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)

The clinical application of anticancer cytokines (interferons, interleukin-1, interleukin-2 and tumor necrosis factor) are reviewed. Although anticancer cytokines have confirmed its usefulness against some tumors which are refractory to the treatment using anticancer drugs, the results of clinical trials have generally been disappointing because the target spectrum and efficiency is somewhat limited. Recently, combined efficacy between interferon and anticancer drugs was reported in some malignancies such as multiple myeloma and colorectal carcinoma. For the development of effective combination treatment, we need more basic and clinical information on dose, schedule and sequence of drug administration.
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PMID:[Clinical application of anticancer cytokines]. 127 41

A cDNA clone, designated TRAP (TNF-related activation protein) was isolated from a collection of T cell activation genes. The polypeptide encoded by a mRNA of approx. 2.3 kb is 261 amino acids long with a calculated M(r) of 29.3 kDa. The structural features predict a type II transmembrane protein, but are also compatible with a secreted form. TRAP is highly similar to an identified murine CD40 ligand both at the cDNA (82.8% identity) and the protein (77.4% identity) levels, and related to tumor necrosis factor/lymphotoxin. Expressed in a murine myeloma, TRAP was identified as a ligand for CD40 by binding to a soluble CD40 construct. TRAP mRNA is expressed in a T cell-specific fashion with a maximum at 8 h after stimulation. The TRAP gene is located in the q26.3-q27.1 region of the X chromosome.
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PMID:Cloning of TRAP, a ligand for CD40 on human T cells. 128 Feb 26

Lytic bone lesions and hypercalcemia are common features of multiple myeloma; however, they are exceptional in other B-cell malignancies. Myeloma bone involvement is related to an uncoupling process associating an increased osteoclastic resorption with decreased bone formation. Several osteoclast-activating factors such as interleukin-1 (IL-1), tumor necrosis factor, and interleukin-6 (IL-6) are involved in this process. IL-6, the major myeloma cell growth factor, could play a critical role in myeloma-induced bone resorption in association with other known or unknown hematopoietic growth factors, however.
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PMID:Mechanisms of bone lesions in multiple myeloma. 158 75

The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.
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PMID:Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. 165 17

The construction, synthesis and secretion of a genetically engineered antibody-cytokine fusion molecule is described. To target tumor necrosis factor (TNF) to tumor cells, recombinant antibody techniques were used to produce a Fab-like antibody-TNF conjugate. At the gene level, the heavy chain gene of an antitransferrin receptor antibody was linked to a synthetic TNF gene encoding human TNF. Transfection of the heavy chain-TNF gene into a myeloma derived cell line which was producing the light chain of the same antibody, allowed the isolation of a cell line secreting a fusion protein of the expected molecular weight and composition. The culture supernatant of the cell line contained TNF cytotoxic activity towards murine L929 cells and human MCF-7 cells. Cytotoxicity towards the human cancer cells was inhibited by an excess of the original antitransferrin receptor antibody, indicating that the antibody-TNF molecules are targeted to the transferrin receptor rich tumor cells. Since the antibody genes used are chimeric (i.e. composed of mouse variable and human constant regions) and since DNA encoding human TNF was used, the hybrid protein is an example of a humanized immunotoxin-like molecule. These results illustrate the possibilities of antibody engineering technology to create and produce improved agents for cancer therapy. Furthermore, they demonstrate for the first time the ability of myeloma cells to secrete an antibody-cytokine chimeric molecule.
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PMID:Targeting of tumor necrosis factor to tumor cells: secretion by myeloma cells of a genetically engineered antibody-tumor necrosis factor hybrid molecule. 206 6

Hypercalcemia occurs for various reasons in patients with malignant diseases. Most of these patients show a relative increase in bone resorption over bone formation. Increased renal tubular calcium reabsorption is also important for maintaining hypercalcemia in the majority of patients. Calcium absorption from the gut is usually decreased. In a few patients, fixed impairment of glomerular filtration contributes to hypercalcemia. Because the pathophysiology of hypercalcemia is heterogeneous, it may be considered as three separate syndromes: the humoral hypercalcemia of malignancy caused by systemic mediators; the hypercalcemia associated with localized osteolytic disease; and the hypercalcemia associated with myeloma and related hematologic malignancies. Increased bone resorption is a key feature in each of these syndromes. In malignant disease, bone resorption is enhanced because osteoclast activity is increased by the production of humoral mediators. These mediators are often produced by the tumor cells but are also produced by normal host cells that have been activated by the presence of the tumor. some of these mediators of hypercalcemia are systemic factors, but some act only locally. They include parathyroid hormone-related protein, transforming growth factor alpha, lymphotoxin, tumor necrosis factor, interleukin-1 alpha and 1,25-dihydroxyvitamin D.
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PMID:Incidence and pathophysiology of hypercalcemia. 210 29

A parathyroid hormone-like peptide that probably causes hypercalcemia associated with solid tumors was recently characterized. It is a potent hypercalcemic and hypophosphatemic factor whose production is strongly associated with hypercalcemia and whose properties account for most aspects of the clinical syndrome. Diagnostic tests for this peptide have been developed. The parathyroid hormone-like peptide as well as other cytokines, such as tumor necrosis factor-alpha, likely play a role in causing hypercalcemia in multiple myeloma and lymphomas.
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PMID:Peptide mediators of hypercalcemia in malignancy. 218 36

During the past decade, specific mediators of bone destruction in hypercalcemia of malignancy have been identified and characterized. These humoral factors include parathyroid hormone-related protein, transforming growth factor alpha, and cytokines such as interleukin-1 and tumor necrosis factor. In metastatic hypercalcemia associated with breast cancer, prostaglandin secretion by tumor cells may be one of the important factors. Among the osteoclast activating factors associated with hypercalcemia in patients with myeloma, lymphotoxin plays a central but probably not exclusive role. Alterations of renal function in hematologic hypercalcemia may potentiate bone destruction that usually occurs in the presence of impaired rates of glomerular filtration. Further research is required to determine the relative contributions of bone and kidney to the pathogenesis of hypercalcemia of malignancy.
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PMID:Pathophysiology of cancer-associated hypercalcemia. 218 48

Interleukin 1 (IL 1), IL 6, and tumor necrosis factor (TNF) are typical examples of multifunctional cytokines involved in the regulation of the immune response, hematopoiesis, and inflammation. Their functions are widely overlapping but each shows its own characteristic properties. IL 6 was originally identified as a B cell differentiation factor, and thus one of the major functions of IL 6 is antibody induction. Transgenic mice have provided much needed information on the pathophysiological role of cytokines. With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis. The cis-regulatory elements and trans-acting nuclear factor (or factors) for the IL 6 expression (NF-IL 6) have been identified. NF-IL 6 was shown to be a member of a C/EBP family, and the possible involvement of NF-IL 6 not only in the IL 6 regulation but also in the induction of various acute phase proteins was also observed. The findings suggest the presence of a positive regulatory loop in acute-phase reaction. IL 1 receptor belongs to an Ig superfamily, but the IL 6 receptor is a member of a newly identified cytokine receptor family. The IL 6 receptor system was shown to be composed of a ligand binding chain and a signal-transducing molecule. IL 6 was found to trigger the association of these two polypeptide chains. This unique mechanism may be applied to other cytokine receptor systems.
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PMID:Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). 219 84

Media from murine pre-B and B lymphoma cell cultures, but not from myeloma cell cultures, was cytotoxic to WEHI 164 cells, causing these TNF-sensitive targets to release 51Cr. The cytotoxic activity in the culture medium reached maximum levels approximately 4 days after the cell culture was initiated. The constitutive production of the factors was not influenced by depletion of serum from the medium or by the addition of either phorbol ester or bacterial endotoxin. The factor has a Mr greater than 10 kDa, and its cytotoxicity was abolished by anti-serum against murine TNF. Northern blot analysis with the use of cDNA probes to murine tumor necrosis factor (TNF-alpha) and lymphotoxin (LT, TNF-beta) showed high levels of TNF-mRNA in the pre-B cell lines, lower levels in the mature B cell lines and no TNF-mRNA in the myeloma cell lines. LT mRNA was present in pre-B cell lines, at a much lower concentration in only one of the B cell lines, and was not present in three other B lymphomas or in the myelomas tested. The results show a positive correlation between the presence of TNF and/or LT mRNA and the 51Cr-releasing activity present in the cell culture medium. Our data indicate that TNF and LT can be produced by murine B cells and that the synthesis of these cytokines may be restricted to certain differentiation stages of the B cell lineage.
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PMID:Production of tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) by murine pre-B and B cell lymphomas. 232 77


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