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Bortezomib.

The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle … n substrate, attached at a COOH terminal "warhead". Notable warheads include boronic acids, such as Bortezomib and epoxyketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI-0052, or salinosporamide A, another inhibitor in clinical trials. The possi …

Bortezomib.

The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle … n substrate, attached at a COOH terminal "warhead." Notable warheads include boronic acids, such as bortezomib and epoxy ketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI-0052, or salinosporamide A, another inhibitor in clinical trials. The poss …

Bortezomib.

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… The mechanism underlying bortezomib-induced thrombocytopenia is unclear and is not secondary to bone marrow injury or thrombopoietin inhibition. Hence, supportive care rather than discontinuation of bortezomib therapy may be appropriate. … DRUG INTERACTIONS Bortezomib may inhibit CYP450 isoenzyme 2C19 and increase the levels/effects of CYP2C19 substrates. Bortezomib is a substrate mainly for CYP3A4 and CYP2C19. …

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in r…

Breathless on bortezomib.

The authors describe a case of episodic acute pneumonitis occurring after repeated doses of bortezomib, a drug being used increasingly to treat multiple myeloma. The delay in presentation each time with fever, dyspnoea, hypoxia and interstitial radiological changes contributed to under-recognition of this complication, which has so far been described in only a handful of patients, but the pattern seen may offer clues to pathogenesis and potential treatments. This case highlights the need for both physicians and patients consenting to bortezomib treatment to be more aware of this potentially fa…

Bone-Targeted Bortezomib Inhibits Bortezomib-Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone.

Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone-residing cancer, especially drug-resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off-target effects. To this end, bone-targeted conjugate (BP-Btz) was generated by linking bortezomib (Btz, an anticancer, bone-stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled…

ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5.

The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed w…

Bortezomib in kidney transplantation.

Although current therapies for pretransplant desensitization and treatment of antibody-mediated rejection (AMR) have had some success, they do not specifically deplete plasma cells that produce antihuman leukocyte antigen (HLA) antibodies. Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma (a plasma cell neoplasm), induces plasma cell apoptosis. In this paper we review the current body of literature regarding the use of this biological agent in the field of transplantation. Although limited experience with bortezomib may seem to show promise in the realm of trans…

Bortezomib in the treatment of cancer.

Bortezomib (Velcade, formerly PS-341) represents the first proteasome inhibitor to have shown anti-tumor activity in both solid and haematological malignancies. It blocks activation of nuclear factor-kappa B (NF-kB), resulting in increased apoptosis, decreased angiogenic cytokine production, and inhibition of tumor cell adhesion to stroma. Additional mechanisms of action include c-Jun N-terminal kinase activation, effects on growth factor expression and anti-angiogenic properties. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro activity, which was followe…

Upfront bortezomib, lenalidomide, and dexamethasone compared to bortezomib, cyclophosphamide, and dexamethasone in multiple myeloma.

OBJECTIVES: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material. METHOD: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 rec…

Bortezomib, lenalidomide, and dexamethasone versus bortezomib, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma.

Bortezomib, lenalidomide, and dexamethasone (VRD), and bortezomib, doxorubicin, and dexamethasone (PAD), are commonly used in induction regimens for patients with newly diagnosed multiple myeloma (NDMM) in China. This real-world study enrolled 390 patients, 195 receiving VRD and 195 receiving PAD induction. The primary endpoint was progression-free survival (PFS) and stringent complete remission/complete remission. Across the entire cohort, VRD demonstrated significantly improved five-year overall survival (OS) (74% vs. 59%, p = 0.0024) and five-year PFS (67% vs. 37%, p = 0.0018) compared to P…

Bortezomib inhibits mammalian carbonic anhydrases.

We investigated the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the clinically used antitumor agent bortezomib, a marketed proteasome inhibitor, against all the catalytically active mammalian isoforms CA I-VII, IX, XII-XV. Bortezomib effectively inhibited all these CAs in the micromolar range. hCA II, the physiologically dominant cytosolic isoform showed the highest affinity for the drug, with a KI of 1.16μM. The cytosolic slow isoform hCA I was also effectively inhibited, with a KI of 1.29μM, whereas the next best affinity was observed for the membrane-anchored form mCA XV, wit…

Bortezomib-induced acute interstitial nephritis.

Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) resulting from inflammatory tubulointerstitial injury induced by medications, infections and systemic diseases. Bortezomib has been increasingly used especially in renal related indications such as multiple myeloma and monoclonal gammopathy of renal significance. Severe allergic reactions from bortezomib treatment including AIN have not been described in the literature. We report a 47-year-old white man who developed biopsy-proven allergic AIN after treatment with bortezomib for his C3 glomerulonephr…

Bortezomib and bilateral herpes zoster.

Bortezomib is a proteasome inhibitor that has proven to be a very effective treatment for multiple myeloma. There is considerable debate about the potential for reactivation of the varicella zoster virus (VZV) in patients with multiple myeloma during treatment with bortezomib. This report describes the case of a 70-year-old patient with multiple myeloma that developed bilateral herpes zoster shortly after being treated with bortezomib. Furthermore, it emphasizes the importance of using an antiviral prophylaxis with acyclovir in these patients treated with bortezomib.

Bortezomib in mantle cell lymphoma.

Mantle cell lymphoma (MCL) represents 6% of non-Hodgkin lymphomas, but is one of the most active fields of clinical investigation. Unfortuna … de of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and the first US FDA-approved drug for MCL), mTOR inhibitors, Bcl-2 inhibitors, antiangiogenesis agents and histone deacetylase inhibitors among others. An obvious effort is needed to enroll patients on clinical trials, the d …