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)

Monoclonal free L chains secreted in immunoproliferative disorders are frequently involved in renal complications, including a specific proximal tubule impairment, the Fanconi's syndrome, which is generally featured by intracellular crystallization of L chain-related material. In a patient with myeloma-associated Fanconi's syndrome, hexagonal crystals (most surrounded by smooth membranes) were found in kidney proximal tubular cells and bone marrow plasma cells and phagocytes. The sequence of the patient's monoclonal kappa-chain was deduced from that of identical kappa-cDNA clones from the tumoral plasma cells. Small protein-enriched gel filtration fractions from urine yielded crystals morphologically similar and with the same 60 A periodicity on electron micrographs as those found in the cells. N-terminal sequencing and mass spectrometry studies showed that the crystals contained a 107-amino acid fragment (with a C-terminal lysine) corresponding to the V domain together with a low proportion of the entire kappa-chain. In vitro trypsin and pepsin treatment of the native entire kappa-chain yielded a homogeneous V domain fragment which, contrary to other monoclonal kappa-chains, was completely resistant to further proteolytic attack. The patient's kappa-chain also displayed an unusual self-reactivity, as demonstrated by a Western blot technique. The peculiar proneness of the V domain to resist proteolysis and to form crystals might prevent the normal cell catabolism of the L chain and lead to crystallization and renal impairment.
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PMID:Monoclonal Ig L chain and L chain V domain fragment crystallization in myeloma-associated Fanconi's syndrome. 846 90

Renal failure (RF) is a common accompaniment of multiple myeloma and is identified in over half of patients at presentation. RF is usually related to the presence of Bence-Jones protein (immunoglobulin light chain) which damages all the compartments of the kidney: glomerule, tubulo-interstitium and vasculature. The most common renal lesion is cast nephropathy, named "myeloma kidney": Cast are produced by two mechanisms: proximal tubule damage and intratubular cast formation. The predominant pathophysiologic mechanism of tubule damage appears to be a precipitation of Bence-Jones protein and Tamm-Horsfall glycoprotein produced by cells of ascending limb of Henle's loop in the tubule lumen. The therapeutic maneuvers to reduce renal damage and preserve renal function are reduction of plasma concentration of light chain with chemotherapy, elimination of factors which favour coprecipitation of Tamm-Horsfall protein with light chain (hypercalcemia, acid urine, radiocontrast material, furosemide, oliguria). At last, colchicine (1.2 mg/day) will also be efficacious in the acute management of patients with cast nephropathy.
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PMID:[Renal involvement in multiple myeloma. Physiopathology and therapy]. 881 49

Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
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PMID:Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. 927 28

Although myeloma light chains are known to undergo receptor-mediated endocytosis in the kidney, the molecular identity of the receptor has not been characterized. We examined the interaction between cubilin (gp280) and four species of light chains isolated from the urine of patients with multiple myeloma. Four lines of evidence identify cubilin, a giant glycoprotein receptor, which is restricted in distribution to endocytic scavenger pathways and which has potent effects on endosomal trafficking, as a potentially physiologically relevant binding site for light chains: 1) light chains coeluted during immunoaffinity purification of cubilin; 2) polyclonal antisera to cubilin but not control sera, displaced human light chain binding from rat renal brush-border membranes; 3) cubilin bound to multiple species of light chains during surface plasmon resonance; 4) anti-cubilin antiserum interfered with light chain endocytosis by visceral yolk sac epithelial cells. However, both binding of light chains to brush-border membranes and endocytosis of light chains by yolk sac epithelial cells were only partially inhibited by anticubilin antibodies, suggesting presence of additional or alternate binding sites for light chains. Excess light chain had a potent inhibitory effect on endosomal fusion in vitro. Binding showed dose and time-dependent saturability with low-affinity, high-capacity equilibrium binding parameters. These data demonstrate that cubilin plays a role in the endocytosis and trafficking of light chains in renal proximal tubule cells.
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PMID:Myeloma light chains are ligands for cubilin (gp280). 969 Oct 15

Monoclonal free light chains secreted in immunoproliferative disorders are frequently involved in renal complications, including a specific proximal tubule impairment, Fanconi's syndrome. The latter is characterized in most cases by intracellular crystallization including a light-chain variable-domain fragment which resists lysosomal proteases. Bence-Jones protein (BJP) DEL was isolated from a patient with myeloma-associated Fanconi's syndrome. The crystal structure of this human kappa immunoglobulin light-chain noncovalent dimer was determined using molecular replacement with the structure of molecule REI, as the variable domain, and that of BJP LOC as the constant domain. To our knowledge, DEL is the first complete kappa BJP structure described to date. The R-factor is 20.7% at 2.8 A resolution. The BJP DEL dimer was compared with other light-chain dimers and with Fab fragments with a kappa light chain. Although the domain-folding pattern was similar, the relative positions of the constant domains differed. BJP DEL showed a noncanonical quaternary structural arrangement which may be attributable to the poor CL-CL affinity and lack of an interchain disulfide bridge, combined with the conformational editing effect of the crystal-packing forces. Our results suggest that, in the absence of a disulfide bridge, most BJP CLs are probably mobile in solution. This may explain their high susceptibility to proteases and the absence of naturally occurring crystals for these dimers. Furthermore, these findings of an unusual quaternary structure of an immunoglobulin light-chain association extend our knowledge about the large and highly diverse structures of the immunoglobulin superfamily.
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PMID:The structure of an entire noncovalent immunoglobulin kappa light-chain dimer (Bence-Jones protein) reveals a weak and unusual constant domains association. 1009 99

Eighteen monoclonal Bence-Jones proteins (BJPs) were examined for their effects on cultured LLC-PK1 (porcine kidney proximal tubule) cells as well as for their amidase and DNase activities. Five proteins were found to enter the cell and to gain access to the nucleus without degradation of epitopes. Intranuclear BJPs ultimately induced DNA fragmentation and cell death. BJPs with relatively high amidase activity were cytotoxic. On the other hand, three of four BJPs with DNase activity had a cytocidal effect on cultured cells; the remaining BJP, which had a relatively high DNase activity but a very low amidase activity, failed to enter the cell and was not cytotoxic in vitro. These results suggest that catalytic and cytotoxic activities of some BJPs may make a significant contribution, in a substantial proportion of myeloma patients, to the development and/or deterioration of the disease.
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PMID:Some Bence-Jones proteins enter cultured renal tubular cells, reach nuclei and induce cell death. 1059 92

Some Bence-Jones proteins have been found to be capable of hydrolyzing DNA, chromogenic amide substrates, such as benzoylarginine p-nitroanilide, and natural oligopeptides, such as arginine vasopressin. Patients who excrete Bence-Jones protein with the DNA-nicking activity have shown moderately severe symptoms. When incubated with LLC-PK1 (porcine kidney proximal tubule) cells, some Bence Jones proteins penetrated the cytoplasm, and entered the nucleus with little or no degradation of epitopes. Intranuclear Bence Jones proteins ultimately induced DNA fragmentation in situ and cell death. This cytocidal activity was not directly associated with the DNA-nicking activity, since Bence Jones proteins with no detectable DNase activity also produced cell death. These results, however, suggest that the biological activities of Bence Jones proteins described here makes a significant contribution to the development and/or deterioration of multiple myeloma.
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PMID:Does catalytic activity of Bence-Jones proteins contribute to the pathogenesis of multiple myeloma? 1082 51

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.
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PMID:Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. 1084 34

We evaluated the effect of eight species of light chains on cultured human kidney proximal tubule cell proliferation. Exposure to light chains for 48 hours caused dose-dependent inhibition in tritium ((3)H)-thymidine incorporation by simian virus 40 immortalized human proximal tubule cells, although the effect was variable among different species of light chains. We studied cytotoxic effects of selected toxic light chains in further detail. Two of these light chains caused significant DNA degradation. A lambda-light chain caused lactate dehydrogenase release from exposed cells at 48 hours, but not at 24 hours. Cytomorphological and electron microscopic examination of cells exposed to light chains for 24 hours showed condensed nuclei, cell detachment, paucity of mitotic activity, and apoptosis, and at 48 hours of exposure, changes consistent with necrosis. Apoptosis assay by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method showed a sixfold increase in the number of apoptotic cells exposed to the same lambda-light chain for 24 hours. Rhodamine-phalloidin staining showed variable but significant disruptions in the actin cytoskeleton. These studies show that some myeloma light chains are toxic to cultured human proximal tubule cells and induce cytoskeletal injury and DNA damage consistent with apoptosis followed by secondary necrosis. Direct proximal tubule cell toxicity may be an important mechanism of renal involvement in multiple myeloma.
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PMID:Cytotoxicity of myeloma light chains in cultured human kidney proximal tubule cells. 1100 75

Multiple myeloma is associated with a wide array of renal diseases that include myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, amyloidosis, cryoglobulinemia, tubular dysfunction, pyelonephritis, nephrocalcinosis, urate nephropathy, and infiltration by atypical plasma cells (or myeloma cells). Filtered immunoglobulin light chains may affect both the distal and, more frequently, the proximal tubule. Tubular abnormalities in patients with plasma cell dyscrasia may be more frequent than previously thought. A patient with a plasma cell dyscrasia is described, who presented with biochemical features consistent with Fanconi syndrome. Immunoelectron microscopy performed on the renal biopsy confirmed the presence of kappa light chain immunoglobulin in intracytoplasmic crystals in proximal tubular epithelial cells. This report is one of a few demonstrating the presence of light-chain immunoglobulin in intratubular crystals in a human renal biopsy obtained from a patient with a plasma cell dyscrasia and Fanconi syndrome.
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PMID:Clinical, biochemical, and pathological features in a patient with plasma cell dyscrasia and Fanconi syndrome. 1101 62


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