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Bortezomib
Kinds of Bortezomib Terms modified by Bortezomib Selected AbstractsThe proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2010Homare Eda Abstract Objectives:,Bortezomib (PS-341; VelcadeÔ), a proteasome inhibitor, is used as a therapeutic agent for multiple myeloma. Bortezomib has been shown to strongly induce osteoblast differentiation and elevate the levels of osteoblast-related differentiation markers in the serum of patients with myeloma. Bortezomib also reportedly increases the activity of the transcription factor, Runx2. However, the mechanism of action by which bortezomib-elevated Runx2 activity mediates osteoblast differentiation remains unclear. On the other hand, fibroblast growth factor 2 (FGF-2) is found at high levels in patients with multiple myeloma. We previously reported that FGF-2 reduces the levels of the transcriptional coactivator with PDZ-binding motif (TAZ). We therefore investigated the effects of bortezomib on TAZ protein levels in the presence of FGF-2. Methods: Osteoblastic MC3T3-E1 cells were treated with different concentrations of bortezomib in the presence or absence of FGF-2 and various biologic responses were investigated by immunoblotting, RT-PCR, quantitative PCR, and alizarin red staining. Results: We found that bortezomib inhibited FGF-2-induced reduction of TAZ levels through a pathway other than that used for proteasome inhibition, while maintaining TAZ function, which in turn, enhanced the expression of Runx2-transcribed osteogenic differentiation markers. Bortezomib also suppressed the antimineralization effect of FGF-2. Conclusions: These findings suggest that bortezomib inhibited FGF-2-induced reduction of TAZ and consequently stimulated osteogenic differentiation independently of proteasome inhibition. These findings may contribute to elucidate the osteolytic mechanism in multiple myeloma, and to the development of new drugs for multiple myeloma and other osteolytic diseases. [source] Efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory multiple myeloma: a systematic comparisonEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2007H. Miles Prince Abstract Objective:, To conduct a systematic review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/refractory multiple. Methods:, Publications in English from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag data-on-file and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of either treatment group with n,30 were included. Studies adding dexamethasone for non-responders were excluded. Statistical pooling was performed for response rate and overallsurvival. Results:, One bortezomib study (n = 333, NEJM 2005, 352; 2487,98) and 15 thalidomide (n = 1007) studies met these criteria and were included. Patient baseline characteristics including age, gender, IgG : IgA, disease duration and beta-2 microglobulin were well matched except that 48% of bortezomib patients had received prior thalidomide. Response rate, defined as serum M-protein reduction ,50%, was 53% for patients receiving bortezomib vs. 32% for thalidomide (P < 0.001, n = 10 studies). Response rate determined by European Group for Blood and Marrow Transplantation (EBMT) criteria was 41% for patients receiving bortezomib vs. 22% for thalidomide (P < 0.001, n = 4 studies). Conclusion:, Bortezomib was associated with a significantly higher response rate and complete remission rate using both M-protein and EBMT criteria. [source] Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation,HEPATOLOGY, Issue 6 2008Masaru Harada The proteasomal and lysosomal/autophagy pathways in the liver and other tissues are involved in several biological processes including the degradation of misfolded proteins. Exposure of hepatocyte cell lines to proteasome inhibitors (PIs) results in the formation of inclusions that resemble Mallory-Denk bodies (MDBs). Keratins are essential for MDB formation and keratin 8 (K8)-overexpressing transgenic mice are predisposed to MDB formation. We tested the hypothesis that PIs induce MDBs in vivo and that autophagy participates in MDB turnover. The effect of the PI bortezomib (which is used to treat some malignancies) on MDB formation was tested in K8-overexpressing mice and in cultured cells. Inclusion formation was examined using immune and conventional electron microscopy (EM). Bortezomib induced MDB-like inclusions composed of keratins, ubiquitin, and p62 in cultured cells. Short-term exposure to bortezomib induced similar inclusions in K8-overexpressing but not in nontransgenic mice, without causing liver injury. In bortezomib-treated mice, autophagy was activated in hepatocytes as determined by EM and biochemical analysis. Further activation of autophagy by rapamycin (Rap) decreased the number of inclusions in bortezomib-treated K8 transgenic mice significantly. Rap also led to resorption of spontaneously formed MDBs in aging K8-overexpressing mice. Immune EM demonstrated K8-positive and ubiquitin-positive structures in autophagic vacuoles in the mouse liver. Conclusion: PIs alone are sufficient to induce MDBs in susceptible animals, while Rap-mediated activation of autophagy prevents MDB formation and causes MDB resorption. These findings suggest that some patients treated with PIs may become predisposed to MDB formation. Autophagy provides a potential cellular mechanism for the resorption of cytoplasmic inclusions. (HEPATOLOGY 2008.) [source] Bortezomib plus intermediate-dose dexamethasone and thalidomide in elderly untreated patients with multiple myeloma: A Chinese experience,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2010Hongfeng Guo Bortezomib has proven to be active in patients with multiple myeloma (MM), including elderly patients. The aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with intermediate-dose dexamethasone (Dex) and thalidomide in untreated MM patients aged ,65 years in a Chinese single center. In this study, 18 patients were treated with bortezomib at 1.3 mg/m2 IV on Days 1, 4, 8, and 11 and Dex at 20 mg/day IV on Days 1,4 and 8,11 simultaneously. Thalidomide at dose of 100 mg/day was given everyday. The mean number of cycles of bortezomib treatment was 2.06. Three patients (17%) achieved a complete response (CR), four (22%) a very good partial response (VGPR), and nine (50%) a PR, resulting in an overall response rate of 89%. The median time to response was 22 days (range 14,50 days). The duration of response was significantly longer in patients achieving a CR/VGPR with respect to those achieving only a PR (8.5 vs. 4.2 months, P = 0.03). Grade 3,4 toxicities occurring in patients comprised weakness, thrombocytopenia, diarrhea, infection, and neuropathy. Only one patient suffered from deep vein thrombosis. This preliminary experience in Chinese patients indicated that bortezomib-Dex-thalidomide is highly effective in elderly untreated patients with MM, even in patients with poor prognostic features. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source] Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A report from the therapeutic advances in childhood leukemia (TACL) consortium,PEDIATRIC BLOOD & CANCER, Issue 2 2010Yoav Messinger MD Abstract Background Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies. Procedure This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L -asparaginase, and doxorubicin (VXLD) in children with relapsed ALL. Results Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1,mg/m2). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3,mg/m2). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia. Conclusions The combination of bortezomib (1.3,mg/m2) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3,mg/m2 cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726). Pediatr Blood Cancer 2010;55:254,259. © 2010 Wiley-Liss, Inc. [source] The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo,AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009Angela Pennisi Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells is closely associated with induction of osteolytic bone disease, induced by stimulation of osteoclastogenesis and suppression of osteoblastogenesis. The ubiquitin-proteasome pathway regulates differentiation of bone cells and MM cell growth. The proteasome inhibitor, bortezomib, is a clinical potent antimyeloma agent. The main goal of this study was to investigate the effect of bortezomib on myeloma-induced bone resorption and tumor growth in SCID-rab mice engrafted with MM cells from 16 patients. Antimyeloma response of bortezomib, which was evident in >50% of 16 experiments and resembled clinical response, was associated with significant increased bone mineral density (BMD) and osteoblast numbers, and reduced osteoclast numbers in myelomatous bones. This bone anabolic effect, which was also visualized on X-ray radiographs and confirmed by static and dynamic histomorphometric analyses, was unique to bortezomib and was not observed in hosts responding to melphalan, a chemotherapeutic drug widely used to treat MM. Bortezomib also increased BMD and osteoblasts number and reduced osteoclasts number in nonmyelomatous implanted bones. In vitro bortezomib directly suppressed human osteoclast formation and promoted maturation of osteoblasts. We conclude that bortezomib promotes bone formation in myelomatous and nonmyelomatous bones by simultaneously inhibiting osteoclastogenesis and stimulating osteoblastogenesis. As clinical and experimental studies indicate that bone disease is both a consequence and necessity of MM progression our results suggest and that bortezomib's effects on bone remodeling contribute to the antimyeloma efficacy of this drug. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Community experience with bortezomib in patients with multiple myelomaAMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2007Adedayo A. Onitilo Abstract Community practice experience allows a nonselective care of patient using information derived from a more controlled clinical trial environment. We present our community experience with multiple myeloma patients with advanced age, long disease duration since diagnosis, advanced stage, multiple prior therapies including stem cell transplantation, co-morbidities, and other poor prognostic features, such as low albumin, high B-2 microglobulin, renal failure, and the presence of poor risk chromosomal abnormalities. Our response rates are comparable to those from clinical trials. Bortezomib is well tolerated in this population of multiple myeloma patients with the exception of infection adverse events that are generally mild grade 1,2. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source] Case Report: Eculizumab, Bortezomib and Kidney Paired Donation Facilitate Transplantation of a Highly Sensitized Patient Without Vascular AccessAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010B. E. Lonze A 43-year-old patient with end-stage renal disease, a hypercoagulable condition and 100% panel reactive antibody was transferred to our institution with loss of hemodialysis access and thrombosis of the superior and inferior vena cava, bilateral iliac and femoral veins. A transhepatic catheter was placed but became infected. Access through a stented subclavian into a dilated azygos vein was established. Desensitization with two cycles of bortezomib was undertaken after anti-CD20 and IVIg were given. A flow-positive, cytotoxic-negative cross-match live-donor kidney at the end of an eight-way multi-institution domino chain became available, with a favorable genotype for this patient with impending total loss of a dialysis option. The patient received three pretransplant plasmapheresis treatments. Intraoperatively, the superior mesenteric vein was the only identifiable patent target for venous drainage. Eculizumab was administered postoperatively in the setting of antibody-mediated rejection and an inability to perform additional plasmapheresis. Creatinine remains normal at 6 months posttransplant and flow cross-match is negative. In this report, we describe the combined use of new agents (bortezomib and eculizumab) and modalities (nontraditional vascular access, splanchnic drainage of graft and domino paired donation) in a patient who would have died without transplantation. [source] Bortezomib as the Sole Post-Renal Transplantation Desensitization Agent Does Not Decrease Donor-Specific Anti-HLA AntibodiesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010R. Sberro-Soussan Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m2× 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies. [source] Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2008Stephanie J. Lee Summary Health-related quality of life (HRQL) was prospectively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire , Core (QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group,Neurotoxicity (NTX) side-effects questionnaires were administered at baseline and every 6 weeks up to 42 weeks. Patients receiving bortezomib (1·3 mg/m2, days 1, 4, 8 and 11 for eight 3-week cycles, then days 1, 8, 15 and 22 for three 5-week cycles; n = 296) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone (40 mg/d, days 1,4, 9,12, and 17,20 for four 5-week cycles, then days 1,4 only for five 4-week cycles; n = 302), plus significantly better physical health, role, cognitive, and emotional functioning scores, lower dyspnoea and sleep symptom scores, and better NTX questionnaire score, using multiple imputation to account for missing data. Results were similar using available-data analyses. Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival. These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone, consistent with the better clinical outcomes seen with bortezomib. [source] Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2007Paul G. Richardson Summary Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age ,65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34,40% vs. 13,19%), including complete response rate (5,8% vs. 0,1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged ,65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma. [source] Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor- ,B ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006Evangelos Terpos Summary The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor- ,B ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma. [source] PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2005Heather E. Oakervee Summary Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1,4, 8,11 and 15,18 during cycle 1 and days 1,4 during cycles 2,4. During days 1,4, patients also received 0, 4·5 or 9 mg/m2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials. [source] Delayed complete remission in a patient with multiple myelomaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2008R. Ria Abstract We report a strikingly positive, late response to bortezomib in conjunction with pegylated liposomal doxorubicin in a 79-year old woman with multiple myeloma (MM). The patient obtained a partial remission after eight courses of therapy and a complete remission about 10 months after the end of therapy. This delayed complete remission may be similar to the spontaneous regression reported for other malignancies such as melanoma or lymphoma. We postulate that the immune response and a persistent anti-angiogenic effect of bortezomib could well explain the delayed complete remission in our patient. [source] First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitroEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Thomas Lund Abstract Objectives:, The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate-naïve, previously untreated patients with myeloma. Methods:, Twenty newly diagnosed patients received four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also studied in vitro. Results:, Treatment with bortezomib caused a significant increase in bone-specific alkaline phosphatase and pro-collagen type I N-terminal propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. Conclusions:, Bortezomib used as first-line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone-healing properties of single-agent bortezomib are currently being explored in a clinical study in patients who have undergone high-dose therapy and autologous stem cell transplantation. [source] Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Fortunato Morabito Abstract The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression-free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front-line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review. [source] Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairmentEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2010Meletios A. Dimopoulos Abstract Objectives:, Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility. Patients & Methods:, Fifty consecutive patients with relapsed/refractory MM received LenDex in 28-d cycles. Median lines of previous therapies were 2 (range: 1,6). Lenalidomide was administered on days 1,21 according to creatinine clearance (CrCl), while dexamethasone was given at a dose of 40 mg on days 1,4 and 15,18 for the first four cycles and only on days 1,4 thereafter. Results:, Twelve patients (24%) had RI at baseline, defined as CrCl < 50 mL/min. Most patients were pretreated with either thalidomide or bortezomib and > 50% of them were refractory to both drugs. At least partial response was documented in 60.5% and 58% of patients with and without RI. Median progression-free survival (PFS) and overall survival (OS) for all patients was 9 and 16 months, respectively. RI was not associated with an inferior PFS or OS. There were no differences in the incidence of adverse events among patients with and without RI. Three of 12 patients with RI (25%) achieved complete renal response and two (16%) achieved minor renal response with LenDex. Conclusions:, We conclude that LenDex is an active treatment even in heavily pretreated MM. With dosing of lenalidomide according to renal function, LenDex can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, LenDex may improve the renal function in approximately 40% of patients with RI. [source] The proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2010Homare Eda Abstract Objectives:,Bortezomib (PS-341; VelcadeÔ), a proteasome inhibitor, is used as a therapeutic agent for multiple myeloma. Bortezomib has been shown to strongly induce osteoblast differentiation and elevate the levels of osteoblast-related differentiation markers in the serum of patients with myeloma. Bortezomib also reportedly increases the activity of the transcription factor, Runx2. However, the mechanism of action by which bortezomib-elevated Runx2 activity mediates osteoblast differentiation remains unclear. On the other hand, fibroblast growth factor 2 (FGF-2) is found at high levels in patients with multiple myeloma. We previously reported that FGF-2 reduces the levels of the transcriptional coactivator with PDZ-binding motif (TAZ). We therefore investigated the effects of bortezomib on TAZ protein levels in the presence of FGF-2. Methods: Osteoblastic MC3T3-E1 cells were treated with different concentrations of bortezomib in the presence or absence of FGF-2 and various biologic responses were investigated by immunoblotting, RT-PCR, quantitative PCR, and alizarin red staining. Results: We found that bortezomib inhibited FGF-2-induced reduction of TAZ levels through a pathway other than that used for proteasome inhibition, while maintaining TAZ function, which in turn, enhanced the expression of Runx2-transcribed osteogenic differentiation markers. Bortezomib also suppressed the antimineralization effect of FGF-2. Conclusions: These findings suggest that bortezomib inhibited FGF-2-induced reduction of TAZ and consequently stimulated osteogenic differentiation independently of proteasome inhibition. These findings may contribute to elucidate the osteolytic mechanism in multiple myeloma, and to the development of new drugs for multiple myeloma and other osteolytic diseases. [source] Multiple myeloma: chemotherapy or transplantation in the era of new drugsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010Antonio Palumbo Abstract Objective:,To review the current results of studies incorporating novel agents in multiple myeloma (MM) and discuss the role of autologous stem-cell transplantation (ASCT) in the era of new active drugs for the treatment of this disease. The outlook for patients with symptomatic MM is changing with the introduction of bortezomib, thalidomide, and lenalidomide into the repertoire of available chemotherapeutic agents. Compared with standard chemotherapy, a survival benefit has been reported for the first time in 30 yrs. Methods: Articles published in English between 1969 and 2008 were identified by searching PubMed for ,myeloma', ,diagnosis', ,thalidomide', ,bortezomib', ,lenalidomide', ,dexamethasone', ,prednisone', ,doxorubicin', ,cyclophosphamide', ,melphalan', ,combination chemotherapy', and ,autologous transplantation'. Results: In randomized studies, bortezomib, thalidomide, and lenalidomide have each been combined with dexamethasone, alkylating agents, or doxorubicin, and such combinations resulted in significant improvement in progression-free survival. Conclusions: The incorporation of new drugs as induction therapy along with ASCT appears to produce very good partial response rates, slightly superior to those achieved by conventional chemotherapy with new drugs. How to best optimize induction, consolidation, and maintenance therapy and how to best select and prepare patients for ASCT are still to be determined. Randomized trials are needed to directly compare the current best chemotherapeutic approach with best ASCT strategies and to guide clinical practice for patients with MM. [source] Vorinostat enhances the antimyeloma effects of melphalan and bortezomibEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Richard A. Campbell Abstract Objectives:, Examine the antitumor activity of the histone deacetylase inhibitor vorinostat's antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model. Methods:, RPMI8226, U266, and MM1S cells were cultured for 48 h in the presence of media, vorinostat, melphalan, or bortezomib alone, or combinations of vorinostat with melphalan or bortezomib. Cell proliferation was measured using the MTS [3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfphophenyl)-2H-tetrazolium, inner salt] assay. Severe combined immunodeficient mice bearing LAG,-1B tumors were treated with vorinostat [30, 60, or 100 mg/kg daily for five consecutive days per week (qd×5d), 100 or 300 mg/kg daily for 2 d/wk (qd×2d)], melphalan (1, 3, or 10 mg/kg qd×1d), bortezomib (0.25 or 0.5 mg/kg qd×2d), or combinations thereof for 35 d. Tumor growth was determined via measurement of human immunoglobulin G (hIgG) levels and tumor volume. Results and Conclusions:, Vorinostat enhanced the anti-MM effects of melphalan and bortezomib in vitro. Synergism was observed with vorinostat and melphalan in RPMI8226 and U266 cell lines. Vorinostat 100 mg/kg in combination with melphalan 3 mg/kg resulted in significant inhibition of tumor growth in vivo, compared with control (tumor volume P = 0.0001; hIgG P = 0.0001), single-agent vorinostat (tumor volume P = 0.0025; hIgG P = 0.0137), and single-agent melphalan (tumor volume P = 0.0043; hIgG P = 0.0426). Vorinostat also enhanced the antimyeloma effects of bortezomib in vivo. Vorinostat enhances the anti-MM activity of melphalan and bortezomib in vitro and in vivo. This study provides rationale for further evaluation of vorinostat in combination with chemotherapeutic agents and bortezomib for the treatment of MM. [source] Update on therapeutic options in Waldenström macroglobulinemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2009Xavier Leleu Abstract Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with demonstration of an IgM monoclonal gammopathy in the blood. WM remains incurable, with 5,6 yr median overall survival for patients with symptomatic WM. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either in monotherapy or in combination. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival are short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to develop new targeted therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors, of them bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Many agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM. [source] Multiple myeloma , an update on diagnosis and treatmentEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2008Jo Caers Abstract Multiple myeloma is a plasma cell (PC) malignancy characterized by the accumulation of monoclonal PCs in the bone marrow and the production of large amounts of a monoclonal immunoglobulin or paraprotein. In the past years, new approaches in the diagnosis and treatment were introduced aiming to identify high-risk patients who need proper anti-myeloma treatment. Intensive therapy including autologous hematopoietic stem cell transplantation and the new agents bortezomib, thalidomide, and lenalidomide have improved patients' responses. Further optimalization of the different treatment schedules in well-defined patient groups may prolong their survival. Patient stratification is currently based on patient characteristics, extent of myeloma disease, and associated cytogenetic and laboratory anomalies. More and more gene expression studies are introduced to stratify patients and to individualize therapy. [source] Preclinical development of velcade (bortezomib; formerly PS-341) for multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2003J. Adams First page of article [source] Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006Alessio Nencioni Dr. Abstract Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X,protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level. [source] Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation,HEPATOLOGY, Issue 6 2008Masaru Harada The proteasomal and lysosomal/autophagy pathways in the liver and other tissues are involved in several biological processes including the degradation of misfolded proteins. Exposure of hepatocyte cell lines to proteasome inhibitors (PIs) results in the formation of inclusions that resemble Mallory-Denk bodies (MDBs). Keratins are essential for MDB formation and keratin 8 (K8)-overexpressing transgenic mice are predisposed to MDB formation. We tested the hypothesis that PIs induce MDBs in vivo and that autophagy participates in MDB turnover. The effect of the PI bortezomib (which is used to treat some malignancies) on MDB formation was tested in K8-overexpressing mice and in cultured cells. Inclusion formation was examined using immune and conventional electron microscopy (EM). Bortezomib induced MDB-like inclusions composed of keratins, ubiquitin, and p62 in cultured cells. Short-term exposure to bortezomib induced similar inclusions in K8-overexpressing but not in nontransgenic mice, without causing liver injury. In bortezomib-treated mice, autophagy was activated in hepatocytes as determined by EM and biochemical analysis. Further activation of autophagy by rapamycin (Rap) decreased the number of inclusions in bortezomib-treated K8 transgenic mice significantly. Rap also led to resorption of spontaneously formed MDBs in aging K8-overexpressing mice. Immune EM demonstrated K8-positive and ubiquitin-positive structures in autophagic vacuoles in the mouse liver. Conclusion: PIs alone are sufficient to induce MDBs in susceptible animals, while Rap-mediated activation of autophagy prevents MDB formation and causes MDB resorption. These findings suggest that some patients treated with PIs may become predisposed to MDB formation. Autophagy provides a potential cellular mechanism for the resorption of cytoplasmic inclusions. (HEPATOLOGY 2008.) [source] Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcomaINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Yuriy Shapovalov Abstract Osteosarcomas are primary bone tumors of osteoblastic origin that mostly affect adolescent patients. These tumors are highly aggressive and metastatic. Previous reports indicate that gain of function of a key osteoblastic differentiation factor, Runx2, leads to growth inhibition in osteosarcoma. We have previously established that Runx2 transcriptionally regulates expression of a major proapoptotic factor, Bax. Runx2 is regulated via proteasomal degradation, and proteasome inhibition has a stimulatory effect on Runx2. In this study, we hypothesized that proteasome inhibition will induce Runx2 and Runx2-dependent Bax expression sensitizing osteosarcoma cells to apoptosis. Our data showed that a proteasome inhibitor, bortezomib, increased Runx2 and Bax in osteosarcoma cells. In vitro, bortezomib suppressed growth and induced apoptosis in osteosarcoma cells but not in nonmalignant osteoblasts. Experiments involving intratibial tumor xenografts in nude mice demonstrated significant tumor regression in bortezomib-treated animals. Immunohistochemical studies revealed that bortezomib inhibited cell proliferation and induced apoptosis in osteosarcoma xenografts. These effects correlated with increased immunoreactivity for Runx2 and Bax. In summary, our results indicate that bortezomib suppresses growth and induces apoptosis in osteosarcoma in vitro and in vivo suggesting that proteasome inhibition may be effective as an adjuvant to current treatment regimens for these tumors. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America. [source] The persisting challenge of selective and specific proteasome inhibition,JOURNAL OF PEPTIDE SCIENCE, Issue 2 2009Michael Groll Abstract Since the discovery of the proteasome and its structure elucidation intensive research programs in academic institutions and pharmaceutical industries led to identification of a wide spectrum of synthetic and natural small proteasomal inhibitors. Activity studies with these small molecules helped to deeply understand the complex biochemical organization and functioning of the proteasome. The new structural and biochemical insights placed the proteasome as an important anti-cancer drug target, as revealed by the dipeptide boronate proteasome inhibitor, bortezomib, which is currently used for treatment of multiple myeloma. Serious side effects and partial cell resistance against bortezomib demand creation and discovery of new improved generations of more specific and potent proteasomal inhibitors. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era,AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2010Daryl Tan Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström MacroglobulinemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Irene M. Ghobrial This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70,98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Durable complete remission of primary plasma cell leukemia with the bortezomib plus melphalan and prednisone (VMP) regimen,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Edward Libby No abstract is available for this article. [source] | |||||||||||||||||||||||||