Biomedical subjects

Enrique M Ocio

Publications and source records attributed to Enrique M Ocio.

8 recordsLinked to original sources

PubMed2006

BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth.

We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27; conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27 phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor, or Dex, to improve patient outcome in MM.

Antineoplastic Agents, Hormonal↗

PubMed2006

The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid-derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC(50) < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients.

Acetylation↗

PubMed2006

Update on treatment recommendations from the Third International Workshop on Waldenstrom's macroglobulinemia.

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.

Alkylating Agents↗

PubMed2006

In vivo and in vitro cytotoxicity of R-etodolac with dexamethasone in glucocorticoid-resistant multiple myeloma cells.

Glucocorticoids have been widely used in the treatment of multiple myeloma (MM) both as single agents and in combination with other drugs. However, primary or acquired glucocorticoid resistance occurs in most cases. It was recently reported that R-etodolac induced in vitro cytotoxicity in MM cell lines and in primary MM cells, as well as synergistically enhanced dexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells. This study examined the in vitro and in vivo effects of combination treatment with R-etodolac and Dex on Dex-resistant OPM1 cells. Treatment with R-etodolac and Dex was found to enhance cytotoxicity, inhibit nuclear factor kappaB activity via upregulation of IkappaBalpha, as well as enhance Dex-induced caspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells. R-etodolac also enhanced Dex cytotoxicity in patient MM cells that were resistant to glucocorticoids. The in vivo anti-tumour effect of this combination on MM cells was evaluated by using severe combined immunodeficient mice engrafted with OPM1. Treatment with R-etodolac or Dex alone did not induce a significant reduction of tumour volume; in contrast, combination treatment with R-etodolac and Dex induced significant synergistic inhibition of tumour growth. These data indicate that R-etodolac overcomes resistance to Dex in glucocorticoid-resistant MM cells, providing the framework for clinical trials of R-etodolac combined with Dex, to improve patient outcome in MM.

Animals↗

PubMed2006

Update on recommendations for assessing response from the Third International Workshop on Waldenstrom's Macroglobulinemia.

This report by an international consensus panel updates current recommendations for defining clinical response in Waldenstrom's macroglobulinemia (WM). The previously published response criteria incorporated parameters for monoclonal protein reduction and/or improvement of marrow and nodal involvement, and included definitions of complete and partial remissions. The criteria have been updated to include minor response and stable disease categories. In addition, the criteria now recognize that delayed responses after treatment with nucleoside analogues and biologic agents and the time point for assessing response in patients with WM should be considered so as to not miss or miscategorize a response. The new criteria should therefore help in better delineating responses to therapy in patients with WM, particularly with the wide use of nucleoside analogues and biologically based agents for this disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena.

Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune-related disorders are rare complications of MCD. We report on an MCD case in a 23-year-old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8). After 8 courses of the anti-CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti-CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune-related disorders are associated.

Adult↗

PubMed2005

Immunophenotypic and cytogenetic comparison of Waldenstrom's macroglobulinemia with splenic marginal zone lymphoma.

Some B-cell lymphoproliferative disorders displaying a serum monoclonal immunoglobulin (Ig) M protein could be difficult to differentiate from Waldenstrom's macroglobulinemia (WM). We report on the immunophenotypic and cytogenetic characteristics of 85 patients with WM and compare them with 29 patients with splenic marginal zone lymphoma (SMZL). For immunophenotyping, WM and SMZL constantly expressed panB-cell markers (CD19, CD20, CD22, and surface Ig). However, there were differences in the k/l ratio (1.2:1 for SMZL and 4.5:1 for WM) and in some markers such as CD22 and CD11c, which were overexpressed in patients with SMZL compared with patients with WM, whereas CD25 was more frequently positive in WM (88% vs. 44%). The CD103 antigen was always negative in WM, whereas it was positive in 40% of SMZL cases. The monoclonal antibody FMC7 was usually positive in both entities: heterogeneous in WM but homogeneous in SMZL. The combination of CD25 and CD22 could differentiate between WM and SMZL. The principal molecular abnormality in WM is 6q deletion (30% in our experience), whereas in SMZL the most common abnormalities are loss of 7q (19%) along with +3q (19%) and +5q (10%). Interestingly, the incidence of IgH rearrangement was low in WM (12%) and SMZL (10%). Immunophenotypic and molecular cytogenetic studies could help to distinguish WM from SMZL.

Antigens, CD↗

PubMed2005

Cell cycle analysis of Waldenstrom's macroglobulinemia.

Little is known about the DNA cell content and cell cycle characteristics of immunoglobulin (Ig) M monoclonal gammopathies. The autonomous clone appears to be rather heterogeneous, from mature B lymphocytes to plasma cells (PCs). We have evaluated the DNA cell content of 27 patients with IgM monoclonal gammopathies: 18 of them had Waldenstrom's macroglobulinemia (WM), and 9 were diagnosed with IgM-monoclonal gammopathy of undetermined significance (MGUS). To specifically analyze the cell cycle of the B lymphocyte and PC populations, we used a flow-cytometric double-staining technique with CD19/CD20/CD22 propidium iodide for B lymphocytes and CD38/CD138 propidium iodide for PCs. In 26 of 27 patients, both subsets of tumor cells (B lymphocyte and PC) showed a diploid DNA cell content (DNA index, 1). The median percentage of proliferating B lymphocytes, S-phase + G2/M-phase, was 1.8% (range, 0.4%-4.1%). This proliferative activity was significantly lower than that observed in nonmalignant cells (5.7%; range, 0.1%-14.2%; P = 0.004) in the same sample. No differences were observed when comparing the proliferative activity of WM with that of IgM MGUS (median, 1.7% vs. 2.2%, respectively). Cell cycle characteristics of PCs were simultaneously evaluated in 9 patients, with 1.8% cells in S phase or G2/M phase. In summary, the cell cycle analysis showed that IgM monoclonal gammopathies are low-proliferative disorders, with a DNA ploidy pattern (diploid) clearly different from that of multiple myeloma.

Cell Cycle↗