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)

Benzene, a common industrial chemical and a component of gasoline, is radiomimetic and exposure may lead progressively to aplastic anaemia, leukaemia, and multiple myeloma. Although benzene has been shown to cause many types of genetic damage, it has consistently been classified as a non-mutagen in the Ames test, possibly because of the inadequacy of the S9 microsomal activation system. The metabolism of benzene is complex, yielding glucuronide and sulphate conjugates of phenol, quinol, and catechol, L-phenylmercapturic acid, and muconaldehyde and trans, trans-muconic acid by ring scission. Quinol is oxidised to p-benzoquinone, which binds to vital cellular components or undergoes redox cycling to generate oxygen radicals; muconaldehyde, like p-benzoquinone, is toxic through depletion of intracellular glutathione. Exposure to benzene may also induce the microsomal mixed function oxidase, cytochrome P450 IIE1, which is probably responsible for the oxygenation of benzene, but also has a propensity to generate oxygen radicals. The radiomimetic nature of benzene and its ability to induce different sites of neoplasia indicate that formation of oxygen radicals is a major cause of benzene toxicity, which involves multiple mechanisms including synergism between arylating and glutathione-depleting reactive metabolites and oxygen radicals. The occupational exposure limit in the United Kingdom (MEL) and the United States (PEL) was 10 ppm based on the association of benzene exposure with aplastic anaemia, but recently was lowered to 5 ppm and 1 ppm respectively, reflecting a concern for the risk of neoplasia. The American Conference of Governmental Industrial Hygienists (ACGIH) has even more recently recommended that, as benzene is considered an A1 carcinogen, the threshold limit value (TLV) should be decreased to 0.1 ppm. Only one study in man, based on nine cases of benzene associated fatal neoplasia, has been considered suitable for risk assessment. Recent re-evaluation of these data indicated that past assessments may have overestimated the risk, and different authors have considered that lifetime exposure to benzene at 1 ppm would result in an excess of leukaemia deaths of 9.5 to 1.0 per 1000. Although in this study, deaths at low levels of benzene exposure were associated with multiple myeloma and a long latency period, instead of leukaemia, which might justify further lowering of the exposure limit, the risk assessment model has been found to be non-significant for response at low levels of exposure. The paucity of data for man, the complexity of the metabolic activation of benzene, the interactive and synergistic mechanisms of benzene toxicity and carcinogenicity, the different disease endpoints (aplastic anaemia, leukaemia, and multiple myeloma), and different individual susceptibilities, all indicate that in such a complex scenario, regulators should proceed with caution before making further changes to the exposure limit for this chemical.
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PMID:The toxicity of benzene and its metabolism and molecular pathology in human risk assessment. 185 46

Lymphocyte egress from the vascular compartment into the lymph node (LN) parenchyma occurs at the postcapillary venules, termed high endothelial venules (HEVs). Lymphocyte adhesion and migration through the HEVs is a receptor-mediated, energy-dependent, process. The aim of this study was to investigate the role of MHC Class II antigen expression on lymphocyte-HEV interaction in normal (CBA) and autoimmune (MRL/l) mice. Using the HEV binding assay, lymphocyte adhesion to LN sections pretreated with monoclonal antibody (MAb; 10-2.16) was decreased compared to diluent (mean of the differences +/- standard deviation; xd +/- SD: 0.749 +/- 0.22, P less than 0.0075)- and myeloma immunoglobulin-pretreated controls (xd = 0.462 +/- 0.13, P less than 0.005). Similar inhibition of binding was found in MRL/l LN sections pretreated with MAb 10-2.16. Binding inhibition was concentration dependent, but total inhibition was never achieved. Several other anti-Ia MAb's were used, but failed to inhibit lymphocyte attachment. Lymphocyte binding to control sections treated with MAb's against MHC Class I antigen, plasminogen activator (PAM-3), anti-thrombin III (AT-IIIm), and MECA-325 antigen was not significantly different from diluent controls. LN cell suspensions pretreated with MAb 10-2.16 bound normally to LN sections. By contrast, MAb to lymphocyte homing receptor (MEL-14) inhibited lymphocyte adhesion. The role of Class II antigens in lymphocyte-HEV interactions is discussed.
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PMID:Anti-Ia monoclonal antibody (10-2.16) inhibits lymphocyte-high endothelial venule (HEV) interaction. 318 Feb 28

BALB/c mice were immunized with a human melanoma cell line, SK-MEL 28, and their spleen cells were fused with mouse NS-1 myeloma cells. Hybrid cells were tested in an indirect 125I-labeled protein A assay for production of antibodies that bound to surface antigens of SK-MEL 28 melanoma cells but not to autologous skin fibroblasts. One hybridoma, designated 4.1, had the required specificity. It was cloned and grown in mice as an ascites tumor. The monoclonal IgG1 antibody produced by the hybridoma was purified from the ascites fluid and labeled with 125I. The labeled antibody bound, at significant levels, to approximately 90% of the melanomas tested and to approximately 55% of other tumor cells, but not to three B-lymphoblastoid cell lines or to cultivated fibroblasts from 15 donors. Immunoprecipitation and sodium dodecyl sulfate gel electrophoresis were used to detect the target antigen in 125I-labeled cell membranes of both cultivated cells and tumor biopsy samples. A protein with a molecular weight of 97,000 was identified. This protein, designated p97, was present in both cultured cells and biopsy material from melanomas and certain other tumors, but it was not detected in eight different samples of normal adult epithelial or mesenchymal tissues obtained from five donors.
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PMID:Identification of a cell surface protein, p97, in human melanomas and certain other neoplasms. 692 44

Over a 5-year period we evaluated 65 myeloma patients aged < or = 55 years as potential candidates for intensive therapy and allogeneic BMT. Twenty six (40%) patients were transplanted; the median duration of disease was 4 months (range 2-58 months) and median number of prior regimens was 1 (range 1-5); all but five patients had chemosensitive disease. Conditioning regimens included combinations of BU+CY+MEL in 14 patients, BUCY2 in eight and CY+TBI in four. Donors were HLA-matched siblings in 19 cases, one antigen mismatched siblings in three and unrelated donors in four. All patients received CsA, plus either methylprednisolone (n = 5) or MTX with or without other agents (n = 19). Grade III or IV regimen-related toxicity (RRT) was relatively infrequent (3 patients) and was not seen in nine patients conditioned with BU (total dose 12 mg/kg) + MEL (100 mg/m2) + CY (90 mg/m2). Grade II-IV acute GVHD occurred in 20 patients, and was the cause of death in three. Chronic GVHD also caused three deaths. Thirteen of 21 evaluable patients (62%) achieved a CR and six achieved a PR. Actuarial progression-free survival (PFS) was 40% (95% confidence interval (CI) 19-61%) at a median follow-up of 14 months (range 3-56 months); the PFS was 52% (95% CI 24-74%) in chemoresponsive patients, compared with 0% in chemoresistant patients (P = 0.0066).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of myeloma using intensive therapy and allogeneic bone marrow transplantation. 774 43

One hundred and thirty-five patients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 to 100 mg/m2 (MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m2 or thiotepa 750 mg/m2 and autologous bone marrow transplant (ABMT) (< or = 30% plasma cells; 21 patients); melphalan 200 mg/m2 (MEL 200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as a double-transplant program (67 patients; 42 have completed and 3 are still awaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (< 500/microL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy. Low beta 2-microglobulin (beta 2M) levels < or = 2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these two parameters, three risk groups were defined: 29 good-risk patients with low beta 2M receiving MEL 200 had the best outcome, with median durations of EFS of 37 months and projected OS of > or = 43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high beta 2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (all P < .0001). Further analysis that excluded treatment as a variable identified high beta 2M and resistant relapse as the two major adverse prognostic factors, one of which was present in 80% of the 135 patients. Among these 108 high-risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy using the double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease.
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PMID:High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. 791 45

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclophosphamide. 843 63

Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low beta 2-microglobulin ([B2M] < or = 2.5 mg/L) and C-reactive protein ([CRP] < or = 0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 ("unfavorable karyotype") became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, < or = 10 months; median OS, < or = 12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.
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PMID:Autotransplants in multiple myeloma: what have we learned? 870 39

Between 1985 and 1990, 133 patients with advanced multiple myeloma (MM) (74% resistance; 41% resistant relapse, RR) were treated with five high-dose therapy (HDT) regimens including: melphalan < or =100 mg/m2 (MEL 100) (46 patients); MEL 100 plus GM-CSF (24 patients); MEL 140 plus autologous bone marrow transplantation (ABMT) (eight patients); MEL 140 plus TBI 850 cGy plus ABMT (37 patients); and thiotepa 750 mg/m2 (THIO 750) + TBI 850 cGy plus ABMT (18 patients). The median follow-up of alive patients as of December 1997 was 9 years. Overall, 17% experienced treatment-related mortality within 60 days (TRM) and 12% achieved stringently defined complete remission (CR) with a median duration of 16 months; four of 16 patients (25%) remain in CR at 10 years. The median durations of event-free survival (EFS)/overall survival (OS) were 6/15 months. Superior EFS/OS were noted with MEL 100 plus GM-CSF and the two TBI-containing regimens (9/24 months among 79 patients) compared to the remaining 54 patients receiving MEL < or =100 or MEL 140 plus ABMT (3/5 months) (P = 0.0001/0.0001, respectively). Multivariate regression analyses (MVA) were performed so that, despite patient heterogeneity among the five treatment groups, potentially relevant disease, host, treatment, and supportive care variables could be identified that were associated with TRM, CR, EFS and OS. TRM was higher with creatinine >2.0 mg/dl, absence of ABMT/GM-CSF support and age >50 years; CR was superior with TBI-containing regimens and < or =12 months of prior therapy; EFS and OS both were longer with B2M < or =2.5 mg/l, age < or =50 years, absence of RR and with ABMT/GM-CSF support. In the presence of >2 favorable variables (32 % of patients), median EFS/OS durations of 18/48 months were observed which progressively declined with 2 and <2 favorable parameters to 6/11 months (28% of patients) to 3/5 months (40% of patients) (P = 0.0001/0.0001). At 10 years, 10 and 20% of patients with >2 favorable variables were event-free and alive, which was also true for the 37 patients receiving MEL 140 plus TBI. To appreciate possible long-term contributions of supportive care or treatment intensity, landmark analyses performed at 1, 2, 4 and 6 months revealed virtually identical ranking orders of prognostically favorable variables to those seen pre-HDT; once supportive care was accounted for, regimen intensity with added TBI did not emerge as an independent favorable feature.
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PMID:Long-term follow-up after high-dose therapy for high-risk multiple myeloma. 964 72

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.
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PMID:Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. 1071 23

Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/m(2) (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No TRM was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and DLI. Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure.
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PMID:High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. 1131 44


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