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)

Interleukin 6 (IL-6) is a major in vitro growth factor for tumoral cells in human multiple myeloma and myeloma cell lines, whose growth is completely dependent on exogenous IL-6, can be reproducibly obtained. IL-6 is overproduced in patients with active myeloma, mainly by the tumoral environment. Injection of anti-IL-6 antibodies to myeloma patients with terminal disease and extramedullary proliferation completely blocked myeloma-cell proliferation in vivo and completely inhibited the C-reactive protein production. Moreover, the serum CRP level is a strong prognostic factor in myeloma, increased serum CRP levels (reflecting an increased IL-6 production) being associated with a poor prognosis. Other cytokines control the IL-6 mediated myeloma cell proliferation. GM-CSF, IL-3 and G-CSF stimulate the IL-6 responsiveness of myeloma cells without affecting the endogenous IL-6 production. Interferon-gamma completely inhibits the IL-6 mediated myeloma-cell proliferation without affecting the endogenous IL-6 production and IFN alpha and TNF alpha stimulate the proliferation of our IL-6 dependent myeloma-cell lines by inducing an autocrine production of IL-6 in these cell lines.
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PMID:[Cytokines and lymphoplasmocytic proliferations: essential role of interleukin 6]. 850 54

In an attempt to offset the impaired hematopoietic progenitors' mobilization and collection which are frequently encountered in multiple myeloma (MM), we have started a pilot study to evaluate the ability of a combination of high-dose melphalan (HDM) and sequential s.c. administration of recombinant human interleukin 3 (rhIL-3) and rh-granulocyte colony-stimulating factor (G-CSF) to mobilize blood cells (BC) in MM patients. Two different schedules for administration were successively tested. Schedule A consisted of IL-3 (5 micrograms/kg/d) from day 7 to day 11 after HDM followed by G-CSF (5 micrograms/kg/d) from day 12 to day 20. Under schedule B, HDM was followed by IL-3 alone at the same dosage from day 1 to day 3, IL-3 and G-CSF (idem) from day 4 to day 7 and G-CSF alone from day 8 until completion of apheresis. Two patients (one previously untreated, one having received prior chemotherapy for one year) underwent schedule A; three patients (one previously untreated, two pretreated) underwent schedule B. The post-HDM aplasia was not shortened in schedule A patients in comparison to what we usually observed following HDM alone (25 days) correlated with a very moderate two- to three-fold CD34+ cell increase. Only one patient was further transplanted with apheresis products: the post-transplant granulocyte recovery was slower than usual (16 days versus 12 days) while platelet count never recovered over 20 x 10(9)/l. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mobilization of peripheral blood stem cells with chemotherapy and cytokines in multiple myeloma. 852 May 4

A 49-year-old man with the idiopathic hypereosinophilic syndrome (HES) and a unique chromosomal abnormality 46,XY,t(5;9)(q32;q33) is reported. Complete cytogenetic remission was induced by interferon alpha-2b (IFN-alpha). The beneficial action of IFN-alpha in different stem-cell disorders such as CML, HES, multiple myeloma and solid tumours such as hypernephroma or malignant melanoma suggests a common regulatory effect possibly by immunomodulation or other (immune-mediated) mechanisms, but the exact pathophysiological mechanisms remain hypothetic and unresolved. Since it has been known for some years that the genes encoding for GM-CSF, IL-3 and IL-5 reside on the long arm of chromosome 5, it could be possible that the chromosomal translocation in our patient resulted in excess production of these cytokines, hence causing the hypereosinophilia. This case report and the results obtained from the literature review support the growing body of evidence that IFN-alpha has a major place in the long-term treatment of HES, especially in those cases resistant to conventional treatment, with cytogenetic abnormalities, or presenting as a myeloproliferative variant of HES. In those cases IFN-alpha results in lower morbidity, lower mortality and long-term survival.
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PMID:Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. 921

Thirty-seven patients with previously treated multiple myeloma (MM) underwent peripheral blood progenitor cell (PBPC) collection following high-dose cyclophosphamide and GM-CSF or sequential IL-3 and GM-CSF. Patients with an inadequate collection were considered for a second or third collection. 25 patients underwent subsequent autotransplant. The only variable predictive of CFU-GM yield was the extent of prior melphalan therapy. All repeat collections were unsuccessful and patients infused with an autograft obtained from multiple sets of collections had a high incidence of delayed engraftment. We conclude that melphalan should be avoided or PBPC collection performed early in the disease course in patients who are potential transplant candidates.
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PMID:Peripheral blood progenitor cell collections in multiple myeloma: predictors and management of inadequate collections. 861 48

A consensus regarding myeloma cell growth factor responsiveness and ability to produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from patients with aggressive disease. Extensive characterization of these cell lines revealed considerable heterogeneity at several levels. Growth factor responsiveness was initially addressed. Although the potent myeloma cell growth factor, IL-6, induced the proliferation and allowed for the expansion of all three cell lines, a panel of other cytokines elicited heterogeneous responses in each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor necrosis factor-alpha also stimulated DNA synthesis in all three cell lines; however, the magnitude of the response was generally lower than that observed in cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6 cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells. The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP-6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR analysis demonstrated that all three cell lines expressed IL-6 mRNA. However, when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6 bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically active IL-6. In summary, although all three of these cell lines were established from myeloma patients, the heterogeneity observed between these cell lines was considerable and may reflect, as well as provide tools to study, the heterogeneity observed in clinical disease.
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PMID:Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6. 865 85

The survival, proliferation, differentiation and function of normal hematopoietic cells are negatively and positively controlled by various cytokines. Survival and proliferation of leukemic cells appears to be influenced, at least in vitro, by several cytokines. Among the different hematopoietic cell lineages, megakaryocytopoiesis represents a complex and unique hematopoietic system that is thought to be supported by some well-known cytokines; however, the hypothetical lineage-specific main regulator of platelet production, termed thrombopoietin (TPO) had remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor superfamily, specific expression on cells of the megakaryocytic lineage and functional involvement in megakaryocytopoiesis. Several groups purified and cloned the MPL ligand. Extensive in vitro and in vivo studies have shown that the MPL ligand has activity in stimulating both megakaryocytopoiesis and platelet production proving that this ligand is the long-sought growth factor TPO itself. The MPL receptor was found at the mRNA and/or protein level in 40-80% of primary acute myeloid leukemia (AML) cases in various series. MPL expression was not limited to certain morphological FAB types, although the highest percentages were seen in the M6 (erythroid) and M7 (megakaryocytic) subclasses. Among the myelodysplastic syndromes (MDS), MPL expression was detected in one third of the cases, in particular in refractory anemia with excess of blasts and chronic myelomonocytic leukemia. Lymphoid malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and myeloma were MPL-negative. Among the large panel of human leukemia-lymphoma cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. Nearly all primary and continuously cultured non-hematopoietic solid tumor samples were negative for MPL expression. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. In several studies TPO induced in vitro proliferation of 14-37% of primary AML cases, predominantly of the M2 and M7 subtypes. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, IL-6 or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (eg HU-3, M-07e, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce any signs of morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. In summary, extensive studies on normal human and animal cells demonstrated the specificity and function of the MPL receptor and proved that its ligand TPO is the major physiological regulator of megakaryocytopoiesis. The data reviewed here document the wide expression of the MPL receptor on AML cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic AML cells as well. Thus, experimental evidence supports the notion that TPO may contribute, at least in part, to leukemogenesis, especially in combination with other hematopoietic cytokines which is of clinical significance. TPO-responsive cell lines represent powerful tools for such analyses.
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PMID:Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. 875 57

Here we review our recent experience addressing the role of SCF in multiple myeloma (MM). We first investigated the proliferation of MM cell lines and bone marrow samples from myeloma patients in response to rh-SCF alone and combined with Interleukin-6 (IL-6), IL-3, and IL-3/GM-CSF fusion protein PIXY 321. Neoplastic plasma cells were highly purified (>90%) by immunomagnetic depletion of T, myeloid, monocytoid and NK cells. The number of S-phase cells was evaluated after 3 days of liquid culture by the bromodeoxyuridine (BRDU) incorporation assay. The proliferation of RPMI 8226 and U266 cell lines was also assessed by a clonogenic assay. All the experiments were performed in serum-free conditions. RPMI 8226 cell line was not stimulated by SCF which also did not augment the proliferative activity of IL-6, IL-3 and PIXY-321. Conversely, SCF addition resulted in 2.4-fold increase of the number of U266 colonies and in a higher number of U266 and MT3 cells in S-phase. The c-kit ligand also enhanced the proliferation of MT3 and U266 cells mediated by the other cytokines. Anti-SCF polyclonal antibodies completely abrogated the proliferative response of MT3 cells to exogenous SCF and markedly reduced the spontaneous growth of the same cell line. Reverse transcriptase-polymerase chain reaction amplification (RT-PCR) did detect SCF mRNA in MT3 and RPMI 8226 cells. Moreover, secreted SCF was found, in a biologically active form, in the supernatant of the two cell lines by the MO7e proliferation assay. These results suggest that an autocrine proliferative loop may be operative in MT3 cell line. When tested on fresh myeloma samples, SCF increased the number of S-phase plasma cells (4.7 +/- 1.6% vs 3.4 +/- 1.3% in control cultures; p = 0.02). Significant proliferation was also induced by IL6, IL-3 and PIXY-321. The addition of SCF significantly enhanced the proliferation of myeloma cells responsive to IL-6. Preliminary experiments performed on circulating plasma cells and myeloma precursors further supported the role of SCF on the proliferation of the neoplastic clone in MM.
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PMID:C-kit ligand (SCF) in human multiple myeloma cells. 883 3

In this article, we review neoplastic contamination in the peripheral blood (PB) of patients with multiple myeloma (MM) upon stem cell mobilization. We first evaluated PB samples from pretreated MM patients following administration of high-dose cyclophosphamide (Cy, 7 g/m2 or 4 g/m2) and granulocyte colony-stimulating factor (G-CSF) for the presence of myeloma cells as well as hematopoietic progenitors. Plasma cells containing intracytoplasmic immunoglobulin (cIg) were counted by immunofluorescence microscopy after incubation with appropriate antisera against light and heavy chain Ig. Flow cytometry studies were performed to determine the presence of malignant B lineage elements, using monoclonal antibodies against the CD19 antigen and the monotypic light chain. Prior to PBSC mobilization, circulating plasma cells were detected in all MM patients at 0.1%-1.8% of the mononuclear cell (MNC) fraction (mean value 0.7 +/- 0.4% SD). In these patients, a higher absolute number of PB neoplastic cells was detected after administration of chemotherapy and G-CSF. Kinetic analysis showed a pattern of tumor cell mobilization similar to that of normal hematopoietic progenitors, with the peak coinciding with the optimal period for the collection of PBSC. The absolute number of plasma cells showed a 10-50-fold increase over the baseline value. Apheresis products contained 0.7 +/- 0.2% SD myeloma cells (range 0.2%-2.7%), which demonstrated the capacity of plasma cells to proliferate, differentiate, and mature in response to c-kit ligand (SCF), IL-3, IL-6, and a combination of IL-3 and IL-6. Subsequently, in an attempt to reduce tumor cell contamination prior to autologous transplantation, circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, cryopreserved, and used to reconstitute bone marrow (BM) function after myeloablative therapy in 13 patients. The median purity of the enriched CD34+ cell population was 89.5% (range 51%-94%), with a 75-fold enrichment compared with the pretreatment samples. The median overall recovery of CD34+ cells and CFU-GM was 58% (range 33%-95%) and 45% (range 7%-100%), respectively. Positive selection of CD34+ cells resulted in 2.5-3 log depletion of plasma cells and CD 19+ B lineage cells as determined by immunofluorescence studies, although DNA analysis of the CDR III region of the IgH gene demonstrated the persistence of minimal residual disease (MRD) in 5 of 6 patient samples studied. Myeloma patients were reinfused with enriched CD34+ cells after myeloablative therapy consisting of total body irradiation (TBI, 1000 cGy) and high-dose melphalan (140 mg/m2) or melphalan (200 mg/m2) alone. They received a median of 5 x 10(6) CD34+ cells/kg and showed a rapid reconstitution of hematopoiesis. The median time to 0.5 x 10(9) neutrophils, 20 x 10(9) and 50 x 10(9) platelets/L of PB was 10, 11, and 12 days, respectively. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (n = 13) receiving unmanipulated PBSC following the same pretransplant conditioning regimen. Our data demonstrate the concomitant mobilization of tumor cells and hematopoietic progenitors in the PB of MM patients. Positive selection of CD34+ cells reduces the contamination of myeloma cells from the apheresis products up to 3 log and provides a cell suspension capable of restoring normal hematopoiesis following a TBI-containing conditioning regimen.
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PMID:Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of patients with multiple myeloma. 887 9

We studied the feasibility of in vitro expansion of CD34+ cells from patients with multiple myeloma (MM) or follicular non Hodgkin lymphoma (NHL). CD34+ cells were selected from peripheral blood (PB) using avidinbiotin immunoadsorption columns: purified CD34+ cells from three MM and five NHL patients were expanded. First, CD34+ cells (2 MM, 4 NHL) were grown for 14 days in 5 ml of IMDM plus 12.5% horse serum (HS), 12.5% fetal calf serum (FCS) and a commonly used combination of cytokines: IL1alpha, IL3, IL6, SCF, GM-CSF, G-CSF (10 ng/ml each) and EP (4 UI/ml). In these conditions, at day 14, average increase in CD34+, CFU-GM and total cell numbers were, respectively: x 6.0 x 23 and x 2,113 fold with 20 to 35% of granulocytic cells. In terms of CD34+ cell, CFU-GM and total cell outputs, MM cultures were comparable to NHL cultures, but MM cultures seemed to produce less granulocytic cells than NHL cultures. Next, in vitro expansion of PB CD34+ cells was tested in culture media suitable for clinical use. Two cultures (1 MM, 1 NHL) were carried out for 14 days in 20 ml of X-Vivo 10 medium, 2% human serum, IL1alpha, IL3, IL6, SCF, GM-CSF, G-CSF (6 ng/ml each) and EP (2 UI/ml). Increase in CD34+, CFU-GM and total cell numbers in these conditions were, respectively: x 5.7 and x 19.7, x 11.9 and x 40.9, x 424 and x 408 fold, with at least 75% of granulocytic cells in both cultures. We conclude that, although further improvements are necessary, in vitro expansion of PB CD34+ cells can presumably be carried out successfully for MM patients as well as for NHL patients, including in conditions suitable for clinical use.
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PMID:In vitro expansion of CD34+ cells from peripheral blood of myeloma and lymphoma patients. 890 29

Peripheral blood stem cells (PBSC) are used increasingly for autotransplantation in the treatment of acute leukemia, lymphoma, multiple myeloma, solid tumors such as ovarian and breast carcinoma. They are collected by leukaphereses during rapid hematopoietic recovery, following cytotoxic chemotherapy with or without administration of hematopoietic growth factors. We studied the clonogenic and cytokine-mediated expansion potential of CD34+ cells from mobilized PBSC. Low density mononuclear cells were processed using the CEPRATE LC CD34 KIT (CellPro). CD34+ purified cells, were cultured in suspension with 6 combined hematopoietic growth factors (IL1beta, IL3, IL6 at 100 U/ml and G-CSF, GM-CSF and stem cell factor at 10 ng/ml of each) for up to four weeks. Every week, cells were counted and CFU-GM assay was performed in a methylcellulose based medium. We have analysed the percentage of cells bearing CD34, CD33, CD38, HLA-DR, CD45RA, CD45RO antigens. Our results showed, that CD34+ cells were obtained with a purity of 92 +/- 2.3% and a yield of 71 +/- 10.7%. The majority co-expressed CD33 (57.76 +/- 34.16%) and CD38 (62.2 +/- 34%) antigens. These culture conditions, are necessary to obtain a fold increase of nucleated cells (377 fold at week 4), of CFU-GM progenitors (41.2 fold at week 3) and of CD34+ cell absolute number (10 fold at week 1) with an important differentiation of progenitors in particular myeloid progenitors.
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PMID:Peripheral blood CD34+ cells: method of purification and ex vivo expansion. 890 32


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