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PMID:29386436
Autor:Komada F
Endereço:Faculty of Pharmaceutical Sciences, Himeji Dokkyo University.
Título:[Analysis of Time-to-onset of Interstitial Lung Disease after the Administration of Small Molecule Molecularly-targeted Drugs].
Fonte:Yakugaku Zasshi; 138(2):229-235, 2018.
ISSN:1347-5231
País de publicação:Japan
Idioma:jpn
Resumo: The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (CH5424802); 0 (Carbazoles); 0 (Piperidines); 0 (Pyrazoles); 0 (Pyridines); 0 (Quinazolines); 41UD74L59M (afatinib); 53AH36668S (crizotinib); 69G8BD63PP (Bortezomib); RBZ1571X5H (Dasatinib)


  2 / 4609 MEDLINE  
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PMID:29209721
Autor:Bridoux F; Carron PL; Pegourie B; Alamartine E; Augeul-Meunier K; Karras A; Joly B; Peraldi MN; Arnulf B; Vigneau C; Lamy T; Wynckel A; Kolb B; Royer B; Rabot N; Benboubker L; Combe C; Jaccard A; Moulin B; Knebelmann B; Chevret S; Fermand JP; MYRE Study Group
Endereço:Department of Nephrology, Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 1402, Centre Hospitalier Universitaire, Poitiers, France.
Título:Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial.
Fonte:JAMA; 318(21):2099-2110, 2017 12 05.
ISSN:1538-3598
País de publicação:United States
Idioma:eng
Resumo:Importance: Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively. Objective: To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability). Design, Setting, and Participants: Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016. Interventions: Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone. Main Outcomes and Measures: Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death. Results: Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, -12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died. Conclusions and Relevance: Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference. Trial Registration: clinicaltrials.gov Identifier: NCT01208818.
Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
Nome de substância:69G8BD63PP (Bortezomib); 7S5I7G3JQL (Dexamethasone)


  3 / 4609 MEDLINE  
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PMID:29254302
Autor:Wang Q; Wang J; Gao D; Li J
Endereço:Tumor Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Título:Inhibition of PAR2 and TRPA1 signals alleviates neuropathic pain evoked by chemotherapeutic bortezomib.
Fonte:J Biol Regul Homeost Agents; 31(4):977-983, 2017 Oct-Dec.
ISSN:0393-974X
País de publicação:Italy
Idioma:eng
Resumo:Bortezomib (BTZ) is generally used as a chemotherapeutic agent for the treatment of multiple myeloma; however, one of the significant limiting complications of BTZ is painful peripheral neuropathy observed during BTZ therapy. There is a lack of drugs which can prevent and/or treat the painful symptoms induced by BTZ, as the underlying molecular mechanism leading to neuropathic pain remains largely unclear. In the present study, we examined engagement of proteinase-activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) in neuropathic pain induced by BTZ in rats. Our results demonstrated that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals (P less than 0.05 vs control rats). Our data further showed that blocking respective PAR2 and TRPA1 attenuated mechanical pain and cold sensitivity observed in control rats and BTZ rats (P less than 0.05 vs vehicle control). Notably, the attenuating effect of blocking PAR2 and TRPA1 on mechanical pain and cold sensitivity was significantly less in BTZ rats than that in control rats. In addition, protein expression of PAR2 and TRPA1 was upregulated in the lumbar dorsal root ganglion of BTZ rats, and inhibition of PAR2 decreased the levels of TRPA1 and attenuated its downstream pathways (namely, PKCÉ› and PKA). Overall, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ and that blocking PAR2 and TRPA1 in sensory nerves is beneficial to improve neuropathic pain during BTZ intervention.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Analgesics); 0 (Antineoplastic Agents); 0 (H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (TRPA1 Cation Channel); 0 (Trpa1 protein, rat); 69G8BD63PP (Bortezomib); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.13 (Protein Kinase C-epsilon)


  4 / 4609 MEDLINE  
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PMID:29193021
Autor:Flinn IW; Thompson DS; Boccia RV; Miletello G; Lipman A; Flora D; Cuevas D; Papish SW; Berdeja JG
Endereço:Sarah Cannon Research Institute/Tennessee Oncology PLLC, Nashville, TN, USA.
Título:Bendamustine, bortezomib and rituximab produces durable complete remissions in patients with previously untreated, low grade lymphoma.
Fonte:Br J Haematol; 180(3):365-373, 2018 02.
ISSN:1365-2141
País de publicação:England
Idioma:eng
Resumo:This Phase II trial evaluated the efficacy of bendamustine, bortezomib and rituximab in patients with previously untreated low-grade lymphoma. Eligible patients had low grade lymphoma with no previous systemic disease treatment. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m intravenously (IV) on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6; bendamustine 90 mg/m IV on days 1 and 2; and bortezomib 1·6 mg/m IV on days 1, 8 and 15. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments had been conducted. Fifty-four eligible patients were enrolled. The most common grade 3/4 toxicities were leucopenia (28%), neutropenia (30%) and lymphopenia (17%). There were no treatment-related deaths and 1 unrelated death on study (embolic stroke). The overall response rate was 94% for all patients. The median follow-up was 54 months. Kaplan-Meier estimates of progression-free survival and overall survival at 36 months were 75% and 88%, respectively. The treatment regimen was well tolerated and produced high response rates. Further study of this regimen in patients with previously untreated lymphoma is warranted.
Tipo de publicação: CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:4F4X42SYQ6 (Rituximab); 69G8BD63PP (Bortezomib); 981Y8SX18M (Bendamustine Hydrochloride)


  5 / 4609 MEDLINE  
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PMID:28466536
Autor:Laubach JP; Moslehi JJ; Francis SA; San Miguel JF; Sonneveld P; Orlowski RZ; Moreau P; Rosiñol L; Faber EA; Voorhees P; Mateos MV; Marquez L; Feng H; Desai A; van de Velde H; Elliott J; Shi H; Dow E; Jobanputra N; Esseltine DL; Niculescu L; Anderson KC; Lonial S; Richardson PG
Endereço:Dana-Farber Cancer Institute, Boston, MA, USA.
Título:A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Fonte:Br J Haematol; 178(4):547-560, 2017 08.
ISSN:1365-2141
País de publicação:England
Idioma:eng
Resumo:This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
Tipo de publicação: JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Antineoplastic Agents); 0 (Proteasome Inhibitors); 69G8BD63PP (Bortezomib)


  6 / 4609 MEDLINE  
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PMID:29264740
Autor:Qin XY; Lu J; Li GX; Wen L; Liu Y; Xu LP; Chang YJ; Liu KY; Jiang ZF; Huang XJ
Endereço:Peking University People's Hospital, Peking University Institute of Hematology, 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
Título:CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens.
Fonte:Ann Hematol; 97(3):485-495, 2018 Mar.
ISSN:1432-0584
País de publicação:Germany
Idioma:eng
Resumo:Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA-4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, -1772 (rs733618), -1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001-0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 69G8BD63PP (Bortezomib)


  7 / 4609 MEDLINE  
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PMID:29284118
Autor:Uematsu A; Kido K; Manabe E; Takeda H; Takahashi H; Hayashi M; Imai Y; Sawasaki T
Endereço:Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Japan.
Título:DANFIN functions as an inhibitor of transcription factor NF-κB and potentiates the antitumor effect of bortezomib in multiple myeloma.
Fonte:Biochem Biophys Res Commun; 495(3):2289-2295, 2018 01 15.
ISSN:1090-2104
País de publicação:United States
Idioma:eng
Resumo:Nuclear factor-κB (NF-κB) proteins are transcription factors that play key roles in regulating most immune responses and cell death. Constitutively active NF-κB has been shown to exhibit chemoresistance by inducing anti-apoptosis in tumor cells. Multiple myeloma is known as a constitutive NF-κB activating disease, and the proteasome inhibitor bortezomib is used to treat multiple myeloma and mantle cell lymphoma. We demonstrate here that DANFIN (N,N'-bis-(2,4-dimethyl-phenyl)-ethane-1,2-diamine) functions as an inhibitor of the p65 family proteins and induces chemosensitization to bortezomib in multiple myeloma. DANFIN was found to be an inhibitor of interactions between p65 and IκBα without the inhibition of the DNA binding activity of the p65 protein. In addition, DANFIN affected the IκBα binding region in Rel Homology Domain (RHD) and suppressed the nuclear translocalization of the p65 protein in cells. Furthermore, in multiple myeloma cells, DANFIN suppressed the expression level of NF-κB target genes and induced apoptosis. The combination therapy of DANFIN with bortezomib dramatically enhanced the apoptosis of multiple myeloma cells and indicated a remarkable anti-tumor effect in a multiple-myeloma xenograft mouse model.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Diamines); 0 (N,N'-bis-(2,4-dimethyl-phenyl)-ethane-1,2-diamine); 0 (NF-kappa B); 0 (Transcription Factors); 69G8BD63PP (Bortezomib)


  8 / 4609 MEDLINE  
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PMID:29231133
Autor:Mateos MV; Dimopoulos MA; Cavo M; Suzuki K; Jakubowiak A; Knop S; Doyen C; Lucio P; Nagy Z; Kaplan P; Pour L; Cook M; Grosicki S; Crepaldi A; Liberati AM; Campbell P; Shelekhova T; Yoon SS; Iosava G; Fujisaki T; Garg M; Chiu C; Wang J; Carson R; Crist W; Deraedt W; Nguyen H; Qi M; San-Miguel J; ALCYONE Trial Investigators
Endereço:From University Hospital of Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca (M.-V.M.), and Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S
Título:Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.
Fonte:N Engl J Med; 378(6):518-528, 2018 02 08.
ISSN:1533-4406
País de publicação:United States
Idioma:eng
Resumo:BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 10 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).
Tipo de publicação: CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Antibodies, Monoclonal); 4Z63YK6E0E (daratumumab); 69G8BD63PP (Bortezomib); Q41OR9510P (Melphalan); VB0R961HZT (Prednisone)


  9 / 4609 MEDLINE  
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PMID:29236701
Autor:Takahashi K; Inukai T; Imamura T; Yano M; Tomoyasu C; Lucas DM; Nemoto A; Sato H; Huang M; Abe M; Kagami K; Shinohara T; Watanabe A; Somazu S; Oshiro H; Akahane K; Goi K; Kikuchi J; Furukawa Y; Goto H; Minegishi M; Iwamoto S; Sugita K
Endereço:Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.
Título:Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines.
Fonte:PLoS One; 12(12):e0188680, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Prognosis of childhood acute lymphoblastic leukemia (ALL) has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ), a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+) ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response. Even in Ph-negative ALL cell lines, IKZF1 deletion and bilallelic loss of CDKN2A were independently associated with higher BTZ sensitivity. BTZ showed only marginal cross-resistance to four representative chemotherapeutic agents (vincristine, dexamethasone, l-asparaginase, and daunorubicin) in B-cell precursor-ALL cell lines. To improve the efficacy and safety of proteasome inhibitor combination chemotherapy, we also analyzed the anti-leukemic activity of carfilzomib (CFZ), a second-generation proteasome inhibitor, as a substitute for BTZ. CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19) ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment. P-glycoprotein inhibitors effectively restored the sensitivity to CFZ, but not BTZ, in P-glycoprotein-positive t(17;19) ALL cell lines. P-glycoprotein overexpressing ALL cell line showed a CFZ-specific resistance, while knockout of P-glycoprotein by genome editing with a CRISPR/Cas9 system sensitized P-glycoprotein-positive t(17;19) ALL cell line to CFZ. These observations suggested that IKZF1 deletion could be a useful biomarker to predict good sensitivity to CFZ and BTZ, and that CFZ combination chemotherapy may be a new therapeutic option with higher anti-leukemic activity for refractory ALL that contain P-glycoprotein-negative leukemia cells.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antineoplastic Agents); 0 (Oligopeptides); 69G8BD63PP (Bortezomib); 72X6E3J5AR (carfilzomib)


  10 / 4609 MEDLINE  
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PMID:29206844
Autor:Gastelum G; Poteshkina A; Veena M; Artiga E; Weckstein G; Frost P
Endereço:Department of Hematology/Oncology, Greater Los Angeles Veteran Administration Healthcare System, Los Angeles, California, United States of America.
Título:Restoration of the prolyl-hydroxylase domain protein-3 oxygen-sensing mechanism is responsible for regulation of HIF2α expression and induction of sensitivity of myeloma cells to hypoxia-mediated apoptosis.
Fonte:PLoS One; 12(12):e0188438, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Multiple myeloma (MM) is an incurable disease of malignant plasma B-cells that infiltrate the bone marrow (BM), resulting in bone destruction, anemia, renal impairment and infections. Physiologically, the BM microenvironment is hypoxic and this promotes MM progression and contributes to resistance to chemotherapy. Since aberrant hypoxic responses may result in the selection of more aggressive tumor phenotypes, we hypothesized that targeting the hypoxia-inducible factor (HIF) pathways will be an effective anti-MM therapeutic strategy. We demonstrated that MM cells are resistant to hypoxia-mediated apoptosis in vivo and in vitro, and that constitutive expression of HIF2α contributed to this resistance. Since epigenetic silencing of the prolyl-hydroxylase-domain-3 (PHD3) enzyme responsible for the O2-dependent regulation of HIF2α is frequently observed in MM tumors, we asked if PHD3 plays a role in regulating sensitivity to hypoxia. We found that restoring PHD3 expression using a lentivirus vector or overcoming PHD3 epigenetic silencing using a demethyltransferase inhibitor, 5-Aza-2'-deoxycytidine (5-Aza-dC), rescued O2-dependent regulation of HIF2α and restored sensitivity of MM cells to hypoxia-mediated apoptosis. This provides a rationale for targeting the PHD3-mediated regulation of the adaptive cellular hypoxic response in MM and suggests that targeting the O2-sensing pathway, alone or in combination with other anti-myeloma chemotherapeutics, may have clinical efficacy.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Basic Helix-Loop-Helix Transcription Factors); 0 (RNA, Messenger); 0 (endothelial PAS domain-containing protein 1); 69G8BD63PP (Bortezomib); EC 1.14.11.29 (EGLN3 protein, human); EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases); S88TT14065 (Oxygen)



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