Mieloma múltiple en Chile. Uso de drogas noveles en dos centros nacionales

Background: The incorporation of novel drugs, such as proteasome inhibitors and immunomodulators, improved considerably the survival of patients with multiple myeloma. Aim: To evaluate the effect on survival of proteasome inhibitors and immunomodulators in patients with multiple myeloma in two national hospitals. Material and Methods: Review of clinical records from two hospitals of Santiago. Epidemiological, clinical, laboratory and therapeutic data was obtained from 144 patients with multiple myeloma diagnosed between 2002 and 2016. Results: Information was retrieved from 78 patients at one center and from 66 at the other center. The mean age at diagnosis was 58 and 62 years, the proportion of males was 53% and 52%, and presentation at stage III was 34% and 46%, respectively. The use of novel drugs, mainly bortezomib, was 90% in one of the centers and 3% in the other one. The use of autologous stem-cell transplantation was 47% and 3% respectively. The median overall survival of patients from the centers with and without access to novel drugs was 117 and 71 months respectively (p < 0.05). The five-year overall survival was 93 and 43% respectively (p < 0.05). Conclusions: The use of novel drugs, especially bortezomib, and autologous stem-cell transplantation significantly improved the survival of multiple myeloma patients treated in national hospitals. It is necessary to include them as a first line treatment.

New proteasome inhibitors in the treatment of multiple myeloma

Abstract The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

Inhibition of the 26S and 20S Proteasomes by the Site-specific Inhibitors

OBJECTIVE: The study was performed to establish the purification processes of both 26S and 20S proteasomes, also to investigate the inhibitory properties and patterns of two different proteasome inhibitors on the isolated proteasomes. METHODS: The 26S and 20S proteasomes were purified respectively using liquid chromatographies and glycerol density gradient fractionation. The inhibitory patterns and kinetics of two different proteasome inhibitors were investigated using purified 26S and 20S proteasomes. RESULTS: The purity of the isolated proteasomes were determined by their biochemical properties and electrophoretic patterns. 3-nitro-4-hydroxy-5-indophenylacetyl-leucyl-leucyl-leucyl-vinylsulfone (Nip-L₃-VS) inhibited exclusively the chymotrypsin-like peptidase activities of the 26S and 20S proteasomes. On the other hand, dansyl-phenylyl-leucyl-boronic acid (DFLB) inhibited chymotrpsin-like, trypsin-like, and caspase-like peptidase activities of both proteasomes with different sensitivity. CONCLUSION: The proposed purification method provides efficient separation and isolation of the 26S and 20S proteasomes. Nip-L₃-VS and DFLB were shown to have different inhibitory effects and kinetics on the peptidase activities of the isolated proteasomes. These studies are suggested to be applied to the researches on proteasome inhibitors as therapeutic reagents for many related diseases.

Effects of a Proteasome Inhibitor on Cardiomyocytes in a Pressure-Overload Hypertrophy Rat Model: An Animal Study

BACKGROUND: The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of NF-κB and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. METHODS: We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and NF-κB was measured in the left ventricle. RESULTS: Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not NF-κB, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). CONCLUSION: MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, NF-κB expression levels were not related to UPS function.

Optimal maintenance and consolidation therapy for multiple myeloma in actual clinical practice

Multiple myeloma is an incurable malignant plasma cell-originating cancer. Although its treatment outcomes have improved with the use of glucocorticoids, alkylating drugs, and novel agents, including proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), relapse remains a serious problem. Strategies to improve outcomes following autologous stem cell transplantation and frontline treatments in non-transplant patients include consolidation to intensify therapy and improve the depth of response and maintenance therapy to achieve long-term disease control. Many clinical trials have reported increased progression-free and overall survival rates after consolidation and maintenance therapy. The role of consolidation/maintenance therapy has been assessed in patients eligible and ineligible for transplantation and is a valuable option in clinical trial settings. However, the decision to use consolidation and/or maintenance therapy needs to be guided by the individual patient situation in actual clinical practice. This review analyzes the currently available evidence from several reported clinical trials to determine the optimal consolidation and maintenance therapy in clinical practice.

HIF-1alpha Upregulation due to Depletion of the Free Ubiquitin Pool

Hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates a variety of hypoxia-induced genes, is rapidly degraded under nomoxia through the hydroxylation-ubiquitination-proteasome pathway. In this study, we addressed how HIF-1alpha is stabilized by proteasome inhibitors. The ubiquitin pool was rapidly reduced after proteasome inhibition, followed by the accumulation of non-ubiquitinated HIF-1alpha. The poly-ubiquitination of HIF-1alpha was resumed by restoration of free ubiquitin, which suggests that the HIF-1alpha stabilization under proteasome inhibition is attributed to depletion of the free ubiquitin pool. Ni2+ and Zn2+ also stabilized HIF-1alpha with depletion of the free ubiquitin pool and these effects of metal ions were attenuated by restoration of free ubiquitin. Ni2+ and Zn2+ may disturb the recycling of free ubiquitin, as MG132 does. Based on these results, the state of the ubiquitin pool seems to be another critical factor determining the cellular level of HIF-1alpha.

Review on special emphasis of bortezomib on relapsed/refractory myeloma.

Refractory or relapsed Multiple Myeloma (MM) is a plasma cell neoplasia characterized by paraproteins in the urine or serum and a bone marrow plasmacytosis of over 10%. Multiple/refractory myeloma is a neoplasm of plasma cells and exact cause of multiple myeloma is remain unidentified, it is characterized by accumulation of malignant plasma cells in the bone marrow, leading to bone marrow failure, anemia, skeletal destruction, renal failure, increased susceptibility to infection and hypercalcemia. The survival time for the patients with refractory or multiple myeloma can be prolonged with treatment of newer and more target specific approach. The proteasome inhibitors are an important class of anti-myeloma drugs that have efficacy to disrupt the proteolytic structure of tumor cells and enhancing their susceptibility to apoptosis. Bortezomib has a significant clinical efficacy against refractory multiple myeloma. Bortezomib is the most commonly used and clinically tested proteasome inhibitor and which is effective in prolonging the overall survival in several trials. Bortezomib combinations with other drugs such as dexamethasone and cyclophosphamide are the choice of treatment for standard risk patients following the mSMART guidelines. The success with lower dosage of bortezomib in elderly patient’s proven efficacious subcutaneous usage and its useful proteasome inhibitor to enhance patient’s compliance and reduces toxicity and costs of therapy. This review discusses on special emphasis of bortezomib on relapsed/refractory multiple myeloma as front-line treatment.

Treatment of Refractory Antibody-mediated Rejection with Bortezomib in a Kidney Transplant Recipient: A Case Report / 대한이식학회지

Antibody-mediated rejection (ABMR) is associated with poor renal allograft survival. It shows poor response to conventional treatment with plasmapheresis, rituximab, and intravenous immunoglobulin. Bortezomib, a proteasome inhibitor used for treatment of multiple myeloma, has recently been reported as a treatment alternative for recipient desensitization and ABMR. A 58-year-old man was diagnosed with mixed-type ABMR with donor specific antibodies and acute T cell-mediated rejection early after kidney transplantation. Conventional therapy was administered, including antithymocyte globulin, plasmapheresis, and rituximab; however, his condition was found to be refractory to these antihumoral therapies. Following administration of bortezomib, his serum creatinine level returned to baseline with stable graft function. His serum creatinine level remains stable at 1.3 mg/dL at 10 months posttransplantation. Bortezomib is effective for treatment of refractory ABMR following kidney transplantation.

Proteasome-Inhibitor-Based Primary Therapy for Antibody-Mediated Rejection in a Renal Transplant Recipient / 대한내과학회지

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.

Proteasome-Inhibitor-Based Primary Therapy for Antibody-Mediated Rejection in a Renal Transplant Recipient / 대한내과학회지

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.

Advance in the medical treatment of multiple myeloma / 中国癌症杂志

Multiple myeloma is one of the common hematological malignant disease,but the treatment response was not very promising with conventional and high-dose chemotherapy.There are many new medicines or new therapies having been developed in recent years,such as thalidomide and its derivant,proteasome inhibitors,arsenic trioxide etc,they are more effective than conventional chemotherapy,such as oral melphalan and prednisone(MP);vincristine,doxorubicin,and dexamethasone(VAD).This paper summarize the recent advances in the new options for the treatment of multiple myeloma

The role of GSK-3?in apoptosis induced by proteasome inhibitors combined with paclitaxel in ovarian cancer cells and its possible mechanism / 中国癌症杂志

Background and purpose:Proteasome inhibitors such as bortezomib,represent an interesting new class of potential anticancer drugs.In the present study,we explored the sensitivity of ovarian cancer cell line SKOV3 to paclitaxel,proteasome inhibitors and their combination,and also studied the involvement of GSK-3?/Mcl-1 signaling pathway in the regulation of apoptosis induced by those agent.Methods:Methyl thiazolyl tetrazolium (MTT)assay was applied to examine the cell viability,Annexin-V/PI apoptosis detection kit was used to determine the apoptosis rate of different groups,and western blot assay was introduced to evaluate the expression levels of phosphorylated GSK-3?and Mcl-1.Results:In the MTT assay,the cell viability ratios of combination group at serial time points from 12 to 72 hr were(65.2?5.8)%,(58.3?14.4)%,(35.3?5.0)%,(19.2?1.5)% and(11.4?2.5)%,and there were significant differences as compared to the treatment of paclitaxel alone(P

Effects of proteasomal peptide aldehydes inhibitors on expression of inflammation factors induced by LPS in Raw264.7 cell line / 中国病理生理杂志

AIM:To investigate the effects of MG132,one of the proteasomal peptide aldehydes inhibitors,on lipopolysaccharide(LPS)-induced nuclear transcription factor-kappa B(NF-?B) activation,the production of nitric oxide(NO) and tumor necrosis factor-alpha(TNF-?),as well as the expression of inducible nitric oxide synthase(iNOS) in murine macrophage line RAW264.7.METHODS:Reporter gene assay was used to examine the activity of NF-?B by pNiFty-SEAP/HEK293 cells,which were transfected with the pNiFty reporter plasmid into human embryo kidney cells(HEK293).Fluorescence substrate DAF-2DA was used to testify NO level in Raw264.7 cell line induced by LPS.Furthermore,the secretion of TNF-? was examined by ELISA.Western blotting was used to reveal the expression of iNOS and I?B-?.RESULTS:MG132 significantly decreased the secretion of TNF-? induced by LPS,with the inhibitory rates of 36.7% and 60.4% to 5 ?mol/L and 10 ?mol/L MG132,respectively.The pro-inflammatory mediator NO production was decreased in a dose-dependent manner with the inhibitory rates increasing from 29.5%(2 ?mol/L) to 55.9%(10 ?mol/L).Pretreatment with MG132 reduced the expression of iNOS,but restored the I?B restrain caused by LPS treatment.Observed by a reporter gene assay,TNF-?-induced NF-?B activity was decreased gradually by addition of increasing concentration of MG132(2.5-10 ?mol/L).CONCLUSION:Our results suggest an anti-inflammation effect of MG132 by the suppression of LPS-induced the production of pro-inflammatory mediators including NO and TNF-?,and the expression of iNOS,which probably mediates the blockage of I?B degradation and NF-?B activation.

Effect of lactacystin and ?-lactacystin on the activation and proliferation of T-lymphocytes / 中国病理生理杂志

AIM: To evaluate the effects of lactacystin (LAC) and ?-lactacystin (?-LAC), proteasome inhibitor, on the proliferation and activation of T lymphocytes. METHODS: Flow cytometry was used to analyse the proliferation and the expression of CD69, CD25 and CD3 in PHA activated T-lymphocytes. Furthermore, the expression of PA28 and IL-2 mRNA were assayed by competitive RT-PCR. RESULTS: (1) LAC and ?-LAC significantly decreased the incorporation in PHA activated T-lymphocytes. (2) Although LAC and ?-LAC did not affect the expression of CD69 at any time, they significantly inhibited the expression of CD25 (48 h, 72 h, P