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)

Mobilization of sequestered intracellular Ca2+ with EGTA or Ca2+ ionophores severely depresses rates of translational initiation in various mammalian cell types including C6 glial, GH3 pituitary and P3X63Ag8 myeloma cells. Within 2-3 h of continuous exposure to either chelator or ionophore, cells adapt or accommodate such that their rates of amino acid incorporation are restored to 40-70% of those of untreated controls. In GH3 and P3X63Ag8 cells, treatment with either a phorbol ester or a cAMP-elevating agent was required to obtain maximal degrees of accommodation of translational initiation. Following the development of accommodation, cells restored with optimal Ca2+ exhibited rates of amino acid incorporation identical with those of nontreated controls but remained resistance to inhibition on subsequent challenge with EGTA or ionophore. Development of translational tolerance to agents depleting Ca2+ stores did not involve alterations in cellular capacity or affinity for the cation. Invariably, the development of tolerance was preceded by transcriptionally dependent, preferential synthesis of the reticuloplasmin GRP78/BiP. In Ca2(+)-deprived GH3 cells, the synthesis of GRP78 was promoted by phorbol ester and cAMP with the extent of induction correlating directly with the degree of translational tolerance to ionophore. Cells pretreated with dithiothreitol, an alternate inducer of GRP78, also became tolerant to translational inhibition by Ca2+ ionophore or EGTA. Amino acid incorporation in nonsecreting NS-1-cloned myeloma cells, which constitutively express high levels of GRP78 and its mRNA, resisted inhibition by EGTA, ionophore, and dithiothreitol. Antisense oligodeoxynucleotides directed against GRP78 mRNA reduced amino acid incorporation in tolerant, but not in non-tolerant, preparations. These results predicate the existence of a mechanism whereby mammalian cells are capable of rapidly developing translational cross-tolerance to either depletion of sequestered Ca2+ or a reducing environment. A role for nascent GRP78 is strongly implicated in this accommodation mechanism.
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PMID:Accommodation of protein synthesis to chronic deprivation of intracellular sequestered calcium. A putative role for GRP78. 212 77

Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty. In a prospective pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate), in addition to standard chemotherapy, in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/day i.v. for seven days followed by 100 mg/day i.m. for 10 days, administered at a mean interval of 4 months (range 3-6). The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits; these effects were maintained throughout the follow-up. In three hypercalcemic episodes serum calcium became normal after 2-5 days of treatment with Clodronate. No toxic or side effects were noticed. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients (p less than 0.001) in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures (p less than 0.001). Supportive Clodronate therapy contributes significantly in controlling the progression of myeloma bone disease.
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PMID:Long-term effects of parenteral dichloromethylene bisphosphonate (CL2MBP) on bone disease of myeloma patients treated with chemotherapy. 213 6

The whole-cell configuration of the patch-clamp technique was used to study the outward Na+ current through Ca channels in hybridoma cell lines (202B and 206), constructed by fusion of S194 myeloma cells with murine splenic B lymphocytes. The concentration of Na+ in the electrode solution, [Na+]p, was changed by isosmotic replacement of Na+ with N-methyl-D-glucamine+ ions. When 2.5 mM calcium was present in the bath, neither the current nor the reversal potential was significantly altered by changes in the level of external Na+ [( Na+]o. By contrast, both of those properties were strongly affected by [Na+]p. At fixed depolarizing potentials, the outward current increased approximately as the square power of [Na+]p, a feature that cannot be easily explained by one-ion models for a channel or by "continuum" theories based on electrodiffusion. Instead, all the data could be well described by a "single-file" model for a two-site pore that admits up to two ions. Although double occupancy of the Ca channel by divalent cations has been proposed previously (Hess and Tsien. 1984. Nature. 309: 453-456; Almers et al., 1984. J. Physiol. 353: 585-608), this study indicates that, in our system, states of the channel with two Na+ ions must also be considered in order to explain the dependence of the outward current on [Na+]p. A good fit to the data could be obtained by assuming that both sites in the channel are "electrically" close to its cytoplasmic end and that most of the voltage dependence pertains to the rates for ion exit to the external medium. The values of the parameters suggest that: (a) Ca2+ is bound most strongly by the site nearest to the cytoplasm (in both singly and doubly occupied channels); (b) in channels with two Ca2+ ions, the dissociation constant of the site close to the external mouth must be greater than 2.5 mM; and (c) in pores occupied by two Na+ ions, the rate constant for Na+ exit to the external solution is larger than the rate constant for Na+ exit to the cytoplasm.
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PMID:Effects of internal Na+ on the Ca channel outward current in mouse neoplastic B lymphocytes. 217 42

Between January 1987 and October 1989, 561 consecutive untreated patients with monoclonal gammopathy of undetermined clinical importance (MGUS) (n = 295) or with multiple myeloma (n = 266) were evaluated in a multicentre trial. Both bone marrow biopsy and aspiration (performed at different anatomical sites) were required at presentation. Bone marrow biopsy data indicated that changes in bone marrow composition from MGUS to early multiple myeloma and to advanced multiple myeloma followed a precise pattern, including an increased percentage of bone marrow plasma cells (BMPC%), a shift from plasmocytic to plasmoblastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual haemopoiesis and an increase in osteoclasts. In multiple myeloma the BMPC% of biopsy specimens and aspirate were closely related, although in 5% of cases the difference between the two values was greater than 20%. Some histological features were remarkably associated with each other. For example, BMPC% was higher in cases with plasmoblastic cytology, heavy fibrosis, or reduced residual haemopoiesis. Anaemia was the clinical characteristic most influenced by bone marrow histology. The BMPC% was the only histological variable which affected the greatest number of clinical and laboratory characteristics, including, besides haemoglobin concentration, erythrocyte sedimentation rate, radiographic skeletal bone disease, and serum concentrations of monoclonal component, calcium, beta 2-microglobulin and thymidine kinase activity. These data indicate that comparative bone marrow histology in monoclonal gammopathies has clinical importance.
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PMID:Bone marrow biopsy in monoclonal gammopathies: correlations between pathological findings and clinical data. The Cooperative Group for Study and Treatment of Multiple Myeloma. 219 32

Primary bone marrow lymphomata are infrequent; most of them are of B-cell origin, and those of a T-cell lineage produce mainly both hypercalcemia and osteolytic lesions apparently due to abnormal production of osteoclast-activating factor. We report a 15-year old patient with a primary bone marrow lymphoma: 85% of his infiltrating malignant lymphocytes displayed cytoplasmic mu-chains compatible with a pre-B phenotype. The cells failed to display the CALLA/CD 10 antigen. Serum calcium was 7.5 mEq/L (range 4-5 mEq/L); the bone biopsy of an osteolytic lesion disclosed a large-cell, diffuse non-Hodgkin's lymphoma. No malignant cells were found in the peripheral blood and there were no enlarged lymph nodes. The patient was treated with 6 courses of chemotherapy: hydroxyldaunorubicin, vincristine and prednisone (HOP). Complete remission was achieved and the patient was placed on continuation chemotherapy with daily six-mercaptopurine and weekly methotrexate, together with HOP pulses every three months. The hypercalcemia disappeared together with the fever and the bone pain: the patient has been followed 6 months. Data on this case are discussed together with those previously published in regard to the low prevalence of bone lesions in primary B-cell lymphomas of the bone marrow, and to the similarity of this B-cell malignancy to others that produce both hypercalcemia and bone lesions, i.e. multiple myeloma.
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PMID:[Hypercalcemia and osteolytic lesions associated with pre-B-cell primary lymphoma of the bone marrow. A case report]. 227 Mar 71

To evaluate the effect of calcitonin on the bone lesions of multiple myeloma, we studied 11 patients treated for 3 months with salmon calcitonin in nasal spray (200 IU) and 500 mg of elemental calcium/day. Pre- and post-treatment biochemical and histomorphometric parameters were compared to those of 12 patients treated for the same time with 500 mg elemental calcium alone. Both groups received the same hematological treatment. In the group treated with calcitonin there was a significant increase (P less than 0.01) in trabecular bone volume, cortical thickness, osteoid volume and osteoid seam thickness index and the osteoclast resorption surface fell significantly (P less than 0.01). There was also a decline (P less than 0.001) in corrected serum calcium and OHP/Cr, which accounts for the diminished bone resorption. The group not treated with calcitonin showed only significant changes in OHP/Cr which increase (P less than 0.05). Calcitonin was perfectly tolerated by all patients and our results show it to be useful in the treatment of bone lesions of multiple myeloma.
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PMID:Treatment of multiple myeloma with nasal spray calcitonin: a histomorphometric and biochemical study. 232 95

Fifteen patients (8 male and 7 female) with multiple myeloma, who were admitted to our hospital between July 1986 and August 1988 and suffering from pain and hypercalcemia, were treated with synthetic calcitonin derivative (elcatonin: ECT). ECT was administered intravenously at a dose of 10-640 units twice daily. Seven patients were treated with ECT (ECT group), and eight patients received combination treatment with ECT and other form of chemotherapy (combination group). With regard to the pain score (PS), significant analgesic effects in both groups were observed during 1-4 week treatments (p less than 0.05). There were no significant differences in PS between two groups. Serum calcium levels in the combination group at 1 and 4 weeks were significantly lower than the initial value (p less than 0.05). Hypocalcemia was not seen in any of the patients. Urinary excretion of calcium at 1 week in ECT group was higher than the initial value (p less than 0.05). The observed toxicities of ECT were slight nausea and vomiting in only 2 patients. These findings suggest that ECT is an useful agent for the treatment of pain and hypercalcemia accompanied with multiple myeloma.
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PMID:[Effectiveness of synthetic calcitonin derivative (elcatonin) on the bone pain and serum calcium concentration in multiple myeloma]. 233 72

There have been major advances in the treatment of multiple myeloma in the past 20 years, but for the individual patient the prognosis still remains uncertain. As the length of survival varies from several months to over 10 years, definition of prognostic parameters at the time of diagnosis, and early detection of disease activity are most important. In our study, median survival was 42 months with very good quality of life. Factors not helpful in prognosis were sex, WBC and platelet counts, BUN, serum M protein type, extent of osteolytic lesions, percentage of plasma cells in bone marrow and plasma cell asynchrony. However, age, hemoglobin, calcium, uric acid, Bence-Jones proteinuria and polyclonal Ig concentrations had a certain degree of prognostic importance. Due to more sensitive and more specific laboratory methods, peripheral blood findings are lately gaining in importance. With new "salvage" protocols, the detection of additional prognostic parameters and sensitive indicators of disease activity may be most important for further improvement in the survival of patients with multiple myeloma.
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PMID:[Prognostic factors in multiple myeloma]. 235 24

Six hundred twelve eligible, previously untreated patients with active multiple myeloma and at least some data available for analysis were entered into a randomized trial (Southwest Oncology Group [SWOG] Phase III myeloma study 8229/30), in which the prognostic significance of pretreatment serum beta 2 microglobulin levels was evaluated. Because there was no statistically significant survival difference between the alternating and syncopating VMCP/VBAP regimens, it was possible to evaluate serum beta 2 microglobulin for the total population all together. The serum beta 2 microglobulin measurements showed the highest significance of any prognostic factor, both in the bivariate and multivariate regression analyses. The median survival was 36 months for the 322 patients with pretreatment serum beta 2 microglobulin values of less than 6 micrograms/mL, as compared with a median survival of 23 months for the 225 patients with a beta 2 level of greater than or equal to 6 mcg/mL (P less than .0001). The stepwise multiple regression model first contained serum beta 2 microglobulin, followed by serum albumin, serum calcium, age, and serum creatinine. Serum beta 2 microglobulin was highly correlated with stage: median values ranged from 3.7 micrograms/mL for stage IA, to 10.1 for stage IIIB. It was possible to stratify myeloma patients based on combinations of serum beta 2 microglobulin with both albumin and age, producing excellent separation of patients into low-, intermediate-, and high-risk categories. It is concluded that serum beta 2 microglobulin is the most powerful prognostic factor currently available for multiple myeloma and that it can be used alone or in combination with other variables for pretreatment stratification.
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PMID:Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study. 220 35

Human basophils release approximately 90 pmol of LTC4/micrograms histamine when challenged with anti-IgE antibody, but donor to donor variation produces a 1000-fold range of response. There is little conversion to LTC4 to LTE4 in purified preparations of basophils, but conversion to LTE4 does occur if cell densities are high during incubation. Like histamine release, leukotriene release is calcium and temperature dependent and is complete in 20 min, with a t1/2 of approximately 8 min. The process of desensitization also ablates leukotriene release, but there is a distinct two phase process where leukotriene release is enhanced after 5 min of desensitization, whereas histamine release is inhibited and total ablation of leukotriene release occurs only after 45 min of desensitization. Human basophils respond well to stimulation with covalently cross-linked trimeric IgE myeloma but respond poorly to dimeric IgE. This differential sensitivity to the two forms of cross-linked IgE is most exaggerated in the context of leukotriene release, where dimer is 30-fold less efficacious and 100- to 1000-fold less potent than trimer on some donors' basophils. This dichotomy of response is also observed in antigen-challenged cells, where the bivalent hapten, BPO2, also poorly induces leukotriene release in accord with the fact that it predominantly induces dimeric cross-links of penicillin-specific IgE. Anti-IgE dose-response curves reveal a region of dimeric cross-link dominance that may explain the peculiar differences observed in pharmacologic studies of basophil release induced with antigen vs anti-IgE. In addition, there is a continuum of "releasability," where some donors' basophils display no response (histamine or leukotriene release) to dimeric IgE, and others' basophils are essentially equally responsive to both dimeric and trimeric IgE. This releasability difference manifests itself by conferring increased sensitivity to antigenic challenge in those donors' basophils capable of responding to dimeric cross-links such that these donors' basophils are capable of releasing histamine upon antigen challenge while possessing only 50 molecules of cell surface antigen-specific IgE; other dimer-insensitive donors' basophils require 6 to 10-fold greater IgE densities for equal histamine release.
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PMID:Characteristics of human basophil sulfidopeptide leukotriene release: releasability defined as the ability of the basophil to respond to dimeric cross-links. 241 27


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