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A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors.

BackgroundNovel therapies are needed for children, adolescents, and young adults with relapse/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of carfilzomib administered in combination with cyclophosphamide and etoposide was conducted.MethodsStudy eligibility included an age of 6 months to 2/day, etoposide 100 mg/m2/day, and carfilzomib was administered every 28 days with growth factor support. The carf

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… It is structurally and mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib [ 1 , 2 , 3 ]. …

Cyclophosphamide, Bortezomib, and Dexamethasone Consolidation in Patients with Multiple Myeloma after Stem Cell Transplantation: The KMM130 Study.

PurposeA three-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CVD) shows significant efficacy and manageable toxicity as induction therapy in patients with multiple myeloma.Materials and methodsIn this phase II study, we enrolled 45 patients who achieved a very good partial response (VGPR) or partial response (PR) after autologous stem cell transplantation (ASCT) and evaluated the efficacy and toxicity of CVD consolidation. CVD consolidation comprised three cycles of cyclophosphamide 300 mg/m2 orally on days 1, 8, and 15, and bortezomib 1.3 mg/m2 subcutaneously on days 1,

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… toxicity due to previous treatment, including ASCT; progressive disease (PD) after ASCT; having received other post-ASCT therapies, such as chemotherapy and/or radiation; positive for human immunodeficiency virus; active hepatitis B and/or hepatitis C infection; previous hypersensitivity to bortezomib, boron …

Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma.

In this phase I/II trial, BID, bendamustine (70, 80, or 90 mg/m2), ixazomib (4 mg), and dexamethasone (40 mg), was administered to 28 patients with relapsed and/or refractory multiple myeloma (RRMM) exposed to bortezomib and lenalidomide and refractory to at least one. A 3 + 3 dose escalation based on dose-limiting toxicities (DLTs) was employed in phase I (total 15); 2/6 patients developed DLTs (neutropenia and thrombocytopenia) at dose level 3 establishing the recommended phase II dose as bendamustine 80 mg/m2, ixazomib 4 mg, and dexamethasone 40 mg. The median age was 67 years (range, 42-72

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… Ixazomib is an orally available peptide boronic acid that preferentially binds to the β 5 subunit of the 20S proteasome 12 . Ixazomib has shown clinical activity both as single agent and in combination in newly diagnosed and relapsed/refractory multiple myeloma (RRMM) 13 – 15 . …

Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma.

Ixazomib is the first oral proteasome inhibitor to enter the clinic. Given the efficacy of bortezomib in combination with cyclophosphamide and dexamethasone, we studied the combination of ixazomib, cyclophosphamide and dexamethasone (ICd) in newly diagnosed multiple myeloma (NDMM) and patients with measurable disease, irrespective of transplant eligibility, were enrolled. The phase 1 was to determine the maximum tolerated dose (MTD) of cyclophosphamide in the combination. Patients received ixazomib 4 mg (days 1, 8, 15), dexamethasone 40 mg (days 1, 8, 15, 22), and cyclophosphamide 300 or 400 m

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… Ixazomib citrate is a modified peptide boronic acid and is the citrate ester of ixazomib (MLN2238), the biologically active moiety. Ixazomib citrate rapidly hydrolyzes to ixazomib upon contact with aqueous solution or plasma. …

Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors.

While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes

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… Ixazomib (Ninlaro ® , Millennium, Takeda Oncology, Cambridge, MA, USA) is a boron-based, orally available PI, and was recently Food and Drug Administration (FDA) approved [ 13 , 14 , 15 , 16 ]. …

Epidemiology, genetics and treatment of multiple myeloma and precursor diseases.

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapi

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… CRBN inducing proteasomal degradation of IKZF1 and IKFZ3 (differing CRBN binding properties and degradation targets when compared to other immunomodulatory agents) | Oral | Bone marrow suppression, venous thromboembolism, rash, teratogenic Proteasome inhibitors Bortezomib | First‐generation reversible boronic … neuropathy, thrombocytopenia, gastrointestinal toxicity, herpes zoster infection Carfilzomib | Second‐generation irreversible tetrapeptide epoxyketone‐based proteasome inhibitor | Intravenous | Hypertension, cardiac failure, acute renal failure; thrombotic microangiopathy; cytopenia Ixazomib | Reversible boronic …

Обобщение и оценка 6-ариламинобензамидов в качестве позитронных фотографических лигандов для рецептора фингозина-1-фосфата-5.

Спингосин-1-фосфат-5 (S1P5) является одним из пяти мембранных белковых рецепторов G, которые активируются лизофосфолипидом, фосфатом-1, что приводит к регулированию многих клеточных процессов. Рецепторы S1P5 расположены на олигодендроцитах и предлагаются для оказания влияния на физиологию олигодендроцитов. Понимание модуляции S1P5 в ходе таких процессов, как ремиелионация, может иметь потенциальные возможности для демиелионизации расстройств CNS, таких, как множественный склероз (MS). В этой связи мы сообщаем об обобщении и предварительной оценке серии фторированных 6-ариламинобензамидов в кач

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… Introduction of the fluorinated (hetero)aryl groups was then achieved using the Suzuki–Miyaura cross-coupling reaction with various boronic acids. 21 This gave compounds 8a–8e in 18–71% yields. Synthesis of 6-arylaminobenzamides 8a–8e. … General procedure D: Suzuki–Miyaura reaction of 3-bromobenzamides To a reaction vessel containing the aryl bromide (1.0 equiv.) in 1,4-dioxane (15 mL mmol −1 ) and water (1.1 mL mmol −1 ) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium( ii ) (1 : 1) (5 mol%), the boronic acid (1.6 …

Clinical performance of implanted devices used in surgical treatment of patients with spinal tumors: a systematic review.

PURPOSE: Implanted devices used in metastatic spine tumor surgery (MSTS) include pedicle screws, fixation plates, fixation rods, and interbody devices. A material to be used to fabricate any of these devices should possess an array of properties, which include biocompatibility, no toxicity, bioactivity, low wear rate, low to moderate incidence of artifacts during imaging, tensile strength and modulus that are comparable to those of cortical bone, high fatigue strength/long fatigue life, minimal or no negative impact on radiotherapy (RT) planning and delivery, and high capability for fusion to

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… Gültan T Yurtsever M Gümüşderelioğlu M NaOH-etched/boron-doped nanohydroxyapatite-coated PEEK implants enhance the proliferation and differentiation of osteogenic cells Biomed Mater 2020 15 035019 10.1088/1748-605X/ab7198 32000154 Gültan T, Yurtsever M, Gümüşderelioğlu M. … NaOH-etched/boron-doped nanohydroxyapatite-coated PEEK implants enhance the proliferation and differentiation of osteogenic cells. Biomed Mater. 2020;15:035019. 32000154 10.1088/1748-605X/ab7198 68. …

Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells.

Head and neck cancer (HNC) has frequently an aggressive course for the development of resistance to standard chemotherapy. Thus, the use of innovative therapeutic drugs is being assessed. Bortezomib is a proteasome inhibitor with anticancer effects. In vitro antitumoral activity of Bortezomib was investigated employing human tongue (SCC-15, CAL-27), pharynx (FaDu), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) originated from a salivary gland adenocarcinoma arising in BALB-neuT male mice transgenic for the oncogene neu. Bortezomib inhibited cell proliferation, trigg

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… Bortezomib ([(1 R )-3-methyl-1-({(2 S )-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid) is a dipeptidyl boronic acid reversible inhibitor of the chymotrypsin-like activity of the 20S proteasome 14 , 20 , 21 . …

Peripheral Neuropathy under Oncologic Therapies: A Literature Review on Pathogenetic Mechanisms.

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients' quality of life. Experience skills are required to recognize symptoms and clinical evidences and the collaboration between different health professionals, in particular oncologists and hospital pharmacists, grants a correct management of this undesirable occurrence. Some classes of drugs (platinates, vinca alkaloids, taxanes) typically develop this kind of side effe

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… Bortezomib Bortezomib is an N-protected dipeptide containing a boronic acid instead of a carboxylic acid and is an anti-cancer drug for the treatment of multiple myeloma and mantle cell lymphoma as first and further line treatment, often co-administered within a complex medical protocol together with … Together with carfilzomib, bortezomib is a reversible proteasome inhibitor thank to its boron atom which binds the catalytic site of the26S proteasome [ 100 , 102 ].with high affinity and specificity, blocking the degradation of cellular proteins and ridding cells of abnormal or misfolded proteins. …

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma.

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three protea

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… Ixazomib is a citrate ester of boronic acid which is a stable prodrug. At physiological conditions, it is hydrolyzed into a free, biologically active boric acid metabolite (MLN2238) which is an N-capped dipeptidyl leucine boronic acid ( 122 ). …

Use of carfilzomib in second-line therapy and beyond for relapsed multiple myeloma.

The development of proteasome inhibitors has been a major advance in therapy of multiple myeloma, accounting, in part, for the significant increase in the survival of patients diagnosed with this disease. Bortezomib was the first proteasome inhibitor to be approved for the therapy of multiple myeloma. Carfilzomib is a second-generation proteasome inhibitor with irreversible binding to proteasome and less off-target toxicity. The drug has been approved for use in relapsed/refractory multiple myeloma. In this article, we review the use of carfilzomib as second-line therapy in multiple myeloma. W

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… cell cycle, such as cyclins A, B, D, E, and cyclin-dependent kinase inhibitor, 26 tumor suppressor proteins such as p53 27 and also I-kB, which is an inhibitor of NF-kappa pathway in plasma cells. 28 Dysregulation of such pathways via proteasome inhibition leads to cell apoptosis. 24 Bortezomib is a boron-containing …

The roles of microRNA families in hepatic fibrosis.

The Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008 (JCMWDDT 2008) was held from September 29 to October 1, 200 … Staphylococcus aureus by Chikara Kaito (The University of Tokyo, Japan) ● Water soluble fluorescent boronic acid sensors for tumor cell-surface saccharide by Hao Fang (Shandong Unviersity, China) ● Molecular characterization of the biosynthetic enzyme for the biotechnological production of tetrahydrocannabinol, the active constituent of marijuana by Fut …

Comparative Effectiveness of Pomalidomide-Based Regimens in Relapsed/Refractory Multiple Myeloma: A Multicenter Real-World Analysis in China.

Background: Although multiple pomalidomide-based combinations are active in relapsed and/or refractory multiple myeloma (RRMM), comparative data to guide regimen selection remain limited. Methods: A total of 230 patients with RRMM from 12 centers in China who received pomalidomide-based regimens were included in this retrospective analysis. Overall response rate (ORR) and progression-free survival (PFS) were compared across regimens incorporating bortezomib or ixazomib (V/IPD), carfilzomib (KPD), or daratumumab (DPD), and multivariable analyses were performed to identify prognostic factors. Re

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… As Bortezomib and Ixazomib are both boronate-based and reversible proteasome inhibitors with similar β5 subunit selectivity [ 11 ], VPD and IPD regimens were combined and analyzed together as the V/IPD group. …

Ixazomib-lenalidomid-dexamethasone (IRd) в повторном рефракторе множественных миеломах (RRMM)-многоцентрах анализа реального мира из Германии и сравнительного обзора литературы.

С внедрением новых агентов (протеозных ингибиторов (ИП), иммуномодуляционных препаратов (ИМИД), иммунологии, иммунотерапевтии) результаты многочисленных пациентов миеломы (ММ) улучшились. Оральный PI ixazomib был разрешен в ЕС 11/2016 и указывается в сочетании с линалидомидом и дексаметазоном (IRd) для лечения пациентов с реанимированным/отверженным MM (RRMMM). Цель исследования состояла в том, чтобы определить типичную реальную популяцию пациентов RRMM в Германии, проходящих лечение с помощью IRd, и сравнить результаты с результатами предыдущих IRd когорт. Наше ретроспективное исследование вк

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… Ixazomib (I) is a reversible, boron-containing PI that is available orally as the prodrug ixazomib citrate. It particularly inhibits the chymotrypsin-like activity of the beta5 subunit of the 20S proteasome. …

Фаза I - исследование TQB3602, перорального протеазонного ингибитора, в рецидиве и множестве миеломы.

ObjectiveTQB3602 — роман с биодоступным ингибитором. Это исследование является первым клиническим испытанием в человеке I для оценки безопасности, терпимости, фармакокинетики и предварительной эффективности TQB3602 в повторной/редактируемой миеломе (RRMM). 3+3 Фаза " доза " и фаза расширения дозы. Пациенты с MM, получившие ≥2 До этого были приняты антимиеломные методы лечения. TQB3602 применяется при дозе 0.5~7 мг по дням 1, 8, 15 В 28-day Цикл.five Пациенты RRMM, которые свернули или потерпели неудачу ≥2 В фазу увеличения дозы были приняты меры терапии. Two пациентов 7.0 группа по д

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… have emerged, offering effective therapy alternatives for patients with RRMM. 3 Proteasome inhibitors‐based therapies have led to more profound and more durable responses, resulting in significantly improved survival for RRMM, and are the current mainstay of MM therapy. 4 , 5 Ixazomib is the first boronate‐based …

Epidemiology of Bacteremia in Patients with Hematological Malignancies and Hematopoietic Stem Cell Transplantation and the Impact of Antibiotic Resistance on Mortality: Data from a Multicenter Study in Argentina.

The epidemiology of bacteremia and the antibiotic resistance profile (ARP) of Gram-negative bacilli (GNB) in hematological malignancies (HM) and hematopoietic stem cell transplant (HSCT) patients may differ according to geographic region. In addition, multidrug-resistant organisms (MDROs) may impact mortality. This is a prospective, observational, and multicenter study. The first episodes of bacteremia in adult patients with HM or HSCT were included. The risk factors for 30-day mortality were identified. One thousand two hundred and seventy-seven episodes were included (HM: 920; HSCT: 357). GN

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… Carbapenemase production was investigated in carbapenem-resistant bacteria using the modified Hodge method, disk synergy tests with a carbapenem disk placed close to the boronic acid disk test for KPC, and the EDTA disk for identification of metallo-β-lactamases. …

Short Course of Antibiotic Therapy for Gram-Negative Bacilli Bacteremia in Patients with Cancer and Hematopoietic Stem Cell Transplantation: Less Is Possible.

Data about short courses of antibiotic therapy for Gram-negative bacilli (GNB) bacteremia in immunosuppressed patients are limited. This is a prospective observational study performed on adult patients with cancer and hematopoietic stem cell transplant (HSCT) who developed GNB bacteremia and received appropriate empirical antibiotic therapy (EAT), had a clinical response within 7 days and survived 48 h after the end of therapy. They received antibiotic therapy in the range of 7-15 days and were divided into short course, with a median of 7 days (SC), or long course, with a median of 14 days (L

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… In carbapenem-resistant bacteria, carbapenemase production was investigated by the Blue-Carba assay and/or the double disk synergy tests (with carbapenems disks placed close to a boronic acid disk for KPC and an EDTA disk for identification of metallo-β-lactamases). …

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical

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… Importantly these two compounds are chemically distinct from carfilzomib, being boronic acid, and leading to reversible proteasome inhibition [ 11 – 16 ]. …

Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis.

BACKGROUND: Subchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis. METHODS: We examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibi

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… There are many possible explanations as to why we observed these contrasting results, the most likely of which is that MG132 and Bortezomib are different types of proteasome inhibitors – MG132 is a peptide aldehyde which also inhibits certain cysteine proteinases, whereas Bortezomib is a peptide boronate …