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)

Glucocorticoids lower the serum calcium in patients with hypercalcemia due to myeloma and related lymphoproliferative disorders. OAF is a potent bone-resorbing lymphokine which is probably responsible for the bone lesions and hypercalcemia which occur in patients with these hematological neoplasms. In this study, we have examined the effects of cortisol on the production of OAF and its biological activity in order to clarify the mechanism of action of glucocorticoids in lowering the serum calcium in these disorders. The effects of OAF-containing media on bone resorption were inhibited by cortisol at concentrations from 10-5M to 10-9M. In contrast, OAF production was not inhibited by cortisol at concentrations less than 10-5M. These data support the hypothesis that glucocorticoids inhibit the effects of OAF in vivo primarily by a direct effect on bone resorption.
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PMID:Effects of glucocorticoids on osteoclast-activating factor. 71 8

Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with "LDH phenotype," which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL-LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan-prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Plasma cell myeloma--new biological insights and advances in therapy. 246 90

Hypercalcemia secondary to malignancies can be divided into two groups according to their calcium elevating mechanism: solid tumors with bony metastases, most frequently originating from the breast or the bronchi, and solid tumors without bony metastases, associated with secretion by the tumor of a substance which increases the calcium level. This substance resembles parathormone in pseudo-hyperparathyroidism, prostaglandins, or other substances not yet identified. The most common tumors involved are bronchial or renal cancers. Diagnostic problems vary depending on whether the cancer has been identified or not, and if bony metastases have or have not been discovered. Primary hyperparathyroidism must also be considered since it is frequently associated with cancer. Hypercalcemia from blood dyscrasias (myeloma and lymphoma) originates from the same mechanisms. It may or may not be associated with bony lesions. The hypercalcemia could be due to a "parathormone like" substance, to prostaglandins, to a substance that stimulates osteoclasts (OAF), or to calcitriol (1,25-dihydroxycholecalciferol). The treatment of hypercalcemia due to malignancies is primarily through the use of antiosteoclastic agents: calcitonin, mithramycin, and more recently diphosphonates. Corticosteroids and the prostaglandin inhibitors can have an additional calcium lowering effect.
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PMID:[Hypercalcemia of cancer and myeloma]. 639 3

Interleukin-1 beta has potent OAF activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production (see Fig. 1). These biologic effects of IL-1 beta closely parallel several of the clinical features of human myeloma, such as osteolytic bone lesions, homing of myeloma cells to the bone marrow, and IL-6-induced cell growth. The increased production of adhesion molecules could explain why myeloma cells are found predominantly in the bone marrow. These fixed monoclonal plasma cells could subsequently stimulate osteoclasts through the production of IL-1 beta and paracrine generation of IL-6, resulting in osteolytic disease. Also, IL-6 produced by either a paracrine or autocrine mechanism can support the growth of the myeloma cells that may be manifested clinically by an elevated labeling index. In the future, continued follow-up of IL-1 beta-positive and IL-1 beta-negative MGUS patients should determine whether aberrant expression of IL-1 beta by monoclonal plasma cells is a critical genetic event in the progression of MGUS to myeloma. Because MGUS is relatively common in the general population and myeloma is incurable in almost all cases, identification of MGUS patients who are likely to progress to active myeloma will be important in the development of new therapeutic strategies. For example, an effective chemopreventive agent that prevents or delays the transition from MGUS to myeloma could have a major effect on the treatment of patients with monoclonal gammopathies.
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PMID:The role of interleukin-1 beta in the pathogenesis of multiple myeloma. 1062 39

Much of the morbidity and mortality associated with the plasma cell (PC) malignancy, multiple myeloma (MM), is owing to the severe osteolytic bone disease seen in patients with this disease. Although the molecular mechanisms responsible for osteolysis remain to be fully elucidated, it is clear from numerous studies that it is owing, in part, to an increase in osteoclastic bone resorption. Several known osteoclast (OC)-activating factors (OAFs) are produced by myeloma PCs (MPCs), or by stromal cells in response to MPCs and include interleukin-1beta (IL-1beta); tumor necrosis factor-alpha (TNF-alpha); IL-6; parathyroid hormone-related protein; macrophage inflammatory protein-1alpha; and, most recently, the TNF-ligand family member receptor activator of nuclear factor-kappaB ligand (RANKL). The identification and significance of any one of these myeloma-derived OAFs is dependent on robust and reliable assays that measure the de novo formation and activation of OCs. A number of in vitro assay systems have been described that examine the requirements for normal OC formation and are easily adaptable for examining which MM-derived OAF and to what extent it is responsible for the bone loss observed in individuals with myeloma. This chapter describes one such in vitro model system.
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PMID:An in vitro osteoclast-forming assay to measure myeloma cell-derived osteoclast-activating factors. 1596 8