemically coupled to the human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis. The resulting immunoconjugate retains antigen binding and enzymatic activity, thus opening the way to anticancer ADEPT applications.
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PMID:Engineering a thermostable human prolyl endopeptidase for antibody-directed enzyme prodrug therapy. 1514 13

Multiple myeloma and other hematological malignancies have been treated by myeloablative radiotherapy/chemotherapy and subsequent stem cell transplantation. [(166)Dy]Dy/(166)Ho-ethylenediaminetetramethylene phosphonate (EDTMP) forms a stable in vivo generator system with selective skeletal uptake in mice; therefore, it could work as a potential and improved agent for marrow ablation. Induced bone marrow cytotoxicity and genotoxicity are determined by the reduction of reticulocytes (RET) and elevation of micronucleated reticulocyte (MN-RET) in peripheral blood and ablation by bone marrow histological studies. The aim of this study was to determine the bone marrow cytotoxic and genotoxic effect of the [(166)Dy]Dy/(166)Ho-EDTMP in vivo generator system in mice and to evaluate by histopathology its myeloablative potential. Enriched (166)Dy(2)O(3) was irradiated and [(166)Dy]DyCl(3) was added to EDTMP in phosphate buffer (pH 8.0) in a molar ratio of 1:1.75. QC was determined by TLC. Dy-EDTMP complex was prepared the same way with nonirradiated dysprosium oxide. A group of BALB/c mice were intraperitoneally injected with the radiopharmaceutical and two groups of control animals were injected with the cold complex and with 0.9% sodium chloride, respectively. A blood sample was taken at the beginning of the experiments and every 48 h for 12 days postinjection. The animals were sacrificed, organs of interest taken out and the radioactivity determined. The femur was used for histological studies. Flow cytometry analysis was used to quantify the frequency of RET and MN-RET in the blood samples. The MCNP4B Monte Carlo computer code was used for dosimetry calculations. Radiochemical purity was 99% and the mean specific activity was 1.3 MBq/mg. The RET and MN-RET frequency were statistically different in the treatment at the end of the 12-day period demonstrating cytotoxicity and genotoxicity induced by the in vivo generator system. The histology studies show that there was complete, or almost complete, acellularity, which means significant suppression of the bone marrow activity. Bone marrow absorbed dose was 18-23 Gy. [(166)Dy]Dy/(166)Ho-EDTMP induces cytotoxicity, genotoxicity and severe myelosuppression in mice. Potentially, it is a good agent for use in humans.
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PMID:Cytotoxic and genotoxic effect of the [166Dy]Dy/166Ho-EDTMP in vivo generator system in mice. 1560 90

A recognition site for the cAMP-dependent protein kinase was introduced into the MAb-chCC49 by site-directed mutation of the coding sequence to make a variant of MAb-chCC49 containing a highly stable phosphate. To design this monoclonal antibody (MAb) without changing its immunoreactivity or biological properties, molecular modeling was used to locate appropriate regions for introduction of the cAMP-dependent phosphorylation site with desirable properties. We selected one position to mutate on the heavy chain based on molecular dynamics study of the solvated antibody. A vector expressing the mutant was constructed and transfected into mouse myeloma NS0 cells that expressed a high level of the resultant MAb-WW5. MAb-WW5 contained the cAMP-dependent phosphorylation site at the hinge region of the heavy chain, could be phosphorylated by the catalytic subunit of cAMP-dependent protein kinase with [gamma-32P]ATP to high specific activity, and retained the phosphate stably. Compared with MAb-chCC49K1, another phosphorylatable variant of MAb-chCC49, the phosphate attached to MAb-WW5 showed much improved stability: about a 10-fold increase in resistance to hydrolysis. MAb-WW5 exhibited the same binding specificity to the TAG-72 antigen on MCF-7 4C10 breast cancer cells as we observed with MAb-chCC49K1. The improved stability of the attached phosphate provides a MAb with potential to be used in diagnosis and therapy of adenocarcinomas.
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PMID:Design and construction of a phosphorylatable chimeric monoclonal antibody with a highly stable phosphate. 1566 96

The novel aryl phosphate derivative of bromo-methoxy zidovudine (ZDV/AZT) (compound WHI-07, CAS 213982-96-8) was found to be a potent antileukemic agent against human leukemia, lymphoma, and multiple myeloma cell lines in MTT and clonogenic assays with low micromolar IC50 values. In addition, WHI-07 was antimitotic, leading to cell fusion and developmental arrest in the Zebrafish model of rapid cell proliferation. WHI-07 was cytotoxic to drug-sensitive (NALM-6, MOLT-3, HL-60, P388) and multi-drug resistant (MDR) leukemia cell lines (HL-60/VCR, HL-60/ADR, P388/ ADR). Treatment of leukemia cells with WHI-07 showed rapid and dramatic depletion of all cellular nucleoside diphosphate and triphosphate (NDP/NTP) pools, which would contribute to the overall reduction of nucleic acid synthesis and cell death. WHI-07 was rapidly metabolized to alaninyl ZDV monophosphate (Ala-ZDV-MP), the levels of which inversely correlated with cytotoxic IC50 values of WHI-07. Glutathione was found to mediate the in vitro and in vivo detoxification pathway of WHI-07 to 3'-azidothymidine-5'-p-bromophenylmethoxyalaninyl phosphate and Ala-ZDV-MP, respectively. The proposed intracellular metabolic pathway for WHI-07 involves a thiol-mediated dehalogenation step followed by the paraoxon-sensitive carboxylesterase-mediated reaction leading to the formation of Ala-ZDV-MP as the major intracellular metabolite.
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PMID:Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07). 1572 64

Thalidomide, which is clinically recognized as an efficient therapeutic agent for multiple myeloma, has been thought to exert antiangiogenic action through an unknown mechanism. We here show a novel mechanism of thalidomide-induced antiangiogenesis in zebrafish embryos. Thalidomide induces the defect of major blood vessels, which is demonstrated by their morphologic loss and confirmed by the depletion of vascular endothelial growth factor (VEGF) receptors such as neuropilin-1 and Flk-1. Transient increase of ceramide content through activation of neutral sphingomyelinase (nSMase) precedes thalidomide-induced vascular defect in the embryos. Synthetic cell permeable ceramide, N-acetylsphingosine (C2-ceramide) inhibits embryonic angiogenesis as well as thalidomide. The blockade of ceramide generation by antisense morpholino oligonucleotides for nSMase prevents thalidomide-induced ceramide generation and vascular defect. In contrast to ceramide, sphingosine-1-phosphate (S1P) inhibits nSMase-dependent ceramide generation and restores thalidomide-induced embryonic vascular defect with an increase of expression of VEGF receptors. In human umbilical vein endothelial cells (HUVECs), thalidomide-induced inhibition of cell growth, generation of ceramide through nSMase, and depletion of VEGF receptors are restored to the control levels by pretreatment with S1P. These results suggest that thalidomide-induced antiangiogenic action is regulated by the balance between ceramide and S1P signal.
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PMID:Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. 1574 Dec 22

Aspiration of lytic bone lesions is an excellent diagnostic test in the initial evaluation of primary bone neoplasia. However, cytologically, it can be difficult to differentiate osteosarcoma (OSA) from other bone neoplasms, including fibrosarcoma, chondrosarcoma, synovial cell sarcoma, and plasma cell myeloma. The purpose of this study is to determine the sensitivity and specificity of alkaline phosphatase (ALP) staining to differentiate OSA from other tumors that express vimentin by immunocytochemistry or immunohistochemistry. ALP is a hydrolytic enzyme present in multiple tissues including liver, kidney, intestine, placenta, and bone. Hypothetically, neoplasms actively producing bone should be specifically positive for ALP staining. Unstained, cytologic specimens were incubated for 8-10 minutes with nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indolyl phosphate toluidine salt-phosphatase substrate. A positive reaction stains the membrane of the cells gray to black. Samples were counterstained with a Romanowsky's stain to determine whether the sample was of representative cellularity. A total of 61 vimentin-positive neoplasms have been evaluated and confirmed histopathologically. Tumors that expressed vimentin and were positive for ALP included 33 OSAs, one multi-lobular tumor of bone, one amelanotic melanoma, and one chondrosarcoma. Tumors that expressed vimentin and were negative for ALP included chondrosarcomas (three of four), multiple fibrosarcomas, and multiple synovial cell sarcomas. The sensitivity is 100%, and the specificity is 89%. In conclusion, ALP appears to be a highly sensitive and fairly specific marker in the diagnosis of OSA.
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PMID:Use of alkaline phosphatase staining to differentiate canine osteosarcoma from other vimentin-positive tumors. 1575 69

Myeloma nephropathy is a disorder characterized by deposition of monoclonal immunoglobulin light chains in the kidneys. The chains deposited form either amyloid fibrils or granular (amorphous) aggregates. Distinct molecular mechanisms leading to the formation of different aggregate types in kidney of patients with multiple myeloma are poorly understood. Here we describe the self-association kinetics of human monoclonal immunoglobulin light chains lambda (GRY) isolated from urine of a patient with multiple myeloma. Under physiological conditions, the isolated light chain exists predominantly in a form of covalent dimer with apparent molecular mass of 50.1 kD. Spectral probe binding, analytical gel filtration, Western blot analysis, and electron microscopy indicate that GRY dimer aggregation occurs via two different pathways producing either amyloid fibrils or amorphous aggregates depending on microenvironment. Incubation of GRY (25 microM) for 4-14 days at 37 degrees C in phosphate buffered saline (PBS), pH 7.0, or in PBS containing urea (0.8 M), pH 6.5, leads to amyloid fibril formation. Under electron microscopy, the fibrils show unbranched thread-like structures, approximately 60-80 x 1000 A in size, which can bind thioflavin T and Congo Red. GRY maintained in acetate buffer, pH 3.5, forms granular aggregates. The structure of GRY oligomers formed during the early stage of amyloid fibril formation (1-4 days) has been examined by means of protein cross-linking with homobifunctional reagents. These oligomers are predominantly trimers and tetramers.
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PMID:Human immunoglobulin light chains lambda form amyloid fibrils and granular aggregates in solution. 1589 13

Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadolinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies. MGd induces apoptosis in B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and highly resistant myeloma cell lines. Furthermore, MGd is additive or synergistic with ionizing radiation, several chemotherapy agents, and rituximab in vitro and in vivo tumor models. Through gene expression profiling, various stress-related genes are upregulated in response to MGd, including genes encoding metallothioneins, heat shock proteins, and heme oxygenase. Preliminary results from clinical trials with MGd in hematopoietic malignancies have shown that it is well tolerated, with minimal hematologic side effects in both; it has single agent activity in very heavily pretreated chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and it has induced prompt complete remissions in combination with 90Yttrium-ibritumomab (Y-90 Zevalin; Biogen Idec Inc., Cambridge, MA) for relapsed non-Hodgkin's lymphoma in the first two cohorts of patients enrolled. Various clinical trials studying MGd as a single agent and in combination with radiation and/or chemotherapy for the treatment of hematologic malignancies are ongoing.
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PMID:Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies. 1596 82

A vertebral fracture, whether originating from osteoporosis or trauma, can be the cause of pain, disability, deformation and neurological deficit. The treatment of vertebral compression fractures has, for many years until the advent of vertebroplasty, consisted of bedrest and analgesics. Vertebroplasty is a percutaneous technique during which bone cement is injected in a vertebral body to provide immediate pain relief by stabilization. Inflatable bone tamps can, prior to the injection of cement, be used to create a void in the vertebral body, in which case the technique is known as balloon vertebroplasty (or kyphoplasty). The chance of extracorporal cement leakage is smaller for balloon vertebroplasty than for vertebroplasty. Some authors also claim to have gained some correction in vertebral body height or angulation. Both interventions can be used for several indications, including osteoporotic compression fractures and osteolytic lesions of the vertebral body such as myeloma, hemangioma or metastasis, and also for traumatic burst fractures in combination with pedicle screw instrumentation. Polymethyl methacrylate cement is the bone void filler that is used most frequently, although the application of calcium phosphate cements has been studied widely in vitro, in vivo and also in small-scale clinical series. The clinical results of (balloon-) vertebroplasty are favorable with 85-95% of all patients experiencing immediate and long-lasting relief of pain. Serious complications are relatively rare but include neurological deficit and pulmonary embolism. In this paper, both vertebroplasty and balloon vertebroplasty and their respective indications, techniques and results are described in relation with the application and limitations of permanent and resorbable injectable bone cements.
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PMID:Anterior spinal column augmentation with injectable bone cements. 1610 18


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