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)

We wanted to study the role of the two TNF receptors (TNFR) in mediating proliferation and nuclear transcription factor kappa-B (NF-kappa B) activation in the human myeloma cell line OH-2. Agonistic antibodies to either of the TNFRs were able to induce proliferation in OH-2 cells, while only antibodies to the p55 TNFR could activate the NF-kappa B. TNF was 100-1000-fold more potent than LT alpha in activation of NF-kappa B and in induction of proliferation in OH-2 cells. Only a 2-fold difference between TNF and LT alpha in affinity for the TNFRs was detected, indicating that the difference in the specific activities of the cytokines can not be explained by different binding affinities. Antagonistic mAbs to either the p55 or p75 TNFR blocked the binding of both cytokines to the cells and significantly inhibited proliferation induced by TNF. On the other hand, only the p55 TNFR mAb was capable of inhibiting the proliferative effect of LT alpha. The p55 mAb 44E potentiated the proliferation induced by LT alpha, but did not affect the TNF-mediated proliferation. The data lead to the following conclusions: (1) both TNFR species trigger proliferation of OH-2 cells, whereas only the p55 TNFR activates the NF-kappa B; (2) TNF signals through both TNFR, whereas LT alpha mediates its signal through the p55 TNFR only; (3) activation of the p55 TNFR by LT alpha is not optimal, but can be facilitated by co-stimulating the receptor with the mAb 44E.
Cytokine 1996 Jun
PMID:The role of the two TNF receptors in proliferation, NF-kappa B activation and discrimination between TNF and LT alpha signalling in the human myeloma cell line OH-2. 881 39

Mouse myeloma cell line VKCK/RM4-IFN-gamma secreting the bifunctional fusion protein RM4/IFN-gamma was used to study the relationship between IFN-gamma secretion of tumor cells and its tumorigenicity and to study the potential mechanism responsible for the immune response. IFN-gamma secretion of VKCK/RM4-IFN-gamma tumor cells was estimated at 90 U/ml using an antiviral assay. To evaluate tumorigenicity, 5 x 10(5) viable IFN-gamma-secreting VKCK/RM4-IFN-gamma and non-IFN-gamma-secreting VKCK tumor cells were injected s.c. into syngeneic BALB/c mice and VKCK/RM4-IFN-gamma-immunized or T cell subset-depleted BALB/c mice, respectively. Tumor progression or regression was evaluated 2 weeks after tumor inoculation. Our animal studies showed that RM4/IFN-gamma secretion by VKCK/RM4-IFN-gamma tumor cells curtailed its tumorigenicity in BALB/c mice and induced a persistant protective immune response against a subsequent graft of parental VKCK tumor. This protective immunity is long term and tumor specific as measured in a 51Cr-release assay. In addition, our animal studies in T cell subset-depleted BALB/c mice showed that CD8 CTL play a major role in the reduction of tumorigenicity. This study thus highlights the potential advantages of localized IFN-gamma in tumors to induce potent antitumor immunity and further suggests that the bifunctional fusion protein RM4/IFN-gamma may be useful in cancer immunotherapy because of its capacity of targeting IFN-gamma to human tumors expressing the human tumor-associated TAG72 antigen [corrected].
J Interferon Cytokine Res 1996 Oct
PMID:Mouse myeloma cell line secreting bifunctional fusion protein RM4/IFN-gamma [corrected] elicits antitumor CD8 MHC class I-restricted T cells that are cytolytic in vitro and tumoricidal in vivo. 891 Jul 61

Cytokine messenger RNA expression was studied using the reverse transcription/polymerase chain reaction in 23 patients with multiple myeloma (MM), 16 with monoclonal gammopathy of undetermined significance (MGUS), 12 with post menopausal osteoporosis, (OP) and 12 normal controls. Messenger RNAs for IL-1 alpha, IL-1 beta, TNF-alpha, TNF-beta, IL-6 and M-CSF were sought in view of their reported pathogenic role in myeloma. Transcripts for IL-1 beta, TNF-alpha, TNF-beta and M-CSF were found frequently in all four groups of patients. The only significant difference in cytokine expression between the groups was for IL-6 which was expressed in 17% of controls compared with 87% of patients with MM (p < 0.001), 62% of patients with MGUS (p < 0.02) and 67% of patients with osteoporosis (p < 0.02). Further analysis of IL-6 expression by quantitative PCR showed significantly higher IL-6 mRNA levels in MM compared with MGUS (p < 0.006). There was no correlation however between expression of individual cytokines and clinical features of myeloma such as osteolytic bone disease or hypercalcaemia. We conclude that expression of IL-6 mRNA is significantly enhanced in multiple myeloma when compared with MGUS. However, since MGUS and osteoporosis were also associated with a high prevalence of IL-6 expression when compared with controls it is probable that factors other than IL-6 are responsible for the local osteolytic lesions which characterise MM, but which are not seen in MGUS or osteoporosis.
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PMID:Cytokine expression in multiple myeloma and monoclonal gammopathy: analysis by reverse transcription/polymerase chain reaction and quantitative PCR. 904 67

A family of cytokines [IL-6, IL-11, oncostatin M (OM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1] involved in various inflammatory or tumoral diseases share the same gp130 signal transducer chain. The complex formed with their specific receptors associates with a common transducing gp130 membrane protein (gp130) resulting in the formation of high avidity receptor and activation of tyrosine kinases. With the view of identifying gp130 domains specifically involved in IL-6 signalling, the authors prepared 37 new anti-gp130 mAb and analysed the structure-function relationship of the molecule. By cross-competition ELISA, the mAb were classified in 10 subgroups called A to J. By ELISA and BIAcore analysis, the mAb were found to recognize at least 18 antigenic specificities of the gp130 chain. The mAb reacted against the soluble and the membrane forms of gp130 as well. Their ability to inhibit the proliferation of the human myeloma cell line XG-4 of which the growth is strictly dependent on the presence of either exogenous IL-6, or LIF, or OM, or CNTF was studied. Besides mAb with no evident neutralizing effect (G and H) and mAb which neutralized equally well the activity of all tested cytokines (all mAb of groups A, I and J), some showed a selective effect. Those of group F inhibited also the proliferation induced by the 4 cytokines, but more specifically that dependent on the CNTF. mAb of groups B and E specifically inhibited the growth induced by IL-6, whereas those of group C inhibited that induced by LIF and OM. These results show the presence of different gp130 epitopes specifically involved in the signaling induced by the cytokines of the gp130 family. In ELISA, only mAb of group B and E were found to inhibit the binding of the IL-6-IL-6R complex to gp130, showing that they identified one or two domains of gp130 involved in its interaction with the IL-6-IL-6R complex. Precise identification of this(ese) epitope(s) would be useful to better understand the mechanisms of the IL-6 signalling.
Cytokine 1997 Apr
PMID:Specific inhibition of IL-6 signalling with monoclonal antibodies against the gp130 receptor. 911 31

Adverse reactions to interferon-alpha (IFN-alpha) therapy include flu-like syndrome, bone marrow suppression, neurotoxic effects, and autoimmunity. A slight increase in triglyceride levels has been described less frequently during IFN-alpha administration. The incidence of IFN-alpha-induced hypertriglyceridemia seems variable, and there are no clear data on how to treat it. We report the effect of long-term (more than 12 months) IFN-alpha treatment on triglyceride levels in 43 patients suffering from hairy cell leukemia (18), multiple myeloma (10), chronic myelogenous leukemia (6), cryoglobulinemia (5), non-Hodgkin's lymphoma (3), and Sezary syndrome (1). Hypertriglyceridemia was found in 6 patients (15%). In 3 patients, gemfibrozil restored normal triglyceride values. This study suggests that hypertriglyceridemia is a minor side effect of long-term IFN-alpha therapy and that gemfibrozil might be considered the treatment of choice.
J Interferon Cytokine Res 1997 May
PMID:Hypertriglyceridemia during long-term interferon-alpha therapy in a series of hematologic patients. 918 61

Recent studies have demonstrated that interferon-beta (IFN-beta) activates extracellular regulated kinases (ERKs) in myeloma cells and have revealed a link between ERKs and the Jak/Stat pathway. The upstream components of the IFN-beta pathway involved in activation of ERKs are unknown. As p21ras is often an upstream component of the ERK pathway, we have investigated p21ras activity following IFN-beta treatment of the human myeloma cell line, U266. IFN-beta was found to strongly activate p21ras at relatively low doses and to exert a negative effect at the higher doses normally employed in signaling studies. There was no direct correlation between p21ras and ERK activity, suggesting that p21ras plays an alternate role in the IFN-beta signaling pathway. These results imply a unique integration of p21ras signaling within the milieu of IFN-induced cytoplasmic signaling events.
J Interferon Cytokine Res 1997 Dec
PMID:Dose-dependent activation of p21ras by IFN-beta. 945 63

Recently, considerable progress has been made in understanding of the biology and treatment of multiple myeloma. Molecular genetic abnormalities such as bcl-2,c-myc, ras, p53, and Rb genes have been identified in this disease and are related to a poor prognosis. Cytokine studies have revealed that interleukin-6 is a potent growth factor for myeloma cells and is also responsible for the progressive bone resorption together with interleukin-1 beta and tumor necrosis factor. Myeloablative chemotherapy followed by allogeneic or autologous hematopoietic stem cell transplantation has increased the incidence of complete remission. However, relapses are still observed because of drug resistance of tumor cells. Immunotherapeutic approaches targeting to cell surface antigens and interleukin-6 signals are being developed to further eliminate myeloma cells. Translating new biological advances into treatment protocols is essential to improve the prognosis of multiple myeloma.
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PMID:Multiple myeloma: new aspects of biology and treatment. 959

Cytokine production in whole blood cell cultures can be an indicator of immune cellular status in neoplastic patients. Production of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) after stimulation with lipopolysaccharide was measured in 1/10 diluted whole blood culture of patients with monoclonal gammopathies [monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM)]. With this system, lower production of IL-6 and TNF-alpha at 4, 24 and 48 h in total blood cultures in patients with symptomatic MM was observed. Thus, the capacity of cytokine production was greater in control subjects and in patients with MGUS and MM in response than in symptomatic MM (P=0.005 at 4 h and P=0. 006 at 24 and 48 h for IL-6 and P<0.0001 at 24 h and P<0.001 at 48 h for TNF-alpha). These differences remained significant after adjustment on the basis of the lymphocyte count (P<0.001 for IL-6 and TNF-alpha at 24 and 48 h). The impaired IL-6 and TNF-alpha production in patients with symptomatic MM is probably due to a tumour-related immunosuppressive status.
Cytokine 1998 Dec
PMID:Impaired production of interleukin 6 and tumour necrosis factor alpha in whole blood cell cultures of patients with multiple myeloma. 1004 25

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells. In patients with multiple myeloma (MM), cell lines whose survival and proliferation are dependent upon addition of exogenous IL-6 have been obtained. We show here that tumor necrosis factor-alpha (TNF-alpha) is also a survival factor for myeloma cell lines, although less potent than IL-6. The survival activity of TNF-alpha is not affected by anti-IL-6 or anti-gp130 monoclonal antibodies (mAbs). TNF-alpha also induces myeloma cells in the cell cycle and promotes the long-term growth of malignant plasma cell lines. As TNF-alpha is produced in patients with MM and associated with a poor prognosis, these results suggest that anti-TNF-alpha therapies could be useful in this disease.
Eur Cytokine Netw 1999 Mar
PMID:Tumor necrosis factor is a survival and proliferation factor for human myeloma cells. 1021 Jul 75

Interferon (IFN)-alpha has a therapeutic effect in several B cell malignancies, including low-grade non-Hodgkin's lymphoma (NHL), multiple myeloma, and hairy cell leukemia, whereas its efficacy in the treatment of B cell chronic lymphocytic leukemia (B-CLL) is rather limited. In the present study, we investigated the effect of IFN-alpha on the biologic functions of B-CLL cells, which were stimulated by cross-linking of the CD40 antigen. In cell samples from 16 B-CLL patients, the addition of IFN-alpha to CD40-stimulated purified B-CLL cells caused a significant increase in [3H]thymidine uptake (p < 0.003). In B-CLL cells maximally activated by CD40 cross-linking and interleukin-2 (IL-2)/IL-10, proliferation was not further enhanced or inhibited by IFN-alpha. In contrast, proliferation of normal tonsillar B cells stimulated by the combination CD40/IL-2/IL-10 was significantly inhibited by IFN-alpha. Because B-CLL activation might be enhanced by induction of the autocrine growth factor tumor necrosis factor-alpha (TNF-alpha), we investigated the effect of IFN-alpha on the secretion of B cell tropic cytokines. In fact, IFN-alpha significantly stimulated the secretion of IL-6 and TNF-alpha in CD40-activated B-CLL cells (p < 0.01). Although exogenous addition of TNF-alpha did not influence activation of CD40-stimulated B-CLL cells, neutralization of TNF-alpha by polyclonal antibodies led to a complete inhibition of CD40-mediated proliferation of B-CLL cells, suggesting that enhanced proliferation and increased cytokine production by CD40-activated B-CLL cells are independent IFN-alpha-mediated events. The studies presented here provide evidence that IFN-alpha mediates costimulatory signals in the context of T cell-mediated B-CLL cell activation.
J Interferon Cytokine Res 1999 Apr
PMID:IFN-alpha stimulates proliferation and cytokine secretion of CD40-stimulated B cell chronic lymphocytic leukemia cells in vitro. 1033 84


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