Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating hemopoietic progenitors were evaluated in 19 multiple myeloma patients at diagnosis. Eleven patients received either high-dose cyclophosphamide (7 g/m2, 8 patients) or etoposide (2 g/m2, 3 patients) followed by GM-CSF administration; the remaining 8 patients received intermediate-dose cyclophosphamide (1.2 g/m2 on days 1 and 3), 4 of them with GM-CSF support. The highest levels of circulating progenitor cells were observed among patients in the high-dose chemotherapy group (median CFU-GM peak value of 6432 per ml), while in patients receiving intermediate-dose, with or without GM-CSF, median peak values were 2588 and 462 per ml, respectively. In all groups a remarkable heterogeneity in the yield of circulating progenitors was observed; this was particularly pronounced in the high-dose group, where CFU-GM peak values ranged between 200 and 38,070 per ml. At variance with the effect observed in previously untreated patients with lymphoma or breast cancer, the degree of mobilization in myeloma patients was rather unpredictable. The only pre-treatment characteristic correlating to some extent with a poor expansion of the circulating progenitor pool was heavy BM infiltration with plasma cells. The mobilizing effect was not restricted to the myeloid lineage, as demonstrated by the rise of BFU-E; CD34+ cells were increased as well. Indeed, a simultaneous evaluation of CFU-GM and CD34+ cells was carried out and a highly significant correlation (r = 0.9) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Role of chemotherapy and GM-CSF on hemopoietic progenitor cell mobilization in multiple myeloma. 768 51

A number of environmental cells in the bone marrow (BM) of multiple myeloma (MM) has been reported to be activated. Evidence is growing that many cytokines, namely IL-6, IL-1 beta, TNF and GM-CSF, are detected in the BM of MM. Tumor environment may support, not only MM cell proliferation, but also bone resorption. In addition, immuno-regulatory cells, both CD8+T cells and NK cells, are also activated. High serum IL-2 levels are indicated. Recently, we detected numerous CD5+NK cells, which may be activated, in the peripheral blood and the BM of MM.
 ...
PMID:[Myeloma cells and cytokines]. 769 93

Peripheral blood progenitor cells (PBPC) are increasingly used for autologous reconstitution following high-dose chemotherapy in multiple myeloma but it is unclear whether these cells are less likely to be contaminated with malignant cells than bone marrow (BM). We have investigated this using immunoglobulin heavy-chain (IgH) gene fingerprinting, a polymerase chain reaction based technique with a sensitivity of 0.1-0.01% (10(-3)-10(-4)). We have looked for patient-specific IgH rearrangements in leukapheresis samples from eight myeloma patients undergoing PBPC harvest. Seven were in first remission (six partial, one complete) and one in second complete remission. Mobilization of PBPC was accomplished using cyclophosphamide (4 or 7 mg/m2) and rhG- or GM-CSF. Between two and five leukaphereses were performed in each patient. Patient-specific IgH rearrangements were identified in diagnostic BM in all patients and bands of identical size were found in one or more leukaphereses from 6/8 patients. Overall, 14/32 leukaphereses were shown to be contaminated. Two patients who showed contamination of at least one PBPC harvest had BM harvests in which contaminating cells were not detectable, suggesting that PBPC are not necessarily less likely to be contaminated than marrow stem cells. These results indicate that PBPC harvests from the majority of myeloma patients are likely to contain contaminating cells. Further studies are needed to determine whether these cells are clonogenic and whether they contribute to relapse.
 ...
PMID:Molecular detection of clonally rearranged cells in peripheral blood progenitor cell harvests from multiple myeloma patients. 780 32

The complication of secondary myelodysplastic syndrome (sMDS) during the course of multiple myeloma (MM) has been recognized for more than a decade. sMDS occurs years after MM diagnosis, and typically, at sMDS presentation the MM is stable or inactive. We report a 56-year-old patient, who developed sMDS 15 years following the diagnosis of IgG-lambda MM, which had been completely stable for 13 years. However, very soon after sMDS was diagnosed, the MM relapsed and required combination chemotherapy. The first cycle of vincristine, adriamycin and dexamethasone (VAD) resulted in severe neutropenia and sepsis, which was treated with antibiotics and recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). Two weeks after GM-CSF administration a transformation to acute myeloblastic leukemia was observed. The relation between GM-CSF and the leukemic transformation is discussed and the possible contribution of the cytokine to the stimulation of this complication is emphasized.
 ...
PMID:Is granulocyte-macrophage colony-stimulating factor (GM-CSF) safe in myelodysplastic syndromes? 789 Feb 61

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.
 ...
PMID:High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. 791 45

Few effective regimens are available for patients with advanced multiple myeloma resistant to alkylating agents and VAD. We treated 65 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 gm/m2) and etoposide (900 mg/m2) followed by GM-CSF at a daily dose of 0.125 mg/m2. Thirty-five percent of patients responded with a 6% mortality rate. After a median of 2 months, 16 patients received myeloablative treatment supported by autologous bone marrow or blood stem cells. Four of ten previously resistant patients responded so that the overall response rate was 42%. The median survival for all patients was 10 months and the median remission was 8 months. The median survival for patients with both low serum lactate dehydrogenase and B2 microglobulin, or for those who received myeloablative treatment, was projected at 18 months. Our combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This program allowed early blood stem cell collection in support of subsequent myeloablative therapy for selected patients.
 ...
PMID:Intensive sequential therapy for VAD-resistant multiple myeloma. 791 63

The authors review contemporary findings on the role of different components of the cytokine network from the aspect of development, prognosis and treatment of multiple myeloma. Greatest attention was devoted to the main growth factor of myeloma elements IL-6, but also to the real or so far sparsely elucidated role of other cytokines (IL-1, IL-2, GM-CSF, G-CSF, IL-3, IL-4, IL-5, IL-10, TNF, interferon alpha and gamma) under conditions in vitro and in vivo. For completeness sake the authors did not omit the problem of the soluble receptor of IL-2 and the role of TNF, TNF beta and in particular IL-1 beta in the pathogenesis of osteolytic lesions and the potential therapeutic role of antibodies against IL-6 (anti IL-6 mab) and interferon alpha and gamma.
 ...
PMID:[The cytokine network in multiple myeloma]. 794 39

The pleiotropic cytokine interleukin 6 (IL-6) plays a role in the pathogenesis of various diseases, such as multiple myeloma, autoimmune and inflammatory diseases and osteoporosis. Therefore, specific inhibitors of IL-6 may have clinical applications. We previously succeeded in developing receptor antagonists of IL-6 that antagonized wild-type IL-6 activity on the human Epstein-Barr virus (EBV)-transformed B cell line CESS and the human hepatoma cell line HepG2. However, these proteins still had agonistic activity on the human myeloma cell line XG-1. We here report the construction of a novel mutant protein of IL-6 in which two different mutations are combined that individually disrupt the association of the IL-6/IL-6 receptor (R) alpha complex with the signaltransducing "beta" chain, gp130, but leave the binding of IL-6 to IL-6R alpha intact. The resulting mutant protein (with substitutions of residues Gln160 to Glu, Thr163 to Pro, and replacement of human residues Lys42-Ala57 with the corresponding residues of mouse IL-6) was inactive on XG-1 cells and weakly antagonized wild-type IL-6 activity on these cells. By introducing two additional substitutions (Phe171Leu, Ser177Arg), the affinity of the mutant protein for IL-6R alpha was increased fivefold, rendering it capable of completely inhibiting wild-type IL-6 activity on XG-1 cells. Moreover, this mutant also antagonized the activity of IL-6, but not that of leukemia inhibitory factor, oncostatin M, or GM-CSF on the human erythroleukemia cell line TF-1, demonstrating its specificity for IL-6. These data demonstrate the feasibility of developing specific IL-6R antagonists. The availability of such antagonists may offer an approach to specifically inhibit IL-6 activity in vivo.
 ...
PMID:Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells. 796 14

This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m2) and etoposide (900 mg/m2) with GM-CSF. During haematological recovery, at least 2 x 10(6) CD34+ mononuclear cells/kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m2), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to > 1.0 x 10(9)/l after a median of 10 d and of platelets to 50 x 10(9)/l after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34+ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.
 ...
PMID:Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma. 798 14

The pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), induction of anti-GM-CSF antibodies, and clinical effects related to the induction of the antibodies were analyzed in patients with metastatic colorectal carcinoma (CRC) who were not on chemotherapy (n = 20, nonimmunocompromised patients). rhGM-CSF (250 micrograms/m2/d; Escherichia coli-derived) was administered subcutaneously for 10 days every month for 4 months. Eight patients with multiple myeloma (MM) on intensive chemotherapy followed by rhGM-CSF treatment were also included (immunocompromised patients). After a single injection of GM-CSF at the first cycle in CRC patients, the maximum calculated concentration (Cmax) was 5.24 +/- 0.56 ng/mL; the half life (T1/2) was 2.91 +/- 0.8 hours; and the area under the concentration curve (AUC) was 30.86 +/- 6.03 hours x ng/mL (mean +/- SE). No anti-GM-CSF antibodies were detected. During the subsequent cycles, 95% of the CRC patients developed anti-GM-CSF IgG antibodies, which significantly altered the pharmacokinetics of rhGM-CSF at the third and fourth cycles with decreased Cmax (2.87 +/- 0.57 ng/mL; P < .05), T1/2 (1.57 +/- 0.2 hours; P < .05), and AUC (14.90 +/- 4.10 hours x ng/mL; P < .005). The presence of anti-GM-CSF antibodies significantly reduced the GM-CSF-induced enhancement of granulocytes, and there was a clear tendency for a decreased increment of monocytes. Antibodies diminished systemic side effects of rhGM-CSF. Only 1 of 8 MM patients showed a very low anti-GM-CSF antibody titer after GM-CSF therapy, as shown by enzyme-linked immunosorbent assay and Western blot. Therefore, in nonimmunocompromised patients, exogenous nonglycosylated GM-CSF induced an anti-GM-CSF IgG antibody response in practically all patients, which seemed to be of clinical significance. In immunocompromised patients, virtually no significant antibody response was shown.
 ...
PMID:Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients. 799 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>