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Sample records for bortezomib doxorubicin dexamethasone

  1. Lambda Light Chain Myeloma with Oliguric Cast Nephropathy and Remission with Bortezomib, Doxorubicin and Dexamethasone

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    R Hada

    2012-12-01

    We report the clinical course and outcome of a patient presenting with acute kidney injury and oliguria, preceded by acute gastroenteritis and intake of Chinese medications and dialysis dependent state for eight weeks. Kidney biopsy revealed cast nephropathy with lambda light chain restriction and severe tubular injury. Serum protein electrophoresis was normal with no “M spike” but serum free light chain ratio was altered with very high lambda and normal kappa light chain levels. Bone marrow biopsy showed >85% atypical plasma cells. Haemodialysis was continued and chemotherapy with bortezomib, doxorubicin and dexamethasone was started. Kidney function gradually improved with discontinuation of dialysis after 1 month and complete remission of acute kidney injury and myeloma in 4 months of chemotherapy. Keywords: acute kidney injury; bortezomib; cast nephropathy; multiple myeloma.

  2. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma

    DEFF Research Database (Denmark)

    San-Miguel, Jesús F; Hungria, Vânia T M; Yoon, Sung-Soo

    2014-01-01

    BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone...

  3. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

    NARCIS (Netherlands)

    P.G. Richardson (Paul Gerard); P. Sonneveld (Pieter); M.W. Schuster (Michael); D. Irwin (David); E.A. Stadtmauer (Edward); T. Facon (Thierry); J-L. Harousseau (Jean-Luc); D. Ben-Yehuda (Dina); S. Lonial (Sagar); H. Goldschmidt (Hartmut); D. Reece (Donna); J.F. San Miguel (Jesús Fernando); J. Bladé (Joan); M. Boccadoro (Mario); J. Cavenagh (Jamie); W. Dalton (William); A.L. Boral (Anthony); D.-L. Esseltine (Dixie-Lee); J.B. Porter (Jane); D. Schenkein (David); K.C. Anderson (Kenneth Carl)

    2005-01-01

    textabstractBACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3

  4. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM

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    Offidani, Massimo; Pégourie, Brigitte; De La Rubia, Javier; Garderet, Laurent; Laribi, Kamel; Bosi, Alberto; Marasca, Roberto; Laubach, Jacob; Mohrbacher, Ann; Carella, Angelo Michele; Singhal, Anil K.; Tsao, L. Claire; Lynch, Mark; Bleickardt, Eric; Jou, Ying-Ming; Robbins, Michael; Palumbo, Antonio

    2016-01-01

    In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048. PMID:27091875

  5. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma

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    Hjorth, Martin; Hjertner, Øyvind; Knudsen, Lene Meldgaard;

    2012-01-01

    Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives....

  6. Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone

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    López-Iglesias, Ana-Alicia; González-Méndez, Lorena; San-Segundo, Laura; Herrero, Ana B.; Hernández-García, Susana; Martín-Sánchez, Montserrat; Gutiérrez, Norma C.; Paíno, Teresa; Avilés, Pablo; Mateos, María-Victoria; San-Miguel, Jesús F.; Garayoa, Mercedes; Ocio, Enrique M.

    2017-01-01

    Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients. PMID:27540138

  7. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma.

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    Jimenez-Zepeda, Victor H; Reece, Donna E; Trudel, Suzanne; Chen, Christine; Tiedemann, Rodger; Kukreti, Vishal

    2013-03-01

    The combination of lenalidomide, bortezomib and dexamethasone (RVD) has shown excellent efficacy in patients with relapsed or refractory multiple myeloma (RRMM). The aim of our study was to assess the efficacy and toxicity profile of RVD for patients with advanced RRMM. We retrospectively reviewed the records of all patients with RRMM treated with RVD between March 2009 and December 2011. Thirty patients received ≥ 1 full cycle of RVD. Primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). After a median of 5 cycles (1-16), a very good partial response (VGPR) was seen in 10%, partial response (PR) in 36.7% and stable disease (SD) in 13.3% (ORR of 46.7%). Disease progression occurred in 21 patients at a median of 3 months (range 1.41-4.59). Eight patients (26%) experienced grade 3/4 adverse events, including anemia, neutropenia, muscle weakness and pneumonia. No patient experienced worsening peripheral neuropathy. Although RVD has been previously shown to be effective in RRMM, the ORR and PFS we observed were affected by very advanced disease status and heavy prior exposure to novel agents. Nevertheless, six of these patients with RRMM experienced a benefit of ≥ 6 months, suggesting synergism of this immunomodulatory derivative/proteasome inhibitor combination and/or re-establishment of drug sensitivity by an emergent myeloma clone.

  8. Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

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    Shenghao Wu

    2015-01-01

    Full Text Available Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM patients with the therapy of subcutaneous (subQ administration of bortezomib and dexamethasone plus thalidomide (VTD regimen. Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group.The efficacy and safety of two groups were analyzed retrospectively. Results. The overall remission (OR after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05. No significant differences in time to 1-year estimate of overall survival (72% versus 75%, P=0.848 and progression-free survival (median 22 months versus 25 months; P=0.725 between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50% than VTD group (80%, P=0.015. Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

  9. Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): Long-term results of a phase 2 study of the European Myeloma Network (EMN)

    NARCIS (Netherlands)

    M.A. Dimopoulos (Meletios); R. Garcia-Sanz (Ramon); M. Gavriatopoulou (Maria); P. Morel; M.-C. Kyrtsonis (Marie-Christine); L.K. Michalis (Lampros); Z. Kartasis (Zafiris); X. Leleu; G. Palladini (Giovanni); A. Tedeschi (Alessandra); D. Gika (Dimitra); G. Merlini; E. Kastritis (Efstathios); P. Sonneveld (Pieter)

    2013-01-01

    textabstractIn this phase 2 multicenter trial, we evaluated the activity of bortezomib, dexamethasone, and rituximab (BDR) combination in previously untreated symptomatic patients with Waldenström macroglobulinemia (WM). To prevent immunoglobulin M (IgM) "flare," single agent bortezomib (1.3 mg/m 2

  10. Changes in circulating endothelial progenitor cells predict responses of multiple myeloma patients to treatment with bortezomib and dexamethasone

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    L. Wang

    2015-08-01

    Full Text Available Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM patients. We investigated whether circulating endothelial progenitor cells (cEPCs could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1α (SDF-1α in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1α was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16, common responders (n=12, and non-responders (n=18. There were no significant differences among these groups at baseline day 1 (P>0.05. cEPC levels decreased slightly at day 21 (8.2±3.3 cEPCs/μL vs day 1 (8.4±2.9 cEPCs/μL in good responders (P>0.05. In contrast, cEPC levels increased significantly in the other two groups (P<0.05. SDF-1α changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1α/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients.

  11. Bortezomib prevents acute doxorubicin ovarian insult and follicle demise, improving the fertility window and pup birth weight in mice.

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    Elon C Roti Roti

    Full Text Available Increasing numbers of female patients survive cancer, but succumb to primary ovarian insufficiency after chemotherapy. We tested the hypothesis that Bortezomib (Bort protects ovaries from doxorubicin (DXR chemotherapy by treating female mice with Bort 1 hour prior to DXR. By preventing DXR accumulation in the ovary, Bort attenuated DXR-induced DNA damage in all ovarian cell types, subsequent γH2AFX phosphorylation, and resulting apoptosis in preantral follicles. Bort pretreatment extended the number of litters per mouse, improved litter size and increased pup weight following DXR treatment, thus increasing the duration of post-chemotherapy fertility and improving pup health. As a promising prophylactic ovoprotective agent, Bort does not interfere with cancer treatment, and is currently used as a chemotherapy adjuvant. Bort-based chemoprotection may preserve ovarian function in a non-invasive manner that avoids surgical ovarian preservation, thus diminishing the health complications of premature menopause following cancer treatment.

  12. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma

    NARCIS (Netherlands)

    Segeren, CM; Sonneveld, P; van der Holt, B; Baars, JW; Biesma, DH; Cornellissen, JJ; Croockewit, AJ; Dekker, AW; Fibbe, WE; Lowenberg, B; Kooy, MV; van Oers, MHJ; Richel, DJ; Vellenga, E; Verhoef, GEG; Wijermans, PW; Wittebol, S; Lokhorst, HM

    1999-01-01

    We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4mg and doxorubicin 9 mg/m(2) as a rapid intravenous infusion for 4d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction

  13. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.

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    Kumar, Shaji; Flinn, Ian; Richardson, Paul G; Hari, Parameswaran; Callander, Natalie; Noga, Stephen J; Stewart, A Keith; Turturro, Francesco; Rifkin, Robert; Wolf, Jeffrey; Estevam, Jose; Mulligan, George; Shi, Hongliang; Webb, Iain J; Rajkumar, S Vincent

    2012-05-10

    Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms)≥very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).

  14. Sequential treatment with bortezomib plus dexamethasone followed by autologous hematopoietic stem cell transplantation in patients with multiple myeloma

    Institute of Scientific and Technical Information of China (English)

    ZHENG Dong; LI Juan; HUANG Bei-hui; LIU Jun-ru; ZOU Wai-yi; SU Chang

    2012-01-01

    Background Whether the sequential treatment with bortezomib plus dexamethasone (BD) followed by autologous hematopoietic stem cell transplantation (ASCT) could extend the overall survival period in multiple myeloma patients is still not clear.Few large case studies about this therapeutics in multiple myeloma were reported in China.Our purpose was to assess the efficacy and adverse effects of sequential treatment with BD chemotherapy and ASCT in patients with multiple myeloma.Methods Fifty-three patients with newly diagnosed or relapsed/refractory multiple myeloma received BD as induction therapy before ASCT.Stem-cell mobilization was undertaken with cyclophosphamide 3-5 g/m2 plus granulocyte colony-stimulating factor 300 μg/d.Target yield was 2.0×106 CD34+ cells/kg.Conditioning for ASCT consisted of melphalan 200 mg/m2.Thalidomide and/or α-interferon was used as post-transplantation maintenance treatment.Results The BD chemotherapy before transplantation was effective in 86.7% of the 53 patients,including 22.6% with complete remission (CR),39.6% with near complete remission (nCR),and 24.5% with partial remission (PR).The best effect was achieved after two treatment courses.Most bortezomib-related adverse effects were classes 1-2.All patients were successfully mobilized after BD for autologous peripheral blood stem cell transplantation.The ASCT was effective in 96.3% of patients,including 49.1% with CR,32.1% with nCR,and 15.1% with PR.The CR rate was significantly increased (49.1% vs.22.6%,P <0.05) by sequential ASCT.Within 27 (range,6-53) months of follow-up,the efficacy of ASCT was maintained in 29 patients and further enhanced by post-transplantation maintenance treatment in four patients.Eleven patients died after transplantation.Among the patients undergoing BD/ASCT treatment,overall survival (OS) was significantly better in newly diagnosed patients in comparison to relapsed/refractory patients (P=0.046).Conclusions BD chemotherapy can

  15. Good clinical activity and favorable toxicity profile of once weekly bortezomib, fotemustine, and dexamethasone (B-MuD) for the treatment of relapsed multiple myeloma.

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    Mangiacavalli, Silvia; Pochintesta, Lara; Pascutto, Cristiana; Cocito, Federica; Pompa, Alessandra; Cazzola, Mario; Corso, Alessandro

    2013-02-01

    Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m² i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.

  16. Bortezomib in treatment of extramedullary plasmacytoma of the pancreas

    Institute of Scientific and Technical Information of China (English)

    Ju-Ying Wei; Hong-Yan Tong; Wei-Fang Zhu; Hui Liu; Feng-Juan Zhang; Wen-Juan Yu; Jie Jin

    2009-01-01

    BACKGROUND: Extramedullary pancreatic plasmacy-toma treated with bortezomib is rarely reported. METHODS: We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months, then an asymptomatic swelling of the pancreas was found. A biopsy on the mass and a ifne needle aspiration of the pancreas were performed. The diagnosis of extramedullary plasmacytoma (EMP) was made. The patient was initially treated with combination chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD regimen). She progressed to painless jaundice during the chemotherapy. Then she was treated with bortezomib and hyper-dose dexamethasone. As a result, she had a near complete remission. RESULTS: The data demonstrated that the diagnosis was EMP of the pancreas. The patient responded very well to bortezomib, while failing to respond to the traditional chemotherapy regimen of VAD. CONCLUSION: EMP of the pancreas is rare. This case gives evidence for an excellent response of EMP of the pancreas to bortezomib.

  17. Long-term reversibility of renal dysfunction associated to light chain deposition disease with bortezomib and dexamethasone and high dose therapy and autologous stem cell transplantation

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    Tomás J. González-López

    2011-11-01

    Full Text Available A 63-year-old woman presented with progressive renal insufficiency, until a glomerular filtration rate (GFR of 12 mL/min. A renal biopsy demonstrated glomerular deposition of immunoglobulin k light chain. The presence of a small population of monoclonal plasmacytes producing an only light k monoclonal component was demonstrated and Bortezomib and Dexamethasone (BD was provided as initial therapy. After seven courses of therapy, renal function improved without dialysis requirements up to a GFR 31 mL/min. Under hematological complete response (HCR the patient underwent high dose of melphalan (HDM and autologous peripheral blood stem cell transplant. Fifty-four months later the patient remains in HCR and the GFR has progressively improved up to 48 mL/min. This report describes a notably renal function improvement in a patient with Light Chain Deposition Disease after therapy with BD followed by HDM, which can support this treatment as a future option for these patients.

  18. Updated survivals and prognostic factor analysis in myeloma treated by a staged approach use of bortezomib/thalidomide/dexamethasone in transplant eligible patients

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    Chim Chor

    2010-11-01

    Full Text Available Abstract Background Bortezomib, an NFkB inhibitor, is an active agent for the treatment of myeloma (MM. We have reported a promising complete remission (CR rate for newly diagnosed myeloma patients treated by a staged approach, in which chemosensitive patients underwent autologous haematopoietic stem cell transplantation (auto-HSCT while less chemosensitive patients received salvage therapy with bortezomib/thalidomide/dexamethasone prior to auto-HSCT. Methods Herein, with an additional 13 months of follow-up, we reported the updated survivals, and examined potential prognostic factors impacting event-free (EFS and overall survival (OS. Results With a median follow-up of 30 months, the projected OS was 73% and EFS was 50.2%. Age, gender, clinical stage and DAPK methylation could not account for the differential chemosensitivity. Advanced ISS stage and DAPK methylation adversely impacted OS whereas oligoclonal reconstitution predicted superior EFS. Conclusions Our staged approach illustrated an economical use of expensive targeted agents while preserving a good CR rate and OS. The comparable survivals of chemosensitive and less chemosensitive patients suggested the staged approach might have abolished the adverse prognostic impact of suboptimal chemosensitivity. Finally, the adverse impact of DAPK methylation and favorable impact of oligoclonal reconstitution in myeloma warrants further study.

  19. Pomalidomide Plus Low-Dose Dexamethasone Improves Survival for Patients with Multiple Myeloma

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    ... Health Professional Plasma Cell Neoplasms Treatment Research Pomalidomide plus Low-Dose Dexamethasone Improves Survival for Patients with ... pomalidomide, bortezomib, and low-dose dexamethasone with bortezomib plus low-dose dexamethasone in patients with previously treated ...

  20. Doxorubicin

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    ... cells), including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML, ANLL). Doxorubicin is also used alone and ... a reliable method of birth control to prevent pregnancy. Doxorubicin may harm the fetus.do not have ...

  1. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN).

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    Dimopoulos, Meletios A; García-Sanz, Ramón; Gavriatopoulou, Maria; Morel, Pierre; Kyrtsonis, Marie-Christine; Michalis, Eurydiki; Kartasis, Zafiris; Leleu, Xavier; Palladini, Giovanni; Tedeschi, Alessandra; Gika, Dimitra; Merlini, Giampaolo; Kastritis, Efstathios; Sonneveld, Pieter

    2013-11-07

    In this phase 2 multicenter trial, we evaluated the activity of bortezomib, dexamethasone, and rituximab (BDR) combination in previously untreated symptomatic patients with Waldenström macroglobulinemia (WM). To prevent immunoglobulin M (IgM) "flare," single agent bortezomib (1.3 mg/m(2) IV days 1, 4, 8, and 11; 21-day cycle), was followed by weekly IV bortezomib (1.6 mg/m(2) days 1, 8, 15, and 22) every 35 days for 4 additional cycles, followed by IV dexamethasone (40 mg) and IV rituximab (375 mg/m(2)) in cycles 2 and 5. Fifty-nine patients were treated; 45.5% and 40% were high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response [PR]). In 11% of patients, an increase of IgM ≥25% was observed after rituximab; no patient required plasmapheresis. After a minimum follow-up of 32 months, median progression-free survival was 42 months, 3-year duration of response for patients with ≥PR was 70%, and 3-year survival was 81%. Peripheral neuropathy occurred in 46% (grade ≥3 in 7%); only 8% discontinued bortezomib due to neuropathy. BDR is rapidly acting, well tolerated, and nonmyelotoxic, inducing durable responses in previously untreated WM.

  2. Comparison of engraftment following different stem cell mobilization modalities in patients with multiple myeloma treated with a uniform induction regimen containing bortezomib, cyclophosphamide and dexamethasone.

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    Benyamini, Noam; Avivi, Irit; Dann, Eldad J; Zuckerman, Tsila; Lavi, Noa; Katz, Tami

    2017-03-01

    Bortezomib-based induction followed by autologous stem cell transplantation is a common treatment for multiple myeloma (MM). Stem cell (SC) mobilization with granulocyte-colony stimulating factor (G-CSF) alone has become an alternative to G-CSF combined with chemotherapeutic agents. This study aimed to compare the efficacy of the two mobilization modalities following induction with a uniform regimen containing bortezomib, cyclophosphamide and dexamethasone (VCD). We retrospectively evaluated results of SC mobilization using either G-CSF alone or combined with high-dose cyclophosphamide (HD-CY) in MM patients after VCD induction. The primary endpoints of the study were engraftment and mobilization-associated toxicity. Parameters of stem cell collection, transplantation and engraftment were assessed. Data of 92 patients were analyzed [56 (61%) mobilized with HD-CY + G-CSF and 36 (39%) with G-CSF only]. HD-CY + G-CSF provided a higher number of CD34 + cells (15.9 vs 8.1 × 10(6)/kg, p = 0.001) with fewer apheresis sessions. However, while no adverse events were observed in patients receiving G-CSF alone, nine patients (16%) receiving HD-CY + G-CSF developed neutropenic fever requiring hospitalization. Although a greater number of cells was transplanted following mobilization with HD-CY + G-CSF, neutrophil and platelet engraftment and duration of transplant-related hospitalization were similar in both cohorts. G-CSF alone provided a sufficient SC amount, without exposing patients to additional toxicity. While HD-CY + G-CSF resulted in a superior SC yield in MM patients induced with VCD, this advantage should be balanced against adverse effects of this mobilization regimen.

  3. SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide) in the treatment of multiple myeloma.

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    Barosi, Giovanni; Merlini, Giampaolo; Billio, Atto; Boccadoro, Mario; Corradini, Paolo; Marchetti, Monia; Massaia, Massimo; Tosi, Patrizia; Palumbo, Antonio; Cavo, Michele; Tura, Sante

    2012-06-01

    In this project, we produced drug-specific recommendations targeting the use of new agents for multiple myeloma (MM). We used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system which separates the judgments on quality of evidence from the judgment about strength of recommendations. We recommended thalidomide and bortezomib in MM patients candidates to autologous stem cell transplantation (ASCT) (weak positive). We did not recommend novel agents as maintenance therapy after ASCT (weak negative). In patients not candidate to ASCT, thalidomide or bortezomib (strong positive) associated with melphalan and prednisone were recommended. In these patients, no specific course of action could be recommended as for maintenance therapy. In patients who are refractory or relapsing after first-line therapy, we recommended bortezomib and pegylated liposomal doxorubicin, or lenalidomide and dexamethasone combinations (weak positive).

  4. 硼替佐米联合地塞米松治疗多发性骨髓瘤52例疗效分析%Clinical Efficacy Analysis of Bortezomib Combined with Dexamethasone in Treatment of Multiple Myeloma

    Institute of Scientific and Technical Information of China (English)

    王平

    2013-01-01

    目的 探讨硼替佐米联合地塞米松对多发性骨髓瘤的治疗效果和不良反应.方法 根据入组的多发性骨髓瘤患者个体情况制定硼替佐米和地塞米松的用量,在治疗过程中监测患者的各项生理指标,详细记录不良反应,治疗结束后随访6个月,观察存活率及用药依从性.结果 所有参与实验的患者均完成了规定的治疗周期,总有效率为78.85%,取得最佳化疗效果的疗程为2个疗程,复发率为11.54%,治疗后仅1例患者死亡.结论 利用硼替佐米联合地塞米松治疗多发性骨髓瘤疗效显著,有效率较高,不良反应在可控范围内,近期存活率也较满意.%Objective To explore the curative effect of bortezomib combined with dexamethasone on multiple myeloma and adverse reaction.Method According to the individual condition of patients develop boron for Zomi and dexamethasone dosage,various physiological indexes of patients during process of treatment were monitored,a detailed record of adverse reactions after the end of treatment were followed up for 6 months to observe the survival rate and medication compliance.Results All the patients in the experiment were completed the prescribed treatment cycle,the total efficiency was 78.85%,to achieve the best effect of chemotherapy for the treatment of 2 courses,the recurrence rate was 11.54%,1 patients died after treatment.Conclusion The use of bortezomib combined with dexamethasone in the treatment of multiple myeloma had high efficiency,adverse reactions in the controlled range,the short-term survival rate is satisfied.

  5. Treatment outcome and prognostic factor analysis in transplant-eligible Chinese myeloma patients receiving bortezomib-based induction regimens including the staged approach, PAD or VTD

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    Chim Chor

    2012-06-01

    Full Text Available Abstract Background We have reported promising outcomes using a staged approach, in which bortezomib/thalidomide/dexamethasone was used only in 14 patients with suboptimal response to VAD (vincristine/adriamycin/dexamethasone before autologous stem cell transplantation (ASCT. Here we compared the outcomes of the staged approach with frontline PAD (bortezomib/doxorubicin/dexamethasone or VTD (bortezomib/thalidomide/dexamethasone induction, and analysed prognostic factors for outcome. Patients and methods Ninety-one transplant-eligible Chinese patients received three induction regimens prior to ASCT [staged approach (N = 25, PAD (N = 31, VTD (N = 35]. and received thalidomide maintenance for 2 years post-ASCT. Results 43 (47.3% patients had International Staging System (ISS III disease. By an intention-to-treat analysis, the overall CR/nCR rate were 37.4% post-induction, and 62.6% post-ASCT. Five-year overall (OS and event-free (EFS survivals were 66% and 45.1%. There was no difference of the post-induction CR/nCR rate, EFS or OS between patients induced by these three regimens. Moreover, ISS III disease did not affect CR/nCR rates. Multivariate analysis showed that ISS and post-ASCT CR/nCR impacted OS while ISS and post-induction CR/nCR impacted EFS. Conclusions These three induction regimens produced comparable and favorable outcomes in myeloma. The unfavorable outcome of ISS stage III persisted despite upfront/early use of bortezomib. CR/nCR predicted favorable survivals.

  6. Immunoglobulin D multiple myeloma, plasma cell leukemia and chronic myelogenous leukemia in a single patient treated simultaneously with lenalidomide, bortezomib, dexamethasone and imatinib

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    Naveed Ali

    2016-03-01

    Full Text Available Multiple myeloma (MM is a neoplastic lymphoproliferative disorder characterized by uncontrolled monoclonal plasma cell proliferation. Among different isotypes of MM, immunoglobulin D (IgD MM is very rare, representing only 1 to 2% of all isotypes. Chronic myelogenous leukemia (CML is a neoplastic myeloproliferative disorder of pluripotent hematopoietic stem cell, which is characterized by the uncontrolled proliferation of myeloid cells. An 88-year-old male was diagnosed simultaneously with IgD kappa MM and CML. A distinctive feature in this patient was the progression to plasma cell leukemia without any symptomatic myeloma stage. He was treated simultaneously with lenalidomide, bortezomib and imatinib. Synchronous occurrence of these rare hematological malignancies in a single patient is an exceedingly rare event. Multiple hypotheses to explain co-occurrence of CML and MM have been proposed; however, the exact etiological molecular pathophysiology remains elusive.

  7. Bortezomib Induced Hepatitis B Reactivation

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    Salwa Hussain

    2014-01-01

    Full Text Available Background. It has recently been reported that hepatitis B (HBV reactivation often occurs after the use of rituximab and stem cell transplantation in patients with lymphoma who are hepatitis B surface antigen (HBsAg negative. However, clinical data on HBV reactivation in multiple myeloma (MM is limited to only a few reported cases. Bortezomib and lenalidomide have remarkable activity in MM with manageable toxicity profiles, but reactivation of viral infections may emerge as a problem. We present a case of MM that developed HBV reactivation after bortezomib and lenalidomide therapy. Case Report. A 73-year-old female with a history of marginal cell lymphoma was monitored without requiring therapy. In 2009, she developed MM, presenting as a plasmacytoma requiring vertebral decompression and focal radiation. While receiving radiation she developed renal failure and was started on bortezomib and liposomal doxorubicin. After a transient response to 5 cycles, treatment was switched to lenalidomide. Preceding therapy initiation, her serology indicated resolved infection. Serial monitoring for HBV displayed seroconversion one month after change in therapy. Conclusion. Bortezomib associated late HBV reactivation appears to be a unique event that requires further confirmation and brings to discussion whether hepatitis B core positive individuals would benefit from monitoring of HBV activation while on therapy.

  8. Characterization of bortezomib-adapted I-45 mesothelioma cells

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    Peddaboina Chander

    2010-05-01

    Full Text Available Abstract Background Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy. Results The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit β5 (PSMB5 as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells. Conclusion These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.

  9. Bortezomib: the evidence of its clinical impact in multiple myeloma

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    Simon Lancaster

    2006-06-01

    Full Text Available Simon LancasterSL Comm Ltd, Macclesfield, UKIntroduction: Multiple myeloma is a relatively common and incurable form of hematologic malignancy for which there is currently no single standard therapy. Bortezomib inhibits the 20S proteasome involved in the degradation of intracellular proteins, induces apoptosis, reverses drug resistance in multiple myeloma cells, and influences their microenvironment by blocking cytokine circuits, cell adhesion and angiogenesis in vivo.Aims: The objective of this review is to evaluate the evidence for the use of bortezomib in the treatment of multiple myeloma.Evidence review: In patients with relapsed multiple myeloma bortezomib significantly prolongs overall survival and time to progression, and improves response rates, duration of response, and quality of life compared with oral high-dose dexamethasone. Although the incidence of grade 4 adverse events was similar, grade 3 events and herpes zoster infections occur more frequently in patients treated with bortezomib than with high-dose dexamethasone. Evidence from a pharmacoeconomic study indicates that the benefits of bortezomib compared to thalidomide plus best standard care may be achieved at a reasonable cost.Clinical value: Bortezomib is a valuable treatment option in the management of relapsed multiple myeloma that improves survival and delays disease progression compared with oral high-dose dexamethasone treatment, albeit with an increased incidence of some adverse events such as grade 3 thrombocytopenia and neutropenia.Key words: bortezomib, evidence, multiple myeloma, outcomes, treatment

  10. Treatment of primary systemic amyloidosis with the combination of bortezomib and dexamethasone%硼替佐米联合地塞米松治疗原发性系统性淀粉样变性

    Institute of Scientific and Technical Information of China (English)

    翟勇平; 刘海宁; 于亚平; 周晓钢; 宋萍; 李锋; 王学文

    2010-01-01

    Objective To evaluate the efficacy and feasibility of bortezomib plus dexamethasone (BD) in patients with primary systemic (AL) amyloidosis. Methods Eleven AL amyloidosis patients, including four relapsed or progressed after previous therapies and 7 newly diagnosed were treated with BD. Ten patients had two or more organs involved. Precursor protein analysis showed that 1 was κ light chain, 9 λ light chain;5 patients with positive immunofixation including 1 IgG κ, 3 IgG λ and 1 IgA λ. BD was administered according to standard two-week schedule. Results Eight patients were evaluable, the median number of treatment cycles was 3 (range 1 -6). Median follow-up duration was 6 months. At least one affected organ response was observed in six patients and median time to organ response was 2 months. Three patients progressed and two of them died. Toxicities were mainly diarrhea, thrombocytopenia, peripheral neuropathy, fatigue and herpes zoster, and 7 evaluable patients who had toxicities were adjusted dosage and 2 of them interrupted therapy. Epilepsia, paralytic ileus, acute cardiac dysfunction, and postural hypotention were occurred in 3 inevaluble patients. Conclusion Bortezomib plus dexamethasone is effective in AL amyloidosis. Adverse events are common, and in some patients are severe.%目的 观察硼替佐米联合地塞米松治疗原发性系统性(AL)淀粉样变性患者的疗效和不良反应.方法 11例AL淀粉样变性患者中明确淀粉样物质者10例:κ型1例,λ型9例.免疫固定电泳阳性者5例:IgG κ型1例,IgGλ型3例,IgAλ型1例.累及肾脏、肝脏、心脏、肠道中2个或以上脏器者10例.11例患者中初治者7例,难治者4例.采用硼替佐米联合地塞米松方案治疗.结果 8例可评价疗效患者,中位疗程3(1~6)个.中位随访时间6个月.器官功能改善者6例,中位起效时间2个月.3例病情进展,2例死亡.常见的不良反应有腹泻、血小板减少、周围神经病

  11. Risk–Benefit Analysis of Pediatric-Inspired Versus Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Protocols for Acute Lymphoblastic Leukemia in Adolescents and Young Adults

    Science.gov (United States)

    Guzauskas, Gregory F.; Villa, Kathleen F.; Vanhove, Geertrui F.; Fisher, Vicki L.

    2017-01-01

    Purpose: To estimate the risk–benefit trade-off of a pediatric-inspired regimen versus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for first-line treatment of adolescents/young adult (AYA; ages 16–39 years) patients with Philadelphia-negative acute lymphoblastic leukemia. Methods: Patient outcomes were simulated using a 6-state Markov model, including complete response (CR), no CR, first relapse, second CR, second relapse, and death. A Weibull distribution was fit to the progression-free survival curve of hyper-CVAD–treated AYA patients from a single-center study, and comparable patient data from a retrospective study of pediatric regimen–treated AYA patients were utilized to estimate a relative progression difference (hazard ratio = 0.51) and model survival differences. Health-state utilities were estimated based on treatment stage, with an assumption that the pediatric protocol had 0.10 disutility compared with hyper-CVAD before the maintenance phase of treatment. Total life-years and quality-adjusted life-years (QALYs) were compared between treatment protocols at 1, 5, and 10 years, with additional probabilistic sensitivity analyses. Results: Treatment with the pediatric-inspired protocol was associated with a 0.04 increase in life-years, but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increase in life-years and 0.25 and 0.32 increase in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was offset by more favorable progression-free survival and overall survival relative to hyper-CVAD. Conclusions: Our exploratory analysis suggests that, compared with hyper-CVAD, pediatric-inspired protocols may increase life-years throughout treatment stages and QALYs in the long term. PMID:27779442

  12. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients.

    Science.gov (United States)

    Palumbo, Antonio; Gay, Francesca; Falco, Patrizia; Crippa, Claudia; Montefusco, Vittorio; Patriarca, Francesca; Rossini, Fausto; Caltagirone, Simona; Benevolo, Giulia; Pescosta, Norbert; Guglielmelli, Tommasina; Bringhen, Sara; Offidani, Massimo; Giuliani, Nicola; Petrucci, Maria Teresa; Musto, Pellegrino; Liberati, Anna Marina; Rossi, Giuseppe; Corradini, Paolo; Boccadoro, Mario

    2010-02-10

    PURPOSE To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. PATIENTS AND METHODS Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m(2) on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m(2) (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). CONCLUSION Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.

  13. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

    OpenAIRE

    Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina

    2016-01-01

    Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethaso...

  14. Efficacy of Bortezomib Combined with Thalidomide and Dexamethasone in the Treat-ment of Autologous Stem Cell Transplantation in Multiple Myeloma:A Meta-analysis%硼替佐米联合沙利度胺和地塞米松治疗自体造血干细胞移植多发性骨髓瘤的Meta分析

    Institute of Scientific and Technical Information of China (English)

    王海雪; 叶云

    2016-01-01

    目的:综合评价硼替佐米联合沙利度胺和地塞米松( VTD)治疗自体造血干细胞移植( ASCT)的多发性骨髓瘤( MM)的有效性和安全性。方法计算机检索Pubmed、Medline、the Cochrane Library、CNKI、VIP和万方等数据库,检索时间从建库至2014年12月。纳入VTD治疗 ASCT 的MM的随机对照试验,按Cochrane系统评价的方法评价纳入研究的质量,采用Review Manager 5.3.5版软件进行Meta分析。结果共纳入5项研究,1271例患者。 Meta分析结果显示,在有效性方面,VTD的完全缓解率与接近完全缓解率(CR+nCR)[RR=1.50,95%CI(1.16,1.94),P=0.002]和总有效率[RR=1.13,95%CI(1.03,1.24),P=0.009]优于其他联合方案,差异有统计学意义;在安全性方面,3~4度总不良反应发生率[RR=1.29,95%CI(1.05,1.59),P=0.02]高于其他联合方案,差异有统计学意义。结论 VTD能够显著提高ASCT的MM患者的CR+nCR和总有效率,但总不良反应发生率增加。%Objective To evaluate the efficacy and safety of bortezomib combined with dexamethasone and thalidomide in the treatment of autologous stem cell transplantation ( ASCT) in multiple myeloma ( MM) . Methods The randomized con-trolled trials ( RCTs) on combined therapy with bortezomib,dexamethasone and thalidomide for ASCT in MM were retrieved from Pubmed,Medline,the Cochrane Library,CNKI,VIP and Wanfang databases (published until December 2014).The method of the Cochrane systematic review was used to evaluate the quality of the included RCTs and the Review Manager 5.3.5 software was em-ployed for Meta-analysis. Results Five RCTs involving 1 271 patients were included.The meta analysis results showed that the complete remission ( CR) rate,near-CR rate and total effective rate were significantly higher after combined treatment with borte-zomib,dexamethasone and thalidomide when compared with those in other combination therapies [CR+nCR, RR=1.50,95%CI (1

  15. Curative effect observation of patients with primary systemic amyloidosis treated by the combination of bortezomib with dexmethasone and cyclophosphamide

    Institute of Scientific and Technical Information of China (English)

    路瑾

    2013-01-01

    Objective To analyze the efficacy and side effects of the combination regimen containing bortezomib,cyclophosphamide and dexamethasone(BCD)in the treatment of primary systemic amyloidosis(PSA).Methods

  16. Bortezomib-Induced Bronchiolitis Obliterans Organizing Pneumonia

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    E. Vandeix

    2012-01-01

    Full Text Available Introduction. Bortezomib is a proteasome inhibitor indicated for the treatment of multiple myeloma patients. The most frequent side effects are gastrointestinal and neurological. Serious pulmonary complications have been described rarely. Observation. This case involves a 74-year-old man suffering from IgG Kappa myeloma treated with bortezomib, melphalan, and dexamethasone. After administering chemotherapy, the patient developed an acute respiratory distress syndrome (ARDS. A surgical pulmonary biopsy proved the existence of bronchiolitis obliterans organizing pneumonia (BOOP lesions. Systemic corticotherapy led to a rapid improvement in the patient’s condition. Conclusion. This is the first reported histologically confirmed case of bortezomid-induced BOOP. Faced with severe respiratory symptoms in the absence of other etiologies, complications due to bortezomid treatment should be evoked and corticotherapy considered.

  17. 来自澳大利亚的经验:成人急性淋巴细胞白血病用Hyper-CVAD治疗的结果%Outcome of Treatment of Adult Acute Lymphoblastic Leukemia with Hyperfractionated Cyclophosphamide,Doxorubicin, Vincristine, Dexamethasone/Methotrexate, Cytarabine: Results from An Australian Population

    Institute of Scientific and Technical Information of China (English)

    李军民; 陆泽生

    2011-01-01

    1 文献来源Morris K,Weston H,Mollee P,et al.Outcome of treatment of adult acute lymphoblastic leukemia with hypeffractionated Cyclophosphamide,Doxorubicin,Vincristine,Dexamethasone/Methotrexate,Cytarabine:Results from an Australian population [J].Leuk Lymphoma,2011,52( 1 ):85-91.2 证据水平2b.%Department of Hematology, Ruijin Hospital, Shanghai Jiaotong Unverisity School of Medicine, Shanghai Institute of Hematology, Shanghai 200025, China

  18. Rare occurrence of bortezomib-induced Sweet′s syndrome in multiple myeloma

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    Chaturbhuj Agrawal

    2016-01-01

    Full Text Available Sweet′s syndrome (SS (acute neutrophilic dermatosis has already been described in cases of acute leukemia. It has been rarely reported in patients receiving bortezomib therapy for multiple myeloma (MM. A 65-year-old male, who was diagnosed as a case of MM 3 years back, initially received lenalidomide- and dexamethasone-based regimen, followed by lenalidomide maintenance, but subsequently had progressive disease with increasing monoclonal M-spike on serum protein electrophoresis, so shifted to bortezomib and dexamethasone along with monthly zoledronic acid-based treatment. He developed itching over face and neck with darkening and thickening of the skin. Examination revealed hyperpigmentation of face along with excoriation and erosions with involvement of "V" of neck with relative sparing of upper eyelid, postauricular area, and nasolabial folds. Histopathological examination of skin biopsy revealed neutrophilic infiltration of dermis suggestive of SS. A wide variety of cutaneous complications has been described in 10-20% of patients receiving bortezomib. However, SS has rarely been described in such patients with only a few case reports reported so far. Our patient developed features of SS while on bortezomib therapy and had shown dramatic response to bortezomib withdrawal and treatment with oral and topical steroids showing temporal association of this rare syndrome with bortezomib therapy.

  19. Ventricular fibrillation after bortezomib therapy in a patient with systemic amyloidosis

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    Satoshi Yamasaki

    2013-09-01

    Full Text Available A 64-year-old female was diagnosed with systemic amyloidosis associated with multiple myeloma. Bortezomib and dexamethasone-therapy was initiated; however, she developed lethal ventricular fibrillation (VF and cardiac arrest after 84 hours of therapy. Cardiopulmonary resuscitation using direct current shocks with epinephrine and amiodarone was initiated but failed to receive cardiac function. Although her arterial pulsations recovered immediately after the injection of vasopressin, she died of heart failure 8 hours after the onset of VF. Cardiac amyloidosis was verified by autopsy. Although the direct association of bortezomib with lethal VF remained to be clarified in our patient, the current report emphasizes on bortezomib as a substantial risk factor for cardiomyocyte damage. The potential risk of lethal events associated with cardiac amyloidosis should be carefully considered during bortezomib treatment for patients with AL amyloidosis.

  20. Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes

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    Vallumsetla N

    2015-11-01

    Full Text Available Nishanth Vallumsetla, Jonas Paludo, Prashant Kapoor Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Abstract: Mantle cell lymphoma (MCL is an incurable, typically aggressive subtype of non-Hodgkin lymphoma, accounting for 4%–7% of newly diagnosed non-Hodgkin lymphoma cases. Chemoresistance commonly ensues in MCL, and patients with this heterogeneous disease invariably relapse, underscoring the unmet need for better therapies. Over the past few years, several novel agents with promising activity and unique mechanisms of action have been deemed effective in MCL. Bortezomib is a reversible proteasome inhibitor, approved as a single agent for patients with relapsed/refractory MCL who have received at least one prior line of therapy. Addition of bortezomib to chemoimmunotherapies has demonstrated good tolerability and superior efficacy, both in the upfront and salvage settings, and recently one such combination of bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone was approved as a frontline regimen in untreated patients with MCL. This review examines the role of bortezomib in a multitude of clinical settings and ongoing clinical trials designed to optimize its integration in the current treatment paradigms of MCL. Keywords: non-Hodgkin lymphoma, proteosome inhibitor, treatment

  1. Dexamethasone Oral

    Science.gov (United States)

    ... of aspirin or other arthritis medication, limit your consumption of alcoholic beverages while taking this drug. Dexamethasone makes your stomach and intestines more susceptible to the irritating effects of alcohol, aspirin, and certain arthritis medications: this ...

  2. Dexamethasone Injection

    Science.gov (United States)

    ... body tissues,) gastrointestinal disease, and certain types of arthritis. Dexamethasone injection is also used for diagnostic testing. ... effects.tell your doctor if you have a fungal infection (other than on your skin or nails). ...

  3. Bone building with bortezomib

    Science.gov (United States)

    Roodman, G. David

    2008-01-01

    In this issue of the JCI, Mukherjee et al. report that bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of mesenchymal stem/progenitor cells (MSCs) — rather than mature osteoprogenitor cells — into osteoblasts, resulting in new bone formation (see the related article beginning on page 491). These results were observed when MSCs were implanted subcutaneously in mice or were used to treat a mouse model of postmenopausal bone loss. Others have reported that immunomodulatory drugs (e.g., thalidomide and lenalidomide), which are active against myeloma, also block the activity of bone-resorbing osteoclasts. These results reflect the utility of targeting endogenous MSCs for the purpose of tissue repair and suggest that combining different classes of agents that are antineoplastic and also inhibit bone destruction and increase bone formation should be very beneficial for myeloma patients suffering from severe bone disease. PMID:18219395

  4. Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells.

    Science.gov (United States)

    Mizuno, Shohei; Hanamura, Ichiro; Ota, Akinobu; Karnan, Sivasundaram; Narita, Tomoko; Ri, Masaki; Mizutani, Motonori; Goto, Mineaki; Gotou, Mayuko; Tsunekawa, Norikazu; Shikami, Masato; Iida, Shinsuke; Hosokawa, Yoshitaka; Miwa, Hiroshi; Ueda, Ryuzo; Nitta, Masakazu; Takami, Akiyoshi

    2015-11-01

    Amylase-producing myeloma exhibits refractoriness to chemotherapy and a dismal prognosis. In this study, we established a human myeloma cell line, 8226/AMY1, in which a lentivirally transfected AMY1 gene was stably expressed and explored its biological characteristics. 8226/AMY1 showed a survival advantage over mock control when treated with dexamethasone, bortezomib, and lenalidomide in vitro partly through inhibition of apoptosis induced by these reagents. In a xenograft murine model, 8226/AMY1 showed rapid tumor growth and reduced sensitivity to bortezomib compared with mock. A microarray gene expression analysis identified TCL1A, which functions as a coactivator of the cell survival kinase Akt, differentially up-regulated in 8226/AMY1. The expression of phosphorylated Akt was increased in the 8226/AMY1 cells following bortezomib treatment, but not in the mock cells. In addition, treatment with perifosine, an inhibitor of Akt phosphorylation, enhanced the anti-myeloma effect of bortezomib in the 8226/AMY1 cells. Our data suggest that amylase-producing myeloma reduced the sensitivity to bortezomib in vitro and in vivo, and the up-regulation of TCL1A may influence the drug susceptibility of 8226/AMY1 via the phosphorylation of Akt. These findings provide clues for developing treatment approaches for not only amylase-producing myeloma, but also relapsed and refractory myelomas.

  5. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

    OpenAIRE

    San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine

    2015-01-01

    Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival a...

  6. Stem cell mobilization chemotherapy with gemcitabine is effective and safe in myeloma patients with bortezomib-induced neurotoxicity.

    Science.gov (United States)

    Mueller, Beatrice U; Keller, Sandra; Seipel, Katja; Mansouri Taleghani, Behrouz; Rauch, Daniel; Betticher, Daniel; Egger, Thomas; Pabst, Thomas

    2016-05-01

    Vinorelbine chemotherapy with granulocyte-colony stimulating factor (G-CSF) stimulation is a widely applied non-myelosuppressive mobilization regimen in Switzerland for myeloma patients, but its neurotoxic potential limits its use in patients with bortezomib-induced polyneuropathy. In this single-center study, we alternatively evaluated safety and effectiveness of gemcitabine chemotherapy with G-CSF for mobilization of autologous stem cells. Between March 2012 and February 2013, all bortezomib-pretreated myeloma patients planned to undergo first-line high-dose melphalan chemotherapy received a single dose of 1250 mg/m2 gemcitabine, with G-CSF started on day 4. The 24 patients in this study had received a median of four cycles of bortezomib-dexamethason-based induction. Bortezomib-related polyneuropathy was identified in 21 patients (88%) by clinical evaluation and a standardized questionnaire. Administration of gemcitabine mobilization did not induce new or aggravate pre-existing neuropathy. Stem cell mobilization was successful in all 24 patients, with a single day of apheresis being sufficient in 19 patients (78%). The median yield was 9.51×10(6) CD34+ cells/kg. Stem collection could be accomplished at day 8 in 67%. Our data suggest that single-dose gemcitabine together with G-CSF is an effective mobilization regimen in myeloma patients and a safe alternative non-myelosuppressive mobilization chemotherapy for myeloma patients with bortezomib-induced polyneuropathy.

  7. The choice of regimens based on bortezomib for patients with newly diagnosed multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Jingsong He

    Full Text Available INTRODUCTION: Bortezomib has significantly improved multiple myeloma (MM response rates, but strategies for choosing bortezomib-based regimens for initial MM therapy are not standardized. Here, we describe four bortezomib-based therapies in Chinese MM patients to determine the optimal chemotherapeutic approach. METHODS: Newly diagnosed symptomatic MM patients at three hematological centers between February 1, 2006 and May 31, 2013 were treated with therapies including bortezomib plus dexamethasone (PD or combinations of PD with either adriamycin (PAD, cyclophosphamide (PCD or thalidomide (PTD for every 28 days. RESULTS: The overall response rate of all the 215 eligible patients was 90.2%. The ORR for PCD, PAD, PTD and PD were 97.4%, 93.2%, 85.3% and 77.8% while the effects with VGPR or better were 63.7%, 62.7%, 44.2% and 37.8%, respectively. The effect of ORR, VGPR and CR/nCR for the PCD regimen was better than the PD protocol. Median PFS for all patients was 29.0 months with significant differences observed among treatment groups. Median OS of all the patients was not reached, but three-drug combinations were superior to PD alone. Frequently observed toxicities were neutropenia, thrombocytopenia, fatigue, infection, herpes zoster, and peripheral neuropathy. The incidence of peripheral neuropathy (PN in PTD group was significantly higher than other three groups, especially grade 2-3 PN. Treatment with anti-viral agent acyclovir significantly reduced the incidence of herpes zoster. CONCLUSIONS: Our experience indicated that bortezomib-based regimens were effective and well-tolerated in the Chinese population studied; three-drug combinations PCD, PAD were superior to PD, especially with respect to PCD.

  8. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone

    OpenAIRE

    Dimopoulos, Meletios A.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine

    2016-01-01

    Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had ...

  9. Doxorubicin Lipid Complex Injection

    Science.gov (United States)

    Doxorubicin lipid complex is used to treat ovarian cancer that has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also used to treat Kaposi's sarcoma ( ...

  10. Pooled analysis of the reports of pomalidomide after failure of lenalidomide and (or) bortezomib for multiple myeloma.

    Science.gov (United States)

    Sheng, Zhixin; Liu, Guangyu

    2016-06-01

    The use of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of pomalidomide after failure of lenalidomide and (or) bortezomib. We searched published reports including pomalidomide, lenalidomide and (or) bortezomib. Seven reports were identified. Pomalidomide-based regimen was pomalidomide plus low-dose dexamethasone (POM + LoDEX). Six randomized controlled trials enrolling a total of 641 patients that evaluated the treatment effects of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma were included. Pooled results showed that the overall response rate (ORR) was 31% in the POM + LoDEX group. Analysis of heterogeneity showed very little (p = 0.997, I(2)  = 0%), suggesting that response rates of POM + LoDEX therapy were consistent across those included trials. Stable disease was achieved in 40% of 603 patients (heterogeneity: p = 0.980, I(2)  = 0%). In those >65 years, overall response was achieved in 32% of 71 patients (heterogeneity: p = 0.77, I(2)  = 0%). POM + LoDEX showed promising activity in the 95 patients with high-risk cytogenetic abnormalities: ORR was 27% (heterogeneity: p = 0.97, I(2)  = 0%). In the pooled analysis, toxicity consisted primarily of myelosuppression: Grade 3 or 4 neutropenia was seen in 53% (heterogeneity: p = 0.857, I(2)  = 0%). Pomalidomide may produce clinical benefits in patients who had shown refractory on prior lenalidomide and (or) bortezomib therapy. Moreover, elder patients and high-risk cytogenetic abnormalities were not negative predictors for pomalidomide response after lenalidomide and (or) bortezomib failure. Copyright © 2015 John Wiley & Sons, Ltd.

  11. The influence of proteasome inhibitor on the expression of cardiomyocytes damage markers after incubation with doxorubicin

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    Tereszkiewicz Sylwia

    2014-06-01

    Full Text Available The aim of the study was to verify the thesis that the cardiotoxic effects of doxorubicin are connected with activation of the ubiquitin - proteasome pathway followed by protein degradation. The expression of myocardial damage markers - fatty acid binding protein (H-FABP and brain natriuretic peptide (BNP was evaluated in rat fetal cardiomyocytes simultaneously treated with doxorubicin and the proteasome inhibitor - bortezomib. The level of H-FABP and BNP protein under the influence of doxorubicin was decreased below the detection threshold with unchanged (H-FABP or elevated (BNP mRNA expression level. Against the expectations, the inhibitor of proteasome did not abolish this effect. The observed abnormal expression of BNP and H-FABP protein after doxorubicin treatment makes their diagnostic significance in anthracycline cardiotoxicity questionable.

  12. Molecular mechanisms of bortezomib resistant adenocarcinoma cells.

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    Erika Suzuki

    Full Text Available Bortezomib (Velcade™ is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM. Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.

  13. Safety and effectiveness of low-dose lenalidomide therapy for multiple myeloma complicated with bortezomib-associated interstitial pneumonia.

    Science.gov (United States)

    Nagamachi, Yasuhiro; Yamauchi, Naofumi; Muramatsu, Hirohito; Okamoto, Tetsuro; Inomata, Hidetoshi; Nozawa, Eri; Koyama, Ryuzo; Ihara, Koji; Nishisato, Takuji; Yamada, Hideyuki; Yano, Tomohiro; Tanaka, Shingo; Ono, Kaoru; Kikuchi, Shohei; Kato, Junji

    2013-05-01

    A 78-year-old woman was diagnosed with multiple myeloma (MM: IgG κ type, stage IIIA, ISS III) at a nearby hospital in August 2010. High-dose dexamethasone therapy was ineffective, and she was treated with 2 courses of bortezomib. She was referred to our hospital with back pain and dyspnea in November. She was diagnosed with interstitial pneumonia (IP) and improved rapidly with steroid pulse therapy. Because the involvement of bortezomib was suspected in IP, lenalidomide therapy was selected for MM. Lenalidomide (15 mg) was administered for 2 courses. The patient achieved a PR and the treatment is still ongoing with a good response. According to the interim report on PMS (post-marketing surveillance), 3 of the 1,177 patients treated with lenalidomide developed IP. The dose level was 25 mg in 2 cases and 10 mg in 1 case. The outcomes of these patients were death in 1 case, not recovered in 1 case, and unknown in 1 case. When lenalidomide is used to treat bortezomib-induced IP, there are no rules or regulations about its dose level. In the present case, the dose of lenalidomide (15 mg) was based on the retreatment dose after bone marrow suppression. Low-dose lenalidomide therapy was effective and safe against MM with a bortezomib-associated lung disorder.

  14. Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine

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    India and Ukraine Haemato-oncology Group

    2016-11-01

    Full Text Available Novel treatment strategies have remarkably improved the multiple myeloma (MM patients’ survival, with associated increased costs.A joint panel meet of international experts from India and Ukraine was held in New Delhi on 19th May 2016 focusing on: MM management, bortezomib role, unmet medical needs, and current challenges.The healthcare system for oncology in India is majorly private versus government-based in Ukraine. In India, electrophoresis, serum-free light chain assays, bone marrow tests, and X-rays are available modes of diagnosis. Despite of the numerous cancer centers and stem cell transplant centers, most patients do not prefer transplant owing to its high-cost and social stigma. Majority of the patients are treated with bortezomib or lenalidomide-based regimens. Most patients buy drug themselves. The expanding generic drugs market is a ray of hope for the affordable drugs.In Ukraine, immuno-fixation, bone-marrow analysis, and magnetic-resonance-imaging are common diagnostic modalities. Due to high-cost, only few patients undergo transplant. Bortezomib-based regimens are preferred in most of the patients, however usage is limited due to high costs and lack of funds. Thalidomide-based regimens are used for maintenance therapy due to affordability. In case of relapsed MM, bortezomib is preferred in triple therapy, however more affordable option is cyclophosphamide, thalidomide, and dexamethasone (CTD. Issues such as cost containment, common treatment strategies, enhanced collaboration, and improved healthcare access need immediate attention. High-quality generics access will improve outcomes and support healthcare cost containment. Pharmacoeconomic studies and head-to-head trials are warranted to determine the cost-effectiveness and benefit of novel therapies in MM.

  15. Retrospective study comparing low-dose versus standard dose of bortezomib in patients with multiple myeloma

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    Marcela Espinoza Zelada

    2015-03-01

    Full Text Available INTRODUCTION Bortezomib is a selective inhibitor of the proteosoma that is used in multiple myeloma. In combination with other antineoplastic drugs, it has a well-documented impact in progression-free survival rates and overall survival rates with standard doses (1.3-1.5 mg/m2. However, up to 88% of patients on standard doses have unwanted side effects (neutropenia, neuropathy or anemia. Standard dose (1.3 mg/m2 is used in almost all patients and low dose (0.7-0.8 mg/m2 is reserved for patients with kidney disease and neuropathy. OBJECTIVE We aim to describe clinical, cytological, and cytometric outcomes, as well as overall survival and side effects of low dose versus standard dose of bortezomib in our institution. METHODS Retrospective, descriptive study based on data recovered from clinical charts of 48 multiple myeloma patients treated in our hospital between 2011 and 2013. We included data on age, gender, type of multiple myeloma, serum albumin, serum creatinine, beta 2 microglobulin, calcemia, imaging studies, disease stage, pre-and post-therapy bone marrow studies, adverse events and rate of progression. We also recorded events like date of death or of the last medical appointment. RESULTS Forty-eight multiple myeloma patients were treated with bortezomib-cyclophosphamide-dexamethasone. Twenty-one patients received low dose and 27 patients were treated with the standard dose. No statistical differences between the two groups were found for clinical response (p=0.6, cytological response (p=0.28, flow cytometric response (p= 0.3, rate of adverse effects and overall survival rates. CONCLUSION This retrospective analysis suggests that lower doses of bortezomib have similar effects in disease control measured by flow cytometry and cytology compared to standard doses in multiple myeloma patients.

  16. Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

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    Tatsuro Joh

    2009-10-01

    Full Text Available We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m2, the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m2/day on days 1–4, vincristine 0.4 mg/m2/day on days 1–4, doxorubicin 10 mg/m2/day on days 1–4, cyclophosphamide 750 mg/m2/day on day 6, and prednisolone 60 mg/m2/day on days 1–6. Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.

  17. Dexamethasone suppression test

    Science.gov (United States)

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

  18. Bortezomib in the management of multiple myeloma

    Directory of Open Access Journals (Sweden)

    Jacob P Laubach

    2009-09-01

    Full Text Available Jacob P Laubach, Constantine S Mitsiades, Teru Hideshima, Robert Schlossman, Dharminder Chauhan, Nikhil Munshi, Irene Ghobrial, Nicole Carreau, Kenneth C Anderson, Paul G RichardsonDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USAAbstract: Multiple myeloma (MM is a B-cell malignancy characterized by clonal expansion of plasma cells within the bone marrow, the presence of a serum and/or urine monoclonal protein, lytic bone lesions, and anemia. On a cellular level, the disease is characterized by complex interactions between tumor cells and the surrounding bone marrow microenvironment. Understanding of the relationship between malignant plasma cells and the microenvironment has sparked ongoing efforts to develop targeted therapeutic agents for treatment of this disease. The successful development of the first-in-class small-molecule proteasome inhibitor bortezomib occurred as a result of these efforts. This review focuses on the rationale for bortezomib therapy in the treatment of patients with newly diagnosed and relapsed MM, important treatment-related side effects, and future directions for use of bortezomib and other, emerging proteasome inhibitors.Keywords: multiple myeloma, bortezomib, stem cell transplantation, peripheral neuropathy

  19. Why bortezomib cannot go with‘green’?

    Institute of Scientific and Technical Information of China (English)

    Li Jia; Feng-Ting Liu

    2013-01-01

    Eat more‘green’ or eat‘ifve a day’ is one of the most important healthy lifestyle behaviours in the 21 century. Aiming to ifght cancer effectively, more than half patients use vitamins or herbs concurrently with conventional anticancer treatment. Flavonoids or polyphenols existing in vegetables, fruits and green tea are common plant pigments with antioxidant properties and considered acting as cancer preventing or anti-cancer agents. Recently it was found that some lfavonoids and vitamin C in diet or supplements have antagonistic effect with the anti-cancer drug bortezomib. Bortezomib is a speciifc inhibitor for proteasome and is currently used for treatment of relapsed and refractory multiple myeloma. Despite its successful rates in treating multiple myeloma and other solid tumors, it is unable to kill leukemic cells in the blood. It was recently revealed that some lfavonoids and vitamin C present in green leaves and green teas in the blood can neutralize bortezomib by directly interaction between two chemicals. Here we summarize why dietary lfavonoids should be avoided in patients who take bortezomib as chemotherapeutic drug.

  20. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Viola Baradari; Michael H(o)pfner; Alexander Huether; Detlef Schuppan; Hans Scherübl

    2007-01-01

    AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin)or the novel anticancer agents sorafenib or bortezomib.METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes.Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH).Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.RESULTS: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore,additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multikinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.CONCLUSION: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new,targeted anticancer agents.

  1. Is Bortezomib a Rare Cause of Acute Pancreatitis?

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    Tevfik Solakoglu

    2013-11-01

    Full Text Available Recently we have read an interesting case with bortezomib-induced pancreatitis in JOP. Journal of the Pancreas (Online by Elouni et al. [1]. To the best of our knowledge, this was the first reported case of bortezomib-induced acute pancreatitis in the English literature. We know that drug-induced pancreatitis is rare and each year the list of drugs associated with acute pancreatitis increases. Bortezomib is a new drug which is selective and reversible proteasome inhibitor used for the treatment of patients with multiple myeloma [2]. Herein we present a case of acute pancreatitis induced by bortezomib.

  2. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma

    DEFF Research Database (Denmark)

    Mellqvist, Ulf-Henrik; Gimsing, Peter; Hjertner, Oyvind

    2013-01-01

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370...

  3. Bortezomib for refractory antibody-mediated cardiac allograft rejection.

    Science.gov (United States)

    Eckman, Peter M; Thorsgard, Marit; Maurer, David; Kim, Youngki; Alloway, Rita R; Woodle, E Steve

    2009-01-01

    This experience demonstrates that a bortezomib-based regimen provided effective therapy for late, refractory AMR in an adult heart transplant recipient and was well tolerated. This remarkably positive experience despite the refractory nature of the AMR episode argues strongly for continued evaluation of bortezomib use in this patient population.

  4. Bortezomib induces autophagic death in proliferating human endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Belloni, Daniela; Veschini, Lorenzo [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Foglieni, Chiara [Department of Cardiology, IRCCS H San Raffaele, Milan (Italy); Dell' Antonio, Giacomo [Department of Pathology, IRCCS H San Raffaele, Milan (Italy); Caligaris-Cappio, Federico [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Universita Vita-Salute IRCCS H San Raffaele, Milan (Italy); Ferrarini, Marina [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Ferrero, Elisabetta, E-mail: elisabetta.ferrero@hsr.it [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy)

    2010-04-01

    The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

  5. Bortezomib Inpatient Prescribing Practices in Free-Standing Children's Hospitals in the United States.

    Directory of Open Access Journals (Sweden)

    Amanda M DiNofia

    Full Text Available This study is a pharmacoepidemiologic description of pediatric bortezomib use. Exposure was identified through billing codes in patients admitted to US children's hospitals that participated with the Pediatric Health Information System between 2004 and 2013. Associated information on underlying diseases, demographics, institutional use, mortality, and physician type was collected. Exposure to bortezomib was identified in 314 patients. Hematologist/Oncologists prescribed half of the bortezomib used. Use increased during the study period. Inpatient volume was positively correlated with bortezomib utilization. Bortezomib use in pediatrics is increasing for a variety of diseases. Variation in use exists across institutions. Further studies are needed to characterize bortezomib's efficacy in pediatric diseases.

  6. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy.

    Directory of Open Access Journals (Sweden)

    Adam Szulkin

    Full Text Available BACKGROUND: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit. MATERIALS AND METHODS: We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers. RESULTS: As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect. CONCLUSIONS: The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

  7. Bortezomib for the treatment of mantle cell lymphoma: an update.

    Science.gov (United States)

    Hambley, Bryan; Caimi, Paolo F; William, Basem M

    2016-08-01

    Bortezomib is a first in class proteasome inhibitor, initially approved by the US Food and Drug Administration for the treatment of plasma cell myeloma. Bortezomib has been approved for the treatment of relapsed and refractory mantle cell lymphoma (MCL) and, more recently, in the upfront setting as well. Treatment algorithms for MCL have rapidly evolved over the past two decades, and the optimal regimen remains to be defined. The choice of treatment regimen is based on disease risk stratification models, the expected toxicity of antineoplastic agents, the perceived patient ability to tolerate the planned treatments and the availability of novel agents. As new drugs with novel mechanisms of action and variable toxicity profiles come into use, treatment decisions for a given patient have become increasingly complex. This article provides an overview of the evolving use of bortezomib in the rapidly changing management landscape of MCL.

  8. ABT-737 synergizes with Bortezomib to kill melanoma cells

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    Steven N. Reuland

    2012-02-01

    The BH3 mimetic ABT-737 is a potent inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w. The Bcl-2 family modulates sensitivity to anticancer drugs in many cancers, including melanomas. In this study, we examined whether ABT-737 is effective in killing melanoma cells either alone or in combination with a proteasome inhibitor already in clinical use (Bortezomib in vitro and in vivo, and further evaluated the mechanisms of action. Results showed that ABT-737 alone induced modest cytotoxicity in melanoma cells, but only at higher doses. Knock-down of the anti-apoptotic proteins Bcl-2, Bcl-XL, or Mcl-1 with siRNAs demonstrated that Mcl-1 is the critical mediator of melanoma's resistance to ABT-737 treatment. However, ABT-737 displayed strong synergistic lethality when combined with Bortezomib. Immunoblot analyses demonstrated that Bortezomib increased expression of Noxa, a pro-apoptotic Bcl-2 member that antagonizes Mcl-1. Additionally, siRNA-mediated inhibition of Noxa expression protected melanoma cells from cytotoxicity induced by the combination treatment. These results demonstrate that Bortezomib synergizes with ABT-737 by neutralizing Mcl-1's function via increased levels of Noxa. In a xenograft mouse model, although drug doses were limited due to toxicity, ABT-737 or Bortezomib slowed melanoma tumor growth compared to the control, and the drug combination significantly decreased growth compared to either drug alone. These data imply that less toxic drugs fulfilling a function similar to Bortezomib to neutralize Mcl-1 are promising candidates for combination with ABT-737 for treating melanomas.

  9. Doxorubicin-induced ovarian toxicity

    Directory of Open Access Journals (Sweden)

    Rizel Shulamith

    2010-03-01

    Full Text Available Abstract Background Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries. Methods Female mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin. Results A single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment. Conclusions Our results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.

  10. Trypanocidal activity of the proteasome inhibitor and anti-cancer drug bortezomib

    Directory of Open Access Journals (Sweden)

    Wang Xia

    2009-07-01

    Full Text Available Abstract The proteasome inhibitor and anti-cancer drug bortezomib was tested for in vitro activity against bloodstream forms of Trypanosoma brucei. The concentrations of bortezomib required to reduce the growth rate by 50% and to kill all trypanosomes were 3.3 nM and 10 nM, respectively. In addition, bortezomib was 10 times more toxic to trypanosomes than to human HL-60 cells. Moreover, exposure of trypanosomes to 10 nM bortezomib for 16 h was enough to kill 90% of the parasites following incubation in fresh medium. However, proteasomal peptidase activities of trypanosomes exposed to bortezomib were only inhibited by 10% and 30% indicating that the proteasome is not the main target of the drug. The results suggest that bortezomib may be useful as drug for the treatment of human African trypanosomiasis.

  11. Chalazia development in multiple myeloma: a new complication associated with bortezomib therapy

    Directory of Open Access Journals (Sweden)

    Charles Yun

    2015-06-01

    Full Text Available Multiple myeloma (MM is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia − which caused intolerable discomfort − started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia.

  12. Synthesis and Characterization of Organic Impurities in Bortezomib Anhydride Produced by a Convergent Technology

    Science.gov (United States)

    Ivanov, Andrey S.; Shishkov, Sergey V.; Zhalnina, Anna A.

    2012-01-01

    A profile of impurities in bortezomib anhydride, produced by a recently developed convergent technology, has been characterized. HPLC-MS analysis of the drug essence revealed three impurities: an epimer of bortezomib, resulting from partial racemization of l-phenylalanine’s stereogenic center during the chemical synthesis, and two epimeric products of oxidative degradation of bortezomib, in which boron is replaced by the OH group. The impurities were obtained by chemical synthesis and characterized by physical methods. PMID:22396904

  13. Differential impact of bortezomib on HL-60 and K562 cells.

    Science.gov (United States)

    Kliková, Katarína; Štefaniková, Andrea; Pilchová, Ivana; Hatok, Jozef; Chudý, Peter; Chudej, Juraj; Dobrota, Dušan; Račay, Peter

    2015-01-01

    Bortezomib (PS-341, or Velcade), reversible inhibitor of 20S proteasome approved for the treatment of multiple myeloma and mantle cell lymphoma, exhibited a cytotoxic effect toward other malignancies including leukaemia. In this study, we have documented that incubation of both HL-60 and K562 leukaemia cells with nanomolar concentrations of bortezomib is associated with the death of HL-60 cells observed within 24 hours of incubation with bortezomib and the death of K562 cells that were observed after 72 hours of incubation with bortezomib. The relative resistance of K562 cells to bortezomib correlated well with significantly higher expression of HSP27, HSP70, HSP90α, HSP90β and GRP75 in these cells. Incubation of both HL-60 and K562 cells with bortezomib induced a cleavage of HSP90β as well as expression of HSP70 and HSP90β but bortezomib did not affect levels of HSP27, HSP90α, GRP75 and GRP78. The death of both types of cells was accompanied with proteolytic activation of caspase 3 that was observed in HL-60 cells and proteolytic degradation of procaspase 3 in K562 cells. Our study has also pointed to essential role of caspase 8 in bortezomib-induced cleavage of HSP90β in both HL-60 and K562 cells. Finally, we have shown that bortezomib induced activation of caspase 9/caspase 3 axis in HL-60 cells, while the mechanism of death of K562 cells remains unknown.

  14. Dexamethasone for pain after outpatient shoulder surgery

    DEFF Research Database (Denmark)

    Bjørnholdt, K. T.; Mønsted, P. N.; Søballe, Kjeld

    2014-01-01

    Background Dexamethasone has analgesic properties when given intravenously before surgery, but the optimal dose has not been determined. We hypothesised that a dose of 40 mg dexamethasone would improve analgesia after outpatient shoulder surgery compared with 8 mg. Methods A randomised, double...... a dose–response relationship, increasing the dexamethasone dose from 8 to 40 mg did not improve analgesia significantly after outpatient shoulder surgery....

  15. Herpes zoster in multiple myeloma patients during bortezomib treatment

    Directory of Open Access Journals (Sweden)

    I. N. Nazarova

    2011-01-01

    Full Text Available Recent advances in multiple myeloma (MM treatment associated with new drug use including bortezomib. Experiences in wide ambul atory drug use confirm therapy success for this serious disease, but at the same time reveals the most common side effects. One of th e most significant is the reactivation of Herpes zoster , which leads to decrease MM therapy results because of inability to perform standard therapy in these patients. Literature data and own experiences about reactivation of Herpes zoster during bortezomib therapy as monothe rapy and in combination, which varies from 7 to 34% according to different authors and 25% of own experiences, is presented. Treatment and preventive schedule of this complication are shown.

  16. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.

    Science.gov (United States)

    Palumbo, Antonio; Ambrosini, Maria Teresa; Benevolo, Giulia; Pregno, Patrizia; Pescosta, Norbert; Callea, Vincenzo; Cangialosi, Clotilde; Caravita, Tommaso; Morabito, Fortunato; Musto, Pellegrino; Bringhen, Sara; Falco, Patrizia; Avonto, Ilaria; Cavallo, Federica; Boccadoro, Mario

    2007-04-01

    In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

  17. A phase I study of bortezomib, etoposide and carboplatin in patients with advanced solid tumors refractory to standard therapy

    NARCIS (Netherlands)

    Lieu, Christopher; Chow, Laura; Pierson, A. Scott; Eckhardt, S. Gail; O'Bryant, Cindy L.; Morrow, Mark; Tran, Zung Vu; Wright, John J.; Gore, Lia

    2009-01-01

    Purpose: To evaluate the toxicity, pharmacological, and biological properties of the combination of bortezomib, etoposide, and carboplatin in adults with advanced solid malignancies. Patients and methods: Patients received escalating doses of bortezomib, etoposide, and carboplatin every 21 days. Sur

  18. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.

    Science.gov (United States)

    Zheng, H; Xiao, W H; Bennett, G J

    2012-12-01

    Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-L-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts.

  19. Guillain Barré Syndrome in a multiple myeloma patient after the first course of bortezomib therapy: A case report

    OpenAIRE

    2015-01-01

    Bortezomib is approved for treating relapsed multiple myeloma (MM) and mantle cell lymphoma, and clinical evidence has shown complete clinical responses in MM patients. Peripheral neuropathy is one of the most common adverse effects of bortezomib. However, rare evidence has shown that bortezomib is associated with Guillain-Barré syndrome (GBS). In the present study, a case of GBS is reported in an MM patient finishing the first course of bortezomib therapy. Based on a bone marrow cell examina...

  20. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

    Science.gov (United States)

    Kuhn, Deborah J; Berkova, Zuzana; Jones, Richard J; Woessner, Richard; Bjorklund, Chad C; Ma, Wencai; Davis, R Eric; Lin, Pei; Wang, Hua; Madden, Timothy L; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Orlowski, Robert Z

    2012-10-18

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

  1. Compound list: dexamethasone [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available dexamethasone DEX 00153 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/dexam...ethasone.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/dexamethasone.Rat.in_vivo.Liver.Single.zip ...

  2. Doxorubicin as an Antioxidant: Maintenance of Myocardial Levels of Lycopene under Doxorubicin Treatment

    Science.gov (United States)

    The mechanism of doxorubicin-induced cardiotoxicity remains controversial. Wistar-rats (n=96) were randomly assigned to either a control (C), Lycopene (L), Doxorubicin (D) or Doxorubicin + Lycopene (DL) group. The L and DL groups received lycopene (5 mg/Kg-body-wt/d by gavage) for 7 wks. The D and D...

  3. Combined effects of lapatinib and bortezomib in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and activity of bortezomib against lapatinib-resistant breast cancer cells.

    Science.gov (United States)

    Ma, Chuandong; Niu, Xiuqing; Luo, Jianmin; Shao, Zhimin; Shen, Kunwei

    2010-10-01

    Lapatinib and bortezomib are highly active against breast cancer cells. Breast cancer patients who initially respond to lapatinib may eventually manifest acquired resistance to this treatment. Thus, the identification of novel agents that may prevent or delay the development of acquired resistance to lapatinib is critical. In the current study, we show that the combination of lapatinib and bortezomib results in a synergistic growth inhibition in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and that the combination enhances apoptosis of SK-BR-3 cells. Importantly, we found that the combination of lapatinib plus bortezomib more effectively blocked activation of the HER2 pathway in SK-BR-3 cells, compared with monotherapy. In addition, we established a model of acquired resistance to lapatinib by chronically challenging SK-BR-3 breast cancer cells with increasing concentrations of lapatinib. Here, we showed that bortezomib notably induced apoptosis of lapatinib-resistant SK-BR-3 pools and further inhibited HER2 signaling in the resistant cells. Taken together, the current data indicate a synergistic interaction between lapatinib and bortezomib in HER2-overexpressing breast cancer cells and provide the rationale for the clinical evaluation of these two noncross-resistant targeted therapies. The combination of lapatinib and bortezomib may be a potentially novel approach to prevent or delay the onset of acquired resistance to lapatinib in HER2-overxpressing/estrogen receptor (ER)-negative breast cancers.

  4. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma.

    Science.gov (United States)

    Dimopoulos, Meletios A; Palumbo, Antonio; Corradini, Paolo; Cavo, Michele; Delforge, Michel; Di Raimondo, Francesco; Weisel, Katja C; Oriol, Albert; Hansson, Markus; Vacca, Angelo; Blanchard, María Jesús; Goldschmidt, Hartmut; Doyen, Chantal; Kaiser, Martin; Petrini, Mario; Anttila, Pekka; Cafro, Anna Maria; Raymakers, Reinier; San-Miguel, Jesus; de Arriba, Felipe; Knop, Stefan; Röllig, Christoph; Ocio, Enrique M; Morgan, Gareth; Miller, Neil; Simcock, Mathew; Peluso, Teresa; Herring, Jennifer; Sternas, Lars; Zaki, Mohamed H; Moreau, Philippe

    2016-07-28

    Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789.

  5. Effect of bortezomib on migration and invasion in cervical carcinoma HeLa cell

    Institute of Scientific and Technical Information of China (English)

    Chong Shi; Guo-Bin Zhang; Shu-Wang Yin

    2015-01-01

    Objective: To explore the effect of bortezomib on migration and invasion of cervical carcinoma HeLa cell and specific molecular mechanism. Methods:The effect of bortezomib on the viability of HeLa cell was measured by MTT assay. The effect of bortezomib on cell migration and invasion was measured by Transwell assay and invasion experiment respectively. The activation of Akt/mTOR signaling pathway and expression level of MMP2, MMP9 were assayed by western blot. Results:MTT assay indicated bortezomib (2.5μM, 5μM, 10μM) could inhibit HeLa cell viability, and the inhibitory rate was highest at 48 h. Transwell assay and invasion experiment results showed that bortezomib inhibited HeLa cell migration and invasion. Western blotting assays presented bortezomib could suppress the phosphorylation of Akt and mTOR, and down-regulate the expression of MMP2 and MMP9. Conclusions:These results suggested bortezomib could inhibit migration and invasion in cervical carcinoma HeLa cell, which might be related to Akt/mTOR signal pathway.

  6. Bortezomib protects from varicose-like venous remodeling.

    Science.gov (United States)

    Pfisterer, Larissa; Meyer, Ralph; Feldner, Anja; Drews, Oliver; Hecker, Markus; Korff, Thomas

    2014-08-01

    Despite the high prevalence of venous diseases that are associated with and based on the structural reorganization of the venous vessel wall, not much is known about their mechanistic causes. In this context, we demonstrated that the quantity of myocardin, a transcriptional regulator of the contractile and quiescent smooth muscle cell phenotype, was diminished in proliferating synthetic venous smooth muscle cells (VSMCs) of human and mouse varicose veins by 51 and 60%, respectively. On the basis of the relevance of proteasomal activity for such phenotypic changes, we hypothesized that the observed VSMC activation is attenuated by the proteasome inhibitor bortezomib. This drug fully abolished VSMC proliferation and loss of myocardin in perfused mouse veins and blocked VSMC invasion in collagen gels by almost 80%. In line with this, topical transdermal treatment with bortezomib diminished VSMC proliferation by 80%, rescued 90% of VSMC myocardin abundance, and inhibited varicose-like venous remodeling by 67 to 72% in a mouse model. Collectively, our data indicate that the proteasome plays a pivotal role in VSMC phenotype changes during venous remodeling processes. Its inhibition protects from varicose-like vein remodeling in mice and may thus serve as a putative therapeutic strategy to treat human varicose veins.

  7. Data for a proteomic analysis of p53-independent induction of apoptosis by bortezomib

    OpenAIRE

    2014-01-01

    This data article contains data related to the research article entitled, “A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line” by Yerlikaya et al. [1]. The research article presented 2-DE and nLC-MS/MS based proteomic analysis of proteasome inhibitor bortezomib-induced changes in the expression of cellular proteins. The report showed that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24 h. In addition,...

  8. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

    Science.gov (United States)

    Hao, Gang; Yu, Yunli; Gu, Bingren; Xing, Yiwen; Xue, Man

    2015-01-01

    1. The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin. 2. Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats. 3. Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin. 4. Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart. 5. These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.

  9. Bortezomib partially protects the rat diaphragm from ventilator-induced diaphragm dysfunction

    NARCIS (Netherlands)

    Agten, A.; Maes, K.; Thomas, D.; Cielen, N.; Hees, H.W. van; Dekhuijzen, R.; Decramer, M.; Gayan-Ramirez, G.

    2012-01-01

    OBJECTIVE: Controlled mechanical ventilation leads to diaphragmatic contractile dysfunction and atrophy. Since proteolysis is enhanced in the diaphragm during controlled mechanical ventilation, we examined whether the administration of a proteasome inhibitor, bortezomib, would have a protective effe

  10. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

    Directory of Open Access Journals (Sweden)

    Kahl Brad S

    2008-05-01

    Full Text Available Abstract Background The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL. However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. Results Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA. Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231 and a breast carcinoma cell line (MDA-MB-468, the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10 displayed bortezomib-resistant constitutive NF-κB activity. Conclusion Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

  11. Compound list: doxorubicin [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available doxorubicin DOX 00149 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/doxorub...icin.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/doxorub...icin.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/doxorub...archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/doxorubicin.Rat.in_vivo.Liver.Repeat.zip ftp://ftp.bios...ciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/doxorubicin.Rat.in_vivo.Kidney.Single.zip

  12. BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma.

    Directory of Open Access Journals (Sweden)

    Sara Busacca

    Full Text Available Based on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM, two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10. However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.

  13. BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma.

    Science.gov (United States)

    Busacca, Sara; Chacko, Alex D; Klabatsa, Astero; Arthur, Kenneth; Sheaff, Michael; Barbone, Dario; Mutti, Luciano; Gunasekharan, Vignesh K; Gorski, Julia J; El-Tanani, Mohamed; Broaddus, V Courtney; Gaudino, Giovanni; Fennell, Dean A

    2013-01-01

    Based on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.

  14. Acupuncture for neuropathic pain due to bortezomib in a patient with multiple myeloma.

    Science.gov (United States)

    Mandıroğlu, Sibel; Cevik, Cemal; Aylı, Meltem

    2014-04-01

    Multiple myeloma (MM) is characterised by an increase in plasma cells, particularly in the bone marrow but also in other organs and systems, and with the abnormal production of immunoglobulin. Bortezomib, a current treatment option, inhibits angiogenesis by proteasome inhibition and is known to be effective in the treatment of MM. Peripheral neuropathy (PN) is a common dose-related side effect of bortezomib in patients with MM. We describe a case of PN due to bortezomib treatment which responded dramatically to acupuncture treatment, enabling his bortezomib treatment to continue. The patient was a 74-year-old man with pain, numbness, tingling and weakness in his hands and feet after 22 days of bortezomib treatment given by the haematology clinic. His neuropathic pain score was 8/10. There were no autonomic symptoms. Electroneurophysiological testing confirmed sensorimotor PN. Acupuncture treatment was planned as his neuropathic pain continued. Acupuncture was administered bilaterally to ST36, SP6 and LI4 15 times (every other day in the first five sessions and then twice a week). The numbness, tingling and pain symptoms substantially decreased after the first two treatments. After the 15th session acupuncture treatment was continued once a month. At the end of the sixth month the neuropathic pain assessment score was 0/10. There was no side effect of acupuncture treatment. Acupuncture seems promising as a complementary medical treatment for neuropathic pain from bortezomib-induced PN. Clinical studies involving more cases and electrophysiological studies are necessary to investigate the effectiveness of acupuncture.

  15. Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines

    OpenAIRE

    2014-01-01

    Background Despite encouraging results with the proteasome inhibitor bortezomib in the treatment of hematologic malignancies, emergence of resistance can limit its efficacy, hence calling for novel strategies to overcome bortezomib-resistance. We previously showed that bortezomib-resistant human leukemia cell lines expressed significantly lower levels of immunoproteasome at the expense of constitutive proteasomes, which harbored point mutations in exon 2 of the PSMB5 gene encoding the β5 subu...

  16. A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

    Science.gov (United States)

    YERLIKAYA, AZMI; ERDOĞAN, ELIF; OKUR, EMRAH; YERLIKAYA, ŞERIFE; SAVRAN, BIRCAN

    2016-01-01

    Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis. The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Subsequently, the present study determined the half maximal inhibitory concentration of intracellular calcium chelator BAPTA-AM (13.6 µM) on 4T1 cells. The combination effect of BAPTA-AM and bortezomib on the 4T1 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and WST-1 assays and an iCELLigence system. The results revealed that the combination of 10 nM bortezomib + 5 µM BAPTA-AM is more cytotoxic compared with monotherapies, including 10 nM bortezomib, 1 µM BAPTA-AM and 5 µM BAPTA-AM. In addition, the present results revealed that bortezomib + BAPTA-AM combination causes cell death through the induction of apoptosis. The present results also revealed that bortezomib + BAPTA-AM combination-induced apoptosis is associated with a clear increase in the phosphorylation of stress-activated protein kinase/Jun amino-terminal kinase SAPK/JNK. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment

  17. Pegylated liposomal doxorubicin in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Robert Strother

    2009-08-01

    Full Text Available Robert Strother1,2, Daniela Matei1–51Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.Keywords: ovarian cancer, doxorubicin, liposomes, pegylated liposomal doxorubicin

  18. Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling

    Science.gov (United States)

    Kram, David E.; Krasnow, Stephanie M.; Levasseur, Peter R.; Zhu, Xinxia; Stork, Linda C.

    2016-01-01

    Background Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. Methods We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children’s Oncology Group (COG) induction therapy from 2014–2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. Results In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. Conclusions Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance. PMID:27997622

  19. Intravitreal Dexamethasone Implant (Ozurdex in Coats' Disease

    Directory of Open Access Journals (Sweden)

    Ali Osman Saatci

    2013-09-01

    Full Text Available We injected an intravitreal dexamethasone implant in two eyes of 2 pediatric patients with Coats' disease in addition to other treatment modalities, such as intravitreal ranibizumab injection and indirect laser photocoagulation. In both eyes, intraocular pressure moderately rose in a temporary fashion. The dexamethasone implant seems to be a valuable addition to the armamentarium of treatment options for Coats' disease as it necessitates fewer injections than anti-VEGF injections and thereby fewer sessions of general anesthesia in the pediatric population.

  20. Effects of bortezomib in sensitizing human prostate cancer cell lines to NK-mediated cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Wei Hu; Rui-Rui Zheng; Hui-Xia Cui; Dan Yue; Yong Wang; You-Hong Jiang

    2012-01-01

    The proteasome inhibitor,bortezomib,has been demonstrated to sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.Natural killer (NK) cells represent potent antitumor effector cells.They also express TRAIL.Therefore.we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing,and have the same effect in human prostate cancer cell lines (LNCaP and DU145).We found that bortezomib strongly inhibits proliferation in both cell lines.Furthermore,compared with LNCaP cells,DU 145 cells are more sensitive to bortezomib-induced apoptosis.However,bortezomib is unable to sensitize these two cell lines to NK cell-mediated killing in short-term assays.In long-term assays,we found that killing mediated by activated NK cells following bortezornib treatment leads to greater antitumor effects than either treatment alone.In addition,treatment with bortezomib causes these cells to upregulate apoptosis-related mRNA as well as death receptors and downregulate the major histocompatibility class (MHC)-Ⅰ molecule on the cell surface of DU145 cells.In contrast,LNCaP cells are not sensitized by this treatment.Death receptors and the MHC-Ⅰ molecule did not change in this cell line.These-data suggest that bortezomib can be used to sensitize prostate cancer cells to NK cell-mediated killing and improve current cancer therapies.This therapeutic strategy may be more effective in patients with androgen-insensitive prostate cancer.

  1. Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Koschny, Ronald; Holland, Heidrun; Sykora, Jaromir; Erdal, Hande; Krupp, Wolfgang; Bauer, Manfred; Bockmuehl, Ulrike; Ahnert, Peter; Meixensberger, Jürgen; Stremmel, Wolfgang; Walczak, Henning; Ganten, Tom M

    2010-04-01

    TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.

  2. Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

    NARCIS (Netherlands)

    Fang, Jing; Rhyasen, Garrett; Bolanos, Lyndsey; Rasch, Christopher; Varney, Melinda; Wunderlich, Mark; Goyama, Susumu; Jansen, Gerrit; Cloos, Jacqueline; Rigolino, Carmela; Cortelezzi, Agostino; Mulloy, James C.; Oliva, Esther N.; Cuzzola, Maria; Starczynowski, Daniel T.

    2012-01-01

    Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces prote

  3. Therapeutic trial of metformin and bortezomib in a mouse model of tuberous sclerosis complex (TSC.

    Directory of Open Access Journals (Sweden)

    Neil Auricchio

    Full Text Available Tuberous sclerosis complex (TSC is a human genetic disorder in which loss of either TSC1 or TSC2 leads to development of hamartoma lesions, which can progress and be life-threatening or fatal. The TSC1/TSC2 protein complex regulates the state of activation of mTORC1. Tsc2(+/- mice develop renal cystadenoma lesions which grow progressively. Both bortezomib and metformin have been proposed as potential therapeutics in TSC. We examined the potential benefit of 1 month treatment with bortezomib, and 4 month treatment with metformin in Tsc2(+/- mice. Results were compared to vehicle treatment and treatment with the mTORC1 inhibitor rapamycin for 1 month. We used a quantitative tumor volume measurement on stained paraffin sections to assess the effect of these drugs. The median tumor volume per kidney was decreased by 99% in mice treated with rapamycin (p = 0.0004. In contrast, the median tumor volume per kidney was not significantly reduced for either the bortezomib cohort or the metformin cohort. Biochemical studies confirmed that bortezomib and metformin had their expected pharmacodynamic effects. We conclude that neither bortezomib nor metformin has significant benefit in this native Tsc2(+/- mouse model, which suggests limited benefit of these compounds in the treatment of TSC hamartomas and related lesions.

  4. Bortezomib and lenalidomide as front-line therapy for multiple myeloma.

    Science.gov (United States)

    Zou, Yandun; Lin, Mingzhen; Sheng, Zhixin; Niu, Shaona

    2014-09-01

    The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.

  5. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.

    Science.gov (United States)

    Bringhen, Sara; Larocca, Alessandra; Rossi, Davide; Cavalli, Maide; Genuardi, Mariella; Ria, Roberto; Gentili, Silvia; Patriarca, Francesca; Nozzoli, Chiara; Levi, Anna; Guglielmelli, Tommasina; Benevolo, Giulia; Callea, Vincenzo; Rizzo, Vincenzo; Cangialosi, Clotilde; Musto, Pellegrino; De Rosa, Luca; Liberati, Anna Marina; Grasso, Mariella; Falcone, Antonietta P; Evangelista, Andrea; Cavo, Michele; Gaidano, Gianluca; Boccadoro, Mario; Palumbo, Antonio

    2010-12-02

    In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

  6. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    Science.gov (United States)

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

  7. Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer

    NARCIS (Netherlands)

    de Wilt, Leonie H. A. M.; Jansen, Gerrit; Assaraf, Yehuda G.; van Meerloo, Johan; Cloos, Jacqueline; Schimmer, Aaron D.; Chan, Elena T.; Kirk, Christopher J.; Peters, Godefridus J.; Kruyt, Frank A. E.

    2012-01-01

    The proteasome inhibitor bortezomib, registered for Multiple Myeloma treatment, is currently explored for activity in solid tumors including non-small cell lung cancer (NSCLC). Here we studied the proteasome-based mechanisms underlying intrinsic and acquired bortezomib resistance in NSCLC cells. Var

  8. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma

    DEFF Research Database (Denmark)

    Dimopoulos, Meletios A; Oriol, Albert; Nahi, Hareth

    2016-01-01

    Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more ...

  9. Dexamethasone Therapy for Bacterial Meningitis: Better Never Than Late?

    Directory of Open Access Journals (Sweden)

    Susan M King

    1994-01-01

    Full Text Available A multicentre randomized controlled trial was conducted in children with bacterial meningitis using dexamethasone or placebo for four days within 24 h of starting antibiotics. Primary outcomes were hearing loss and neurological abnormalities at 12 months after meningitis. The dexamethasone (n=50 and placebo (n=51 groups were similar in age, severity of illness and etiological agent. Hearing loss occurred in 10% and 11% of the dexamethasone and placebo groups and neurological deficits occurred in 20% and 18% of patients, respectively. Duodenal perforation occurred in one dexamethasone-treated child. In conclusion, there was no significant benefit in those receiving dexamethasone. The lack of benefit may have been due to the delay in administration of dexamethasone (median delay of 11 h after antibiotics. Therefore, if dexamethasone is used for meningitis it should be given immediately with the antibiotic.

  10. Near-tetraploidy clone can evolve from a hyperdiploidy clone and cause resistance to lenalidomide and bortezomib in a multiple myeloma patient.

    Science.gov (United States)

    Yuan, Ji; Shah, Radhika; Kulharya, Anita; Ustun, Celalettin

    2010-07-01

    Aneuploidy is a very common prognostic factor in multiple myeloma (MM). Nonhyperdiploidy including near-tetraploidy (NT) is a poor prognostic indicator, compared to hyperdiploidy in multiple myeloma (MM). NT results from endoduplication of hypodiploidy. We report of a 55-year-old female patient diagnosed with advanced stage MM with hyperdiploidy and t(8;14)(q24;q32). The patient responded well to lenalidomide and dexamethasone for approximately 1 year. At the time of progression, she had become unresponsive to lenalidomide and subsequently bortezomib, and was found to have NT and loss of choromosome 13. There is another reported patient who had a possible interchange from nonhyperdiploidy to hyperdiploidy status, however, artifact could not be ruled out. To our knowledge, this is the first patient in whom evolution of an abnormal clone from a hyperdiploidy to a NT abnormal clone has been confirmed during the natural course of MM. This evolution is associated with resistance to novel drugs and poor prognosis in MM.

  11. Antiproliferative effects of Bortezomib in endothelial cells transformed by viral G protein-coupled receptor associated to Kaposi's sarcoma.

    Science.gov (United States)

    Suares, A; Mori Sequeiros Garcia, M; Paz, C; González-Pardo, V

    2017-04-01

    The Kaposi's Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. We have previously demonstrated that the proteasome inhibitor Bortezomib inhibits NF-κB pathway, which is required for tumor maintenance in endothelial cells that express vGPCR (vGPCR cells). In this work, we further investigated Bortezomib anti-proliferative mechanism of action. We demonstrated that Bortezomib decreases vGPCR cell number in a dose-dependent manner and induces cell morphology changes. Bortezomib decreases ERK1/2 phosphorylation whereas induces the accumulation of MKP-3 - a specific ERK1/2 MAP kinase phosphatase - in time and concentration dependent manner (1.5-32h; 0.25-1nM). The transcription factor FOXO1 is activated by dephosphorylation and regulates p21 expression. Here, we demonstrated that Bortezomib increases FOXO1 protein and decreases its phosphorylation in a concentration dependent manner (0.25-1nM). Bortezomib (0.5nM, 24h) also increase nuclear FOXO1 protein, in line with FOXO1 dephosphorylation induced by the drug. Consistent with FOXO1 dephosphorylation/activation, p21 mRNA expression is increased by Bortezomib in a MKP-3-dependent way. Bortezomib (0.5nM, 24h) also decreases VEGF, an ERK1/2 -dependent effect. It is concluded that in vGPCR cells, Bortezomib decreases ERK1/2 and FOXO1 phosphorylation through MKP-3 accumulation, leading ERK1/2 deactivation and FOXO1 activation respectively and, consequently, to cell proliferation inhibition, p21 induction and VEGF repression. Taken together, all these events contribute to the anti-tumoral effect of Bortezomib.

  12. The protective effects of the proteasome inhibitor bortezomib (velcade on ischemia-reperfusion injury in the rat retina.

    Directory of Open Access Journals (Sweden)

    Fang-Ting Chen

    Full Text Available PURPOSE: To evaluate the protective effects of bortezomib (Velcade on ischemia-reperfusion (IR injury in the rat retina. METHODS: The rats were randomized to receive treatment with saline, low-dose bortezomib (0.05 mg/kg, or high-dose bortezomib (0.2 mg/kg before the induction of IR injury. Electroretinography (ERG was used to assess functional changes in the retina. The expression of inflammatory mediators (iNOS, ICAM-1, MCP-1, TNF-α, anti-oxidant proteins (heme oxygenase, thioredoxin, peroxiredoxin, and pro-apoptotic proteins (p53, bax were quantified by PCR and western blot analysis. An immunofluorescence study was performed to detect the expression of iNOS, oxidative markers (nitrotyrosine, 8-OHdG, acrolein, NF-κB p65, and CD 68. Apoptosis of retinal cells was labeled with in situ TUNEL staining. Neu-N staining was performed in the flat-mounted retina to evaluate the density of retinal ganglion cells. RESULTS: ERG showed a decreased b-wave after IR injury, and pretreatment with bortezomib, especially the high dosage, reduced the functional impairment. Bortezomib successfully reduced the elevation of inflammatory mediators, anti-oxidant proteins, pro-apoptotic proteins and oxidative markers after IR insult in a dose-dependent manner. In a similar fashion, NF-κB p65- and CD 68-positive cells were decreased by bortezomib treatment. Retinal cell apoptosis in each layer was attenuated by bortezomib. The retinal ganglion cell density was markedly decreased in the saline and low-dose bortezomib groups but was not significantly changed in the high-dose bortezomib group. CONCLUSIONS: Bortezomib had a neuro-protective effect in retinal IR injury, possibly by inhibiting the activation of NF-κB related to IR insult and reducing the inflammatory signals and oxidative stress in the retina.

  13. Doxorubicin plus paclitaxel in advanced breast cancer

    DEFF Research Database (Denmark)

    Dombernowsky, P; Boesgaard, M; Andersen, E

    1997-01-01

    between administration of a short infusion of doxorubicin followed by a 3-hour infusion of paclitaxel was evaluated. Included were patients with metastatic breast cancer, who received doxorubicin 50 mg/m2 followed by paclitaxel 200 mg/m2 at intervals of 30 minutes, 4 hours, and 24 hours every 3 weeks......The combination of bolus doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as a 3-hour infusion is highly active in patients with metastatic breast cancer, but it has considerable cardiotoxicity. In this ongoing study, the potential effect of increasing the interval....... As of February 1997, 34 patients have been enrolled, two patients are too early to evaluate, and 13 are continuing treatment. The preliminary response rate is 69% (95% confidence interval, 50% to 84%), ranging from 60% to 80% within the three schedules. The main toxicities consisted of grade 3/4 neutropenia...

  14. Monoclonal gammopathy-associated pauci-immune extracapillary-proliferative glomerulonephritis successfully treated with bortezomib.

    Science.gov (United States)

    Grundmann, Franziska; Witthus, Marco; Göbel, Heike; Kisner, Tuelay; Siewert, Rainer; Benzing, Thomas; Kurschat, Christine E

    2013-06-01

    Extracapillary-proliferative glomerulonephritis is a rare complication of multiple myeloma. Partial remission of kidney involvement with cyclophosphamide therapy has previously been described. We report the case of a 60-year-old male patient diagnosed with rapidly progressive glomerulonephritis associated with IgG kappa monoclonal gammopathy. His kidney biopsy revealed pauci-immune extracapillary-proliferative glomerulonephritis without cryoglobulinaemia. Treatment with the proteasome inhibitor bortezomib induced rapid clinical and histological remission of his kidney disease. The patient's renal function remained stable on bortezomib maintenance therapy. Our findings suggest that bortezomib is a promising therapeutic approach to ameliorate severe kidney damage in monoclonal gammopathy- and myeloma-associated pauci-immune extracapillary-proliferative glomerulonephritis.

  15. The challenge of relapsed/refractory myeloma: An emerging role of bortezomib

    Directory of Open Access Journals (Sweden)

    Bhargav Vyasa

    2012-01-01

    Full Text Available The treatment of multiple myeloma (MM has undergone significant developments in recent years. The availability of the novel agents includes thalidomide and its analogs, proteasome inhibitors, arsenic trioxide, farnesyltransferase inhibitors 2-methoxyestradiol and lenalidomide has extended treatment options and has improved the outcome and quality of life of patients with MM. This review presents the totality of evidence through a systematic review that assessed the efficacy, safety or toxicity of bortezomib in patients with relapsed/refractory myeloma with or without concomitant complications. This review has precisely covered the role of bortezomib in patients with relapsed/refractory myeloma and not the newly detected populace.

  16. Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence.

    Science.gov (United States)

    Russo, Antonio; Fratto, Maria E; Bazan, Viviana; Schiró, Valentina; Agnese, Valentina; Cicero, Giuseppe; Vincenzi, Bruno; Tonini, Giuseppe; Santini, Daniele

    2007-12-01

    The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.

  17. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia

    DEFF Research Database (Denmark)

    Gudbrandsdottir, Sif; Birgens, Henrik Sverre; Frederiksen, Henrik

    2013-01-01

    In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding...... symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained...... response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007...

  18. An overview of doxorubicin formulations in cancer therapy.

    Science.gov (United States)

    Rivankar, Sangeeta

    2014-01-01

    The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical approval against malignancies including solid tumours, transplantable leukemias and lymphomas was Doxorubicin HCl. This review is aimed at providing an overview of doxorubicin in cancer therapy. Pegylated liposomal doxorubicin has a polyethylene glycol (PEG) layer around doxorubicin-containing liposome as the result of a process known as pegylation. Non-pegylated liposomal doxorubicin (NPLD) was developed to overcome the drawbacks associated with previous formulations. Nudoxa; (NPLD) with its unique drug delivery system offers the benefit of pegylated liposomal doxorubicin without hand foot syndrome as the major side effect. Future studies will be directed towards estimating the costs of treatment with the novel liposomal doxorubicin formulations in order to assess their widespread use and robustness in treating patients with cancer.

  19. Analgesic effects of dexamethasone in burn injury

    DEFF Research Database (Denmark)

    Werner, Mads U; Lassen, Birgit Vibeke; Kehlet, Henrik

    2002-01-01

    differences between treatments in regard to skin erythema (P >.8), thermal or mechanical thresholds (P >.2), thermal or mechanical pain response (P >.2), or mechanical secondary hyperalgesia (P >.2). Dexamethasone had no analgesic effects in normal skin. CONCLUSIONS: The study indicates that systemic...... administration of dexamethasone 2 hours before a burn injury does not reduce the inflammatory-mediated changes in quantitative sensory thresholds, pain perception, or skin erythema in humans....... injury was produced on the medial aspect of the nondominant calf (12.5 cm2, 47 degrees C for 7 minutes). Quantitative sensory testing included pain ratings to thermal and mechanical stimuli (visual analog scale [VAS]), assessments of thermal and mechanical detection thresholds, and areas of allodynia...

  20. A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis.

    Science.gov (United States)

    Chen, Shuang; Zhang, Yu; Zhou, Liang; Leng, Yun; Lin, Hui; Kmieciak, Maciej; Pei, Xin-Yan; Jones, Richard; Orlowski, Robert Z; Dai, Yun; Grant, Steven

    2014-10-23

    Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.

  1. Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Yamei; Wang, Lingxian; Wang, Lu; Wu, Xuefeng; Wu, Xudong [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Gu, Yanhong; Shu, Yongqian [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Sun, Yang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Shen, Yan, E-mail: shenyan@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China)

    2015-02-15

    Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SW872-S cells compared with its parental SW872 cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo. Treatment of cells with Jun-N-terminal kinase (JNK) inhibitor SP60015 or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. Bortezomib inhibited MDR1 expression and function more effectively in SW872-S cells than in SW872 cells, indicating that the increased cytotoxicity relies on the degree of proteasome inhibition. Furthermore, the pharmacological or genetic inhibition of sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2, which is highly expressed in SW872-S cells, resulted in partial reversal of cell growth inhibition and increase of MDR1 expression in bortezomib-treated SW872-S cells. These results show that bortezomib exhibits preferential cytotoxicity toward SW872-S cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma. - Highlights: • We compare the cytotoxicity of different drugs between SW872-S and SW872 cells. • Highly malignant liposarcoma cells SW872-S show hypersensitivity to bortezomib. • Apoptotic signaling is robustly enhanced in bortezomib-treated SW872-S cells. • Bortezomib has strong suppression on MDR1 expression and function in SW872-S cells. • Inhibition of SERCA2 protects SW872-S cells from bortezomib.

  2. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients

    DEFF Research Database (Denmark)

    Morabito, Fortunato; Bringhen, Sara; Larocca, Alessandra;

    2014-01-01

    Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty...

  3. Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial

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    Salzer Shanta

    2007-12-01

    Full Text Available Abstract Background COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. Methods Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days, in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. Results No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. Conclusion The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. Trial registration number NCT00290680.

  4. Data for a proteomic analysis of p53-independent induction of apoptosis by bortezomib

    Science.gov (United States)

    Yerlikaya, Azmi; Okur, Emrah; Tarık Baykal, Ahmet; Acılan, Ceyda; Boyacı, İhsan; Ulukaya, Engin

    2014-01-01

    This data article contains data related to the research article entitled, “A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line” by Yerlikaya et al. [1]. The research article presented 2-DE and nLC-MS/MS based proteomic analysis of proteasome inhibitor bortezomib-induced changes in the expression of cellular proteins. The report showed that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24 h. In addition, the report demonstrated that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The data here show for the first time the increased expressions of Card10, Dffb, Traf3 and Trp53bp2 in response to inhibition of the 26S proteasome. The information presented here also shows that both Traf1 and Xiap (a member of IAPs) are also downregulated simultaneously upon proteasomal inhibition. The increases in the level of Card10 and Trp53bp2 proteins were verified by Western blot analysis in response to varying concentrations of bortezomib for 24 h. PMID:26217687

  5. Data for a proteomic analysis of p53-independent induction of apoptosis by bortezomib

    Directory of Open Access Journals (Sweden)

    Azmi Yerlikaya

    2014-12-01

    Full Text Available This data article contains data related to the research article entitled, “A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line” by Yerlikaya et al. [1]. The research article presented 2-DE and nLC-MS/MS based proteomic analysis of proteasome inhibitor bortezomib-induced changes in the expression of cellular proteins. The report showed that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24 h. In addition, the report demonstrated that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The data here show for the first time the increased expressions of Card10, Dffb, Traf3 and Trp53bp2 in response to inhibition of the 26S proteasome. The information presented here also shows that both Traf1 and Xiap (a member of IAPs are also downregulated simultaneously upon proteasomal inhibition. The increases in the level of Card10 and Trp53bp2 proteins were verified by Western blot analysis in response to varying concentrations of bortezomib for 24 h.

  6. Bortezomib improves progression-free survival in multiple myeloma patients overexpressing preferentially expressed antigen of melanoma

    Institute of Scientific and Technical Information of China (English)

    Qin Yazhen; Lu Jin; Bao Li; Zhu Honghu; Li Jinlan; Li Lingdi; Lai Yueyun

    2014-01-01

    Background Significant efforts have been made to identify factors that differentiate patients treated with novel therapies,such as bortezomib in multiple myeloma (MM).The exact expression pattern and prognostic value of the cancer/testis antigen preferentially expressed antigen of melanoma (PRAME) in MM are unknown and were explored in this study.Methods The transcript level of PRAME was detected in bone marrow specimens from 100 newly diagnosed MM patients using real-time quantitative polymerase chain reaction,and the prognostic value of PRAME was determined through retrospective survival analysis.PRAME expression higher than the upper limit of normal bone marrow was defined as PRAME overexpression or PRAME (+).Results Sixty-two patients (62.0%) overexpressed PRAME.PRAME overexpression showed no prognostic significance to either overall survival (n=100) or progression-free survival (PFS,n=96,all P >0.05) of patients.The patients were also categorized according to regimens with or without bortezomib.PRAME overexpression tended to be associated with a lower two-year PFS rate in patients treated with non-bortezomib-containing regimens (53.5% vs.76.9%,P=0.071).By contrast,it was not associated with the two-year PFS rate in patients with bortezomib-containing regimens (77.5% vs.63.9%,P >0.05).When the patients were categorized into PRAME (+) and PRAME (-) groups,treatment with bortezomib-containing regimens predicted a higher two-year PFS rate in PRAME (+) patients (77.5% vs.53.5%,P=0.027) but showed no significant effect on two-year PFS rate in PRAME (-) patients (63.9% vs.76.9%,P >0.05).Conclusion PRAME overexpression might be an adverse prognostic factor of PFS in MM patients treated with non-bortezomib-containing regimens.Bortezomib improves PFS in patients overexpressing PRAME.

  7. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

    Science.gov (United States)

    Sivaraj, Dharshan; Green, Michael M; Li, Zhiguo; Sung, Anthony D; Sarantopoulos, Stefanie; Kang, Yubin; Long, Gwynn D; Horwitz, Mitchell E; Lopez, Richard D; Sullivan, Keith M; Rizzieri, David A; Chao, Nelson J; Gasparetto, Cristina

    2017-02-01

    Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m(2) once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an

  8. Synergistic Effect and Molecular Mechanism of Homoharringtonine and Bortezomib on SKM-1 Cell Apoptosis.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    Full Text Available Myelodysplastic syndromes (MDS are clonal marrow stem-cell disorders with a high risk of progression to acute myeloid leukemia (AML. Treatment options are limited and targeted therapies are not available for MDS. In the present study, we investigated the cytotoxicity and the molecular mechanism of Homoharringtonine (HHT and Bortezomib towards high-risk MDS cell line SKM-1 in vitro and the role of miR-3151 was first evaluated in SKM-1 cells.SKM-1 cells were treated with different concentrations of HHT or Bortezomib, and cell viability was analyzed with CCK-8 assay. The influence on cell proliferation, cell cycle distribution and the percentage of apoptosis cells were analyzed by flow cytometry. Calcusyn software was used to calculate combination index (CI values. Western blot was used to analysis phosphorylation of Akt and nuclear NF-κB protein expression in SKM-1 cells. Mature miR-3151 level and p53 protein level were detected after HHT or Bortezomib treatment. The cell proliferation and p53 protein level were reassessed in SKM-1 cells infected with lentivirus to overexpress miR-3151.Simultaneous exposure to HHT and Bortezomib (10.4:1 resulted in a significant reduction of cell proliferation in SKM-1 cells (P < 0.05. Cell cycle arrest at G0/G1 and G2/M phase was observed (P < 0.05. HHT and Bortezomib synergistically induced cell apoptosis by regulating members of caspase 9, caspase 3 and Bcl-2 family (P < 0.01. The mechanisms of the synergy involved Akt and NF-κB signaling pathway inhibition, downregulation of mature miR-3151 and increment of downstream p53 protein level. Overexpression of miR-3151 promoted cell proliferation and inhibited p53 protein expression in SKM-1 (P < 0.01.HHT and Bortezomib synergistically inhibit SKM-1 cell proliferation and induce apoptosis in vitro. Inhibition of Akt and NF-κB pathway signaling contribute to molecular mechanism of HHT and Bortezomib. miR-3151 abundance is implicated in SKM-1 cell viability, cell

  9. Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

    Directory of Open Access Journals (Sweden)

    Colpo Anna

    2010-10-01

    Full Text Available Abstract Background Glycogen Synthase Kinase-3 (GSK-3 α and β are two serine-threonine kinases controlling insulin, Wnt/β-catenin, NF-κB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK-3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3α and GSK-3β function in multiple myeloma (MM. Methods GSK-3 α and β expression and cellular localization were investigated by Western blot (WB and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 α and β isoforms. Survival signaling pathways were studied with WB analysis. Results GSK-3α and GSK-3β were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles: GSK-3β knock down decreased MM cell viability, while GSK-3α knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of β-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3α knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself. Conclusions These data suggest that in MM cells GSK-3α and β i play distinct roles in cell survival and ii modulate the sensitivity to proteasome inhibitors.

  10. Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis.

    Science.gov (United States)

    Dimopoulos, Meletios A; Roussou, Maria; Gavriatopoulou, Maria; Psimenou, Erasmia; Eleutherakis-Papaiakovou, Evangelos; Migkou, Magdalini; Matsouka, Charis; Mparmparousi, Despoina; Gika, Dimitra; Kafantari, Eftychia; Ziogas, Dimitrios; Fotiou, Despoina; Panagiotidis, Ioannis; Terpos, Evangelos; Kastritis, Efstathios

    2016-05-01

    Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)-based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib-treated patients with severe RF (eGFR dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11-724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis-independent had longer survival than those remaining on dialysis. In conclusion, VD-based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response.

  11. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment.

    Science.gov (United States)

    Morabito, Fortunato; Gentile, Massimo; Mazzone, Carla; Rossi, Davide; Di Raimondo, Francesco; Bringhen, Sara; Ria, Roberto; Offidani, Massimo; Patriarca, Francesca; Nozzoli, Chiara; Petrucci, Maria Teresa; Benevolo, Giulia; Vincelli, Iolanda; Guglielmelli, Tommasina; Grasso, Mariella; Marasca, Roberto; Baldini, Luca; Montefusco, Vittorio; Musto, Pellegrino; Cascavilla, Nicola; Majolino, Ignazio; Musolino, Caterina; Cavo, Michele; Boccadoro, Mario; Palumbo, Antonio

    2011-11-24

    We assessed efficacy, safety, and reversal of renal impairment (RI) in untreated patients with multiple myeloma given bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide (VMPT-VT) maintenance or bortezomib-melphalan-prednisone (VMP). Exclusion criteria included serum creatinine ≥ 2.5 mg/dL. In the VMPT-VT/VMP arms, severe RI (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min), moderate RI (eGFR 31-50 mL/min), and normal renal function (eGFR > 50 mL/min), were 6%/7.9%, 24.1%/24.9%, and 69.8%/67.2%, respectively. Statistically significant improvements in overall response rates and progression-free survival were observed in VMPT-VT versus VMP arms across renal cohorts, except in severe RI patients. In the VMPT group, severe RI reduced overall survival (OS). RI was reversed in 16/63 (25.4%) patients receiving VMPT-VT versus 31/77 (40.3%) receiving VMP. Multivariate analysis showed male sex (P = .022) and moderate RI (P = .003) significantly predicted RI recovery. VMP patients achieving renal response showed longer OS. In both arms, greater rates of severe hematologic adverse events were associated with RI (eGFR < 50 mL/min), however, therapy discontinuation rates were unaffected. VMPT-VT was superior to VMP for cases with normal renal function and moderate RI, whereas VMPT-VT failed to outperform VMP in patients with severe RI, although the relatively low number of cases analyzed preclude drawing definitive conclusions. VMPT-VT had no advantage in terms of RI reversal over VMP.

  12. Does dexamethasone have a perineural mechanism of action?

    DEFF Research Database (Denmark)

    Jæger, P; Grevstad, Jens Ulrik; Koscielniak-Nielsen, Z J

    2016-01-01

    BACKGROUND: Dexamethasone prolongs block duration. Whether this is achieved via a peripheral or a central mechanism of action is unknown. We hypothesized that perineural dexamethasone added as an adjuvant to ropivacaine prolongs block duration compared with ropivacaine alone, by a locally mediated...

  13. Oval pulsed high-dose dexamethasone for myositis

    NARCIS (Netherlands)

    Hoogendijk, JE; Wokke, JHJ; de Visser, M

    2000-01-01

    To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Sis patients responded. Side effects w

  14. Pegylated liposomal doxorubicin in ovarian cancer

    OpenAIRE

    Matei, Daniela

    2009-01-01

    Robert Strother1,2, Daniela Matei1–51Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Lip...

  15. Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

    DEFF Research Database (Denmark)

    Nijhof, I. S.; Groen, R. W. J.; Noort, W. A.;

    2015-01-01

    Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new...... with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. Experimental Design: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide...... or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Results: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from...

  16. Pilot study of Bortezomib for Patients with Imatinib-Refractory Chronic Myeloid Leukemia in Chronic or Accelerated Phase

    Science.gov (United States)

    Santos, Fabio P S; Kantarjian, Hagop; McConkey, David; O'Brien, Susan; Faderl, Stefan; Borthakur, Gautam; Ferrajoli, Alessandra; Wright, John; Cortes, Jorge

    2015-01-01

    Background Proteasome inhibitors are anticancer compounds that disrupt the proteolytic activity of the proteasome and lead to tumor cell growth arrest and apoptosis. Bortezomib is a proteasome inhibitor that is currently approved for use in multiple myeloma and mantle cell lymphoma. It induces apoptosis of chronic myeloid leukemia (CML) cells in vitro, but the activity of bortezomib in patients with imatinib-resistant CML is unknown. Methods We conducted a pilot trial to evaluate the activity of single agent bortezomib in CML. Seven patients with imatinib-refractory CML were treated with bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8 and 11 every 3 weeks. Results The median number of cycles received was 2. No patient had a hematologic or cytogenetic response. Three patients had a temporary decrease in basophil counts associated with therapy with bortezomib. Six patients developed grade 3-4 nonhematological toxicities. Conclusion Bortezomib had minimal efficacy and considerable toxicity in patients with imatinib-refractory CML. Further studies should focus on alternative approaches to employ proteasome inhibitors in the treatment of CML, such as in combination with tyrosine kinase inhibitors or as a strategy to eradicate leukemic stem cells. PMID:21816374

  17. Atg3 Overexpression Enhances Bortezomib-Induced Cell Death in SKM-1 Cell.

    Directory of Open Access Journals (Sweden)

    Lin Zhuang

    Full Text Available Myelodysplastic syndrome (MDS is a group of heterogeneous hematopoietic stem cell malignancies with a high risk of transformation into acute myeloid leukemia (AML. Clonal evolutions are significantly associated with transformation to AML. According to a gene expression microarray, atg3 is downregulated in MDS patients progressing to leukemia, but less is known about the function of Atg3 in the survival and death of MSD/AML cells. Moreover, the role of autophagy as a result of bortezomib treatment is controversial. The current study was designed to investigate the function of Atg3 in SKM-1 cells and to study the effect of Atg3 on cell viability and cell death following bortezomib treatment.Four leukemia cell lines (SKM-1, THP-1, NB4 and K562 and two healthy patients' bone marrow cells were analyzed for Atg3 expression via qRT-PCR and Western blotting analysis. The role of Atg3 in SKM-1 cell survival and cell death was analyzed by CCK-8 assay, trypan blue exclusion assay, DAPI staining and Annexin V/PI dual staining with or without bortezomib treatment. Western blotting analysis was used to detect proteins in autophagic and caspase signaling pathways. Electron microscopy was used to observe ultrastructural changes after Atg3 overexpression.Downregulation of Atg3 expression was detected in four leukemia cell lines compared with healthy bone marrow cells. Atg3 mRNA was significantly decreased in MDS patients' bone marrow cells. Overexpression of Atg3 in SKM-1 cells resulted in AKT-mTOR-dependent autophagy, a significant reduction in cell proliferation and increased cell death, which could be overcome by the autophagy inhibitor 3-MA. SKM-1 cells overexpressing Atg3 were hypersensitive to bortezomib treatment at different concentrations via autophagic cell death and enhanced sensitivity to apoptosis in the SKM-1 cell line. Following treatment with 3-MA, the sensitivity of Atg3-overexpressing cells to bortezomib treatment was reduced. Atg3 knockdown

  18. A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

    OpenAIRE

    2016-01-01

    Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study...

  19. Pharmacovigilance of patients with multiple myeloma being treated with bortezomib and/or thalidomide

    Directory of Open Access Journals (Sweden)

    T.B.M. Castro

    2016-01-01

    Full Text Available In order to evaluate the main adverse effects of drug protocols using bortezomib and/or thalidomide for the treatment of multiple myeloma, we conducted a prospective study. Data were collected through interviews, clinical observation, and from hospital records. A total of 59 patients were included. There was a predominance of females, 36 (61% vs 23 (39% males, and of whites, 49 (83.1% vs 10 (16.9% blacks. Age ranged from 40 to 94 years, with a median of 65 years (SD=11.6. Regarding staging at diagnosis, 27 (45.7% patients were in stage III-A, with 12 (20.3% patients having serum creatinine ≥2 mg/dL. The main adverse effects in the bortezomib treatment group (n=40 were: neutropenia (42.5%, diarrhea (47.5%, and peripheral neuropathy in 60% of cases, with no difference between the iv (n=26 and sc (n=14 administration routes (P=0.343. In the group treated with thalidomide (n=19, 31.6% had neutropenia, 47.4% constipation, and 68.4% peripheral neuropathy. Neutropenia was associated with the use of alkylating agents (P=0.038. Of the 3 patients who received bortezomib in combination with thalidomide, only 1 presented peripheral neuropathy (33.3%. Peripheral neuropathy was the main adverse effect of the protocols that used bortezomib or thalidomide, with a higher risk of neutropenia in those using alkylating agents. Improving the identification of adverse effects is critical in multiple myeloma patient care, as the patient shows improvements during treatment, and requires a rational and safe use of medicines.

  20. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

    Science.gov (United States)

    Dimopoulos, Meletios A; Oriol, Albert; Nahi, Hareth; San-Miguel, Jesus; Bahlis, Nizar J; Usmani, Saad Z; Rabin, Neil; Orlowski, Robert Z; Komarnicki, Mieczyslaw; Suzuki, Kenshi; Plesner, Torben; Yoon, Sung-Soo; Ben Yehuda, Dina; Richardson, Paul G; Goldschmidt, Hartmut; Reece, Donna; Lisby, Steen; Khokhar, Nushmia Z; O'Rourke, Lisa; Chiu, Christopher; Qin, Xiang; Guckert, Mary; Ahmadi, Tahamtan; Moreau, Philippe

    2016-10-06

    Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10(5) white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. Conclusions The addition of daratumumab to lenalidomide and

  1. Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.

    Science.gov (United States)

    Pédeboscq, Stéphane; L'Azou, Béatrice; Passagne, Isabelle; De Giorgi, Francesca; Ichas, François; Pometan, Jean-Paul; Cambar, Jean

    2008-01-01

    Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.

  2. Treatment of multiple myeloma: thalidomide-, bortezomib-, and lenalidomide-induced peripheral neuropathy.

    Science.gov (United States)

    Koeppen, Susanne

    2014-01-01

    Over the last 15 years, substantial progress has been made in the treatment of patients with multiple myeloma (MM). New chemotherapeutic options with the immunomodulatory drugs thalidomide and lenalidomide and with the proteasome inhibitor bortezomib have increased the response rates before and after autologous hematopoietic stem cell transplantation (ASCT). Incorporation of the novel agents into the treatment of newly diagnosed MM and at relapse is now standard of care also for patients with MM not eligible for ASCT. However, the use of thalidomide and bortezomib is frequently associated with a dose-limiting peripheral neuropathy. In order to take full advantage of the therapeutic potential, a risk assessment for neurotoxicity is needed on a case-by-case basis. This assessment includes pre-existing neurological symptoms due to the MM, any comorbidities, and past or planned treatment regimens. The aim is to achieve maximum efficacy while minimizing the risk of developing chemotherapy-induced polyneuropathy (CIPN). This requires a neurological evaluation of the patient at regular intervals, the implementation of preventive measures, and the development of validated therapeutic strategies for emerging neurotoxic side effects. This review focuses on the incidence, prevention, and management of peripheral neurotoxicity due to thalidomide, bortezomib, and lenalidomide in the treatment of MM.

  3. Phase I Trial Using the Proteasome Inhibitor Bortezomib and Concurrent Chemoradiotherapy for Head-and-Neck Malignancies

    Energy Technology Data Exchange (ETDEWEB)

    Kubicek, Gregory J. [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Axelrod, Rita S. [Department of Medical Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Machtay, Mitchell [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH (United States); Ahn, Peter H.; Anne, Pramila R. [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Fogh, Shannon [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA (United States); Cognetti, David [Department of Otolaryngology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Myers, Thomas J. [EMD Serono, Rockland, MA (United States); Curran, Walter J. [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Dicker, Adam P., E-mail: Adam.dicker@jeffersonhospital.org [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States)

    2012-07-15

    Purpose: Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC. Methods and Materials: Eligible patients received cisplatin once weekly at 30 mg/m{sup 2} per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m{sup 2} and escalation levels of 1.0 and 1.3 mg/m{sup 2}. Dose escalation was performed only after assessment to rule out any dose-limiting toxicity. Results: We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m{sup 2} (7 patients), 1.0 mg/m{sup 2} (10 patients), and 1.3 mg/m{sup 2} (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients). Conclusion: Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m{sup 2} in patients previously treated for HNC and 1.3 mg/m{sup 2} in radiation-naive patients.

  4. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease.

    Science.gov (United States)

    Herrera, Alex F; Kim, Haesook T; Bindra, Bhavjot; Jones, Kyle T; Alyea, Edwin P; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Nikiforow, Sarah; Blazar, Bruce R; Ritz, Jerome; Antin, Joseph H; Soiffer, Robert J; Koreth, John

    2014-11-01

    Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated.

  5. Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma.

    Science.gov (United States)

    Huang, Shang-Yi; Lin, Chung-Wu; Lin, Hsiu-Hsia; Yao, Ming; Tang, Jih-Luh; Wu, Shang-Ju; Chen, Yao-Chang; Lu, Hsiao-Yun; Hou, Hsin-An; Chen, Chien-Yuan; Chou, Wen-Chien; Tsay, Woei; Chou, Sheng-Je; Tien, Hwei-Fang

    2014-08-01

    Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0-8) and a score ≥4.5 was used for CRBN positivity (CRBN(+)) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN(+) NDMM patients, CRBN(-) NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN(+) patients than CRBN(-) patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN(+) for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN(+) was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.

  6. Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells

    DEFF Research Database (Denmark)

    Aggerholm-Pedersen, Ninna; Demuth, Christina; Safwat, Akmal;

    2016-01-01

    ) treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal......) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI...... growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8...

  7. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma

    DEFF Research Database (Denmark)

    Judson, Ian; Verweij, Jaap; Gelderblom, Hans;

    2014-01-01

    routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. METHODS: We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries...

  8. Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

    Science.gov (United States)

    Kohl, Randall Lee

    Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, we tested the efficacy of dexamethasone and metyrapone in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80% more stressful motion ( P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

  9. Curcumin and Its Analogue Induce Apoptosis in Leukemia Cells and Have Additive Effects with Bortezomib in Cellular and Xenograft Models

    Directory of Open Access Journals (Sweden)

    L. I. Nagy

    2015-01-01

    Full Text Available Combination therapy of bortezomib with other chemotherapeutics is an emerging treatment strategy. Since both curcumin and bortezomib inhibit NF-κB, we tested the effects of their combination on leukemia cells. To improve potency, a novel Mannich-type curcumin derivative, C-150, was synthesized. Curcumin and its analogue showed potent antiproliferative and apoptotic effects on the human leukemia cell line, HL60, with different potency but similar additive properties with bortezomib. Additive antiproliferative effects were correlated well with LPS-induced NF-κB inhibition results. Gene expression data on cell cycle and apoptosis related genes, obtained by high-throughput QPCR, showed that curcumin and its analogue act through similar signaling pathways. In correlation with in vitro results similar additive effect could be obsereved in SCID mice inoculated systemically with HL60 cells. C-150 in a liposomal formulation given intravenously in combination with bortezomib was more efficient than either of the drugs alone. As our novel curcumin analogue exerted anticancer effects in leukemic cells at submicromolar concentration in vitro and at 3 mg/kg dose in vivo, which was potentiated by bortezomib, it holds a great promise as a future therapeutic agent in the treatment of leukemia alone or in combination.

  10. Bortezomib Treatment Produces Nocifensive Behavior and Changes in the Expression of TRPV1, CGRP, and Substance P in the Rat DRG, Spinal Cord, and Sciatic Nerve

    Directory of Open Access Journals (Sweden)

    M. Quartu

    2014-01-01

    Full Text Available To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN, we examined the effects of a single-dose intravenous administration of bortezomib and a well-established “chronic” schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP were studied in L4-L5 dorsal root ganglia (DRGs, spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.

  11. Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Low-Grade Follicular Lymphoma, Waldenstrom Macroglobulinemia, or Mantle Cell Lymphoma

    Science.gov (United States)

    2016-04-13

    Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Nodal Marginal Zone Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

  12. Bortezomib, Rituximab, and Dexamethasone With or Without Temsirolimus in Treating Patients With Untreated or Relapsed Waldenstrom Macroglobulinemia or Relapsed or Refractory Mantle Cell or Follicular Lymphoma

    Science.gov (United States)

    2017-01-31

    Cognitive Side Effects of Cancer Therapy; Fatigue; Neurotoxicity Syndrome; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Therapy-Related Toxicity; Waldenstrom Macroglobulinemia

  13. Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone

    NARCIS (Netherlands)

    D.I. Lichter (David); H. Danaee (Hadi); M.D. Pickard (Michael); O. Tayber (Olga); M. Sintchak (Michael); H. Shi (Hongliang); P.G. Richardson (Paul Gerard); J. Cavenagh (Jamie); J. Bladé (Joan); T. Facon (Thierry); R. Niesvizky; M. Alsina (Melissa); W. Dalton (William); P. Sonneveld (Pieter); S. Lonial (Sagar); H. van de Velde (Helgi); D. Ricci (Deborah); D.-L. Esseltine (Dixie-Lee); W.L. Trepicchio (William); G. Mulligan (George); K.C. Anderson (Kenneth Carl)

    2012-01-01

    textabstractVariations within proteasome β (PSMB) genes, which encode the β subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bort

  14. Hyperbaric Oxygen Preconditioning Provides Preliminary Protection Against Doxorubicin Cardiotoxicity

    Science.gov (United States)

    Tezcan, Orhan; Karahan, Oguz; Alan, Mustafa; Ekinci, Cenap; Yavuz, Celal; Demirtas, Sinan; Ekinci, Aysun; Caliskan, Ahmet

    2017-01-01

    Background Doxorubicin (DOX) is generally recognized to have important cardiotoxic side effects. Studies are contradictory about the interaction between hyperbaric oxygen (HBO2) therapy and doxorubicin-induced cardiomyotoxicity. Recent data suggests that HBO2 therapy can lead to preconditioning of myocardium while generating oxidative stress. Herein we have investigated the effect of HBO2 therapy in a DOX-induced cardiomyocyte injury animal model. Methods Twenty-one rats were divided into three equal groups as follows: 1) Group 1 is a control group (without any intervention), used for evaluating the basal cardiac structures and determining the normal value of cardiacs and serum oxidative markers; 2) Group 2 is the doxorubicin group (single dose i.p. 20 mg/kg doxorubicin) for detecting the cardiotoxic and systemic effects of doxorubicin; 3) Group 3 is the doxorubicin and HBO2 group (100% oxygen at 2.5 atmospheric for 90 minutes, daily), for evaluating the effect of HBO2 in doxorubicin induced cardiotoxicity. At the end of the protocols, the hearts were harvested and blood samples (2 ml) were obtained. Results The doxorubicin treated animals (Group 2) had increased oxidative stress markers (both cardiac and serum) and severe cardiac injury as compared to the basal findings in the control group. Nevertheless, the highest cardiac oxidative stress index was detected in Group 3 (control vs. Group 3, p = 0.01). However, histological examination revealed that cardiac structures were well preserved in Group 3 when compared with Group 2. Conclusions Our results suggest that HBO2 preconditioning appears to be protective in the doxorubicin-induced cardiotoxicity model. Future studies are required to better elucidate the basis of this preconditioning effect of HBO2. PMID:28344418

  15. Role of fibronectin under conditions of doxorubicin action

    Directory of Open Access Journals (Sweden)

    A. I. Shevtsova

    2015-02-01

    Full Text Available There is no standard as to treatment of anthracycline chemotherapy complications. The reduction of cytotoxic drugs toxicity without weakening of their antitumor action remains relevant. The extracellular matrix which key component is fibronectin is present in all tissues and it continuously undergoes controlled remodeling. So, the purpose of our work was to study the level of fibronectin in the experimental model of doxorubicin-induced cardiomyopathy and effects of this cytostatic and its co-administration with antioxidants of different nature.The level of fibronectin was measured by ELISA using monospecific antibodies against fibronectin (Sigma, USA, secondary anti-IgG labeled with horseradish peroxidase (Sigma, USA and fibronectin standard (Sigma, USA. The study was conducted on Wistar male rats with weight of 210 ± 50 g which were divided into 4 groups by 8 animals in each group: 1 – control, rats receiving saline i/p; 2 – doxorubicin 1 mg/kg i/p once a week during 4 weeks; 3 – doxorubicin by the same scheme plus 1% 2-oxoglutarate in drinking water during 4 weeks;4 – doxorubicin by the same scheme and korvitin injection 30 min before doxorubicin application once a week during 4 weeks. Obtained data indicate the effect of doxorubicin to decrease in index mass heart in 38% of animals compared to control animals; decrease in total protein concentration by 8% (Р < 0,05 and increase of the level of fibronectin by 67% (P < 0,001 in blood plasma of rats and decrease in the level of fibronectin in the heart extract by 19% (Р < 0,05 under development of doxorubicin-induced cardiotoxicity. Increased fibronectin concentration in blood plasma had strong correlation with decreased total protein concentration in blood (r=0,80 and heart extract (r=0,59 in rats with doxorubicin-induced cardiomiophaty indicating the sensitive reaction of fibronectin to development of metabolic disorders under doxorubicin influence.

  16. Successful treatment of refractory systemic lupus erythematosus using proteasome inhibitor bortezomib followed by belimumab: description of two cases.

    Science.gov (United States)

    Sjöwall, C; Hjorth, M; Eriksson, P

    2017-01-01

    Although the putative therapeutic options for patients with systemic lupus erythematosus (SLE) are steadily increasing, refractory disease is indeed a major challenge to many clinicians and patients. The proteasome inhibitor bortezomib - approved for the treatment of multiple myeloma since the beginning of this century - was recently reported successful in twelve cases of refractory SLE by German colleagues. Herein, we describe two Swedish SLE cases with refractory renal and pulmonary manifestations that were rescued by bortezomib as induction of remission followed by monthly doses of belimumab. The patients were carefully monitored with regard to disease activity and renal function. Anti-dsDNA and anti-C1q antibodies, complement proteins and lymphocyte subsets were analysed in consecutive samples. In December 2016, the patients had been in clinical remission post bortezomib administration for a period of 28 and 22 months, respectively. Potential benefits of using belimumab as maintenance therapy to prevent regeneration of autoreactive B cell clones are discussed.

  17. Depletion of alloreactive T-cells in vitro using the proteasome inhibitor bortezomib preserves the immune response against pathogens.

    Science.gov (United States)

    Blanco, Belén; Sánchez-Abarca, Luis Ignacio; Caballero-Velázquez, Teresa; Santamaría, Carlos; Inogés, Susana; Pérez-Simón, José Antonio

    2011-10-01

    Current graft-versus-host disease (GVHD) inhibition approaches lead to abrogation of pathogen-specific T-cell responses. We propose an approach to inhibit GVHD without hampering immunity against pathogens: in vitro depletion of alloreactive T cells with the preoteasome inhibitor bortezomib. We show that PBMCs stimulated with allogeneic cells and treated with bortezomib greatly reduce their ability to produce IFN-γ when re-stimulated with the same allogeneic cells, but mainly preserve their ability to respond to citomegalovirus stimulation. Unlike in vivo administration of immunosuppressive drugs or other strategies of allodepletion, in vitro allodepletion with bortezomib maintains pathogen-specific T cells, representing a promising alternative for GVHD prophylaxis.

  18. Evaluation healing of jejunal anastomosis in preoperative dexamethasone treated dogs

    Directory of Open Access Journals (Sweden)

    A.S. Al-Qadhi

    2015-06-01

    Full Text Available The objective of this study is to evaluate the healing process of jejunal anastomosis by the aid of histopathology and measurement of bursting pressure of anastomosis site in thirty two adult preoperatively with dexamethasone. The animals were randomly divided into 2 equal groups: Group 1: consists of 16 dogs underwent apposition end-to-end jejunal anastomosis using simple interrupted suture technique which in turn divided into 2 subgroups: subgroup A: consists of 8 dogs treated preoperatively for 15 days with dexamethasone at a dose of (0.2mg/kg given I/M. Subgroup B: control group consists of 8 dogs not treated with dexamethasone. Group 2: consists of 16 dogs underwent inverted end-to-end jejunal anastomosis using continuous Lembert suture pattern that also divided into 2 subgroups: subgroup A: consists of 8 dogs treated preoperatively for 15 days with dexamethasone at a dose of (0.2mg/kg given I/M. subgroup B: control group consists of 8 dogs not treated with dexamethasone. The result of bursting pressure measurement showed higher tensile strength in the control groups (445±9.6 in comparison with the steroidal groups (255±25.3 for both techniques. The histopathological study showed that the healing was good in all groups but the rupture that occur due to shedding the pressure lead to non discrimination between which is better in terms of healing. Massonʼs trichrome showed that collagen content of subgroups taking dexamethasone was lower than that of subgroups not treated with dexamethasone.

  19. Efficacy of lenalidomide, bortezomib, and prednisolone in patients with relapsed or refractory multiple myeloma

    Directory of Open Access Journals (Sweden)

    T. A. Мitinа

    2015-01-01

    Full Text Available 49 patients aged 28 to 81 years old (median age of 55 years old with relapsed or refractory multiple myeloma (MM were enrolled in the study. The relapse was diagnosed in 25 (51 % patients, the refractory disease was determined in 24 (49 % patients (including primary refractory disease in 14 (28.6 % patients. The prior therapy for all patients included bortezomib-based treatment in combination with thalidomide and autologus stem cell transplantation (8.1 %. Lenalidomide had not been used in the previous therapeutic regimens. All patients were given the original treatment regimen, which included lenalidomide, bortezomib, and prednisolone (RVP. The therapy was made up of seven induction cycles with each one lasting for 48 days. Length of courses was 14 days. After seven cycles of RVP therapy were over, such results were achieved: complete response (CR in 1 (2 % patient; very good partial response (VGPR in 4 (8 % patients; partial response (PR in 26 (53 % patients; minimal response (MR in 2 (4 % patients; stable disease (SD in 8 (16.3 % patients, and progressive disease (PD in 8 (16.3 % patients. The objective response rate, including CR+VGPR+PR, was obtained in 31 (63.1 % patients. The objective response rate, including MR, was seen in 33 (67.1 % patients. Hematological and non-hematological toxicities were moderate. Taking into account the above, the RVP therapeutic regimen has demonstrated its efficacy as a second-line therapy for MM, and its clinical use can solve the problem of relapsed/refractory to bortezomib-based regimens MM management.

  20. Pathophysiology of persistent doxorubicin cardiotoxicity : metabolic landscaping of the epigenome

    OpenAIRE

    Ferreira, André

    2015-01-01

    FERREIRA, André - Pathophysiology of persistent doxorubicin cardiotoxicity : metabolic landscaping of the epigenome. Coimbra : [s.n.], 2015. Dissertação de Mestrado em Biologia Molecular Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes a cumulative dose-dependent cardiomyopathy of late-onset that may ultimately lead to congestive heart failure. The mechanisms responsible for the delayed nature of DOX cardiotoxicity remain poorly understood. Since DOX ind...

  1. Dexamethasone regulates glutamine synthetase expression in rat skeletal muscles

    Science.gov (United States)

    Max, Stephen R.; Konagaya, Masaaki; Konagaya, Yoko; Thomas, John W.; Banner, Carl; Vitkovic, Ljubisa

    1986-01-01

    The regulation of glutamine synthetase by glucocorticoids in rat skeletal muscles was studied. Administration of dexamethasone strikingly enhanced glutamine synthetase activity in plantaris and soleus muscles. The dexamethasone-mediated induction of glutamine synthetase activity was blocked to a significant extent by orally administered RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves dramatically increased levels of glutamine synthetase mRNA. The induction of glutamine synthetase was selective in that glutaminase activity of soleus and plantaris muscles was not increased by dexamethasone. Furthermore, dexamethasone treatment resulted in only a small increase in glutamine synthetase activity in the heart. Accordingly, there was only a slight change in glutamine synthetase mRNA level in this tissue. Thus, glucocorticoids regulate glutamine synthetase gene expression in rat muscles at the transcriptional level via interaction with intracellular glutamine production by muscle and to mechanisms underlying glucocorticoid-induced muscle atrophy.

  2. Ghrelin attenuates gastrointestinal epithelial damage induced by doxorubicin

    Institute of Scientific and Technical Information of China (English)

    Mohamed A Fahim; Hazem Kataya; Rkia El-Kharrag; Dena AM Amer; Basel al-Ramadi; Sherif M Karam

    2011-01-01

    AIM: To examine the influence of ghrelin on the regenerative potential of gastrointestinal (GI) epithelium.METHODS: Damage to GI epithelium was induced in mice by two intravenous injections of doxorubicin (10 and 6 mg/kg). Some of the doxorubicin-treated mice received a continuous subcutaneous infusion of ghrelin (1.25 μg/h) for 10 d via implanted mini-osmotic pumps. To label dividing stem cells in the S-phase of the cell cycle, all mice received a single intraperitoneal injection of 5'-bromo-2'-deoxyuridine (BrdU) one hour before sacrifice. The stomach along with the duodenum were then removed and processed for histological examination and immunohistochemistry using anti-BrdU antibody. RESULTS: The results showed dramatic damage to the GI epithelium 3 d after administration of chemotherapy which began to recover by day 10. In ghrelin-treated mice, attenuation of GI mucosal damage was evident in the tissues examined post-chemotherapy. Immunohistochemical analysis showed an increase in the number of BrdU-labeled cells and an alteration in their distribution along the epithelial lining in response to damage by doxorubicin. In mice treated with both doxorubicin and ghrelin, the number of BrdU-labeled cells was reduced when compared with mice treated with doxorubicin alone. CONCLUSION: The present study suggests that ghrelin enhances the regenerative potential of the GI epithelium in doxorubicin-treated mice, at least in part, by modulating cell proliferation.

  3. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity.

    Science.gov (United States)

    Fouad, Amr A; Albuali, Waleed H; Al-Mulhim, Abdulruhman S; Jresat, Iyad

    2013-09-01

    The potential protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against doxorubicin cardiotoxicity in rats. Cardiotoxicity was induced by six equal doses of doxorubicin (2.5mgkg(-1) i.p., each) given at 48h intervals over two weeks to achieve a total dose of 15mgkg(-1). Cannabidiol treatment (5mgkg(-1)/day, i.p.) was started on the same day of doxorubicin administration and continued for four weeks. Cannabidiol significantly reduced the elevations of serum creatine kinase-MB and troponin T, and cardiac malondialdehyde, tumor necrosis factor-α, nitric oxide and calcium ion levels, and attenuated the decreases in cardiac reduced glutathione, selenium and zinc ions. Histopathological examination showed that cannabidiol ameliorated doxorubicin-induced cardiac injury. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin in cardiac tissue of doxorubicin-treated rats. These results indicate that cannabidiol represents a potential protective agent against doxorubicin cardiac injury.

  4. Randomized clinical trial of dexamethasone versus placebo in laparoscopic inguinal hernia repair

    DEFF Research Database (Denmark)

    Tolver, M A; Strandfelt, P; Bryld, Clara E;

    2012-01-01

    The effect of dexamethasone on recovery and length of convalescence has not been evaluated in patients after laparoscopic groin hernia repair. It was hypothesized that preoperative intravenous dexamethasone would reduce postoperative pain....

  5. HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY AS A SIDE-EFFECT OF DEXAMETHASONE TREATMENT FOR BRONCHOPULMONARY DYSPLASIA

    NARCIS (Netherlands)

    BRAND, PLP; VANLINGEN, RA; BRUS, F; TALSMA, MD; ELZENGA, NJ

    1993-01-01

    We report three infants who developed hypertrophic obstructive cardiomyopathy during dexamethasone treatment for bronchopulmonary dysplasia. In all three infants, echocardiography had ruled out cardiac abnormalities prior to the dexamethasone course. The hypertrophic obstructive cardiomyopathy appea

  6. The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Dijk, Marianne van; Murphy, Eoin [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland); Morrell, Ruth [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland); School of Medicine, National University of Ireland, University Road, Galway (Ireland); Knapper, Steven [Department of Haematology, School of Medicine, Cardiff University, Heath Park, CF14 4XN Cardiff (United Kingdom); O' Dwyer, Michael [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Medicine, National University of Ireland, University Road, Galway (Ireland); Samali, Afshin; Szegezdi, Eva, E-mail: eva.szegezdi@nuigalway.ie [Apoptosis Research Center, National University of Ireland, University Road, Galway (Ireland); School of Natural Sciences, National University of Ireland, University Road, Galway (Ireland)

    2011-03-15

    Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

  7. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.

    Science.gov (United States)

    Ghobrial, I M; Redd, R; Armand, P; Banwait, R; Boswell, E; Chuma, S; Huynh, D; Sacco, A; Roccaro, A M; Perilla-Glen, A; Noonan, K; MacNabb, M; Leblebjian, H; Warren, D; Henrick, P; Castillo, J J; Richardson, P G; Matous, J; Weller, E; Treon, S P

    2015-12-01

    We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

  8. Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib.

    Science.gov (United States)

    Podar, Klaus; Shringarpure, Reshma; Tai, Yu-Tzu; Simoncini, Melissa; Sattler, Martin; Ishitsuka, Kenji; Richardson, Paul G; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C

    2004-10-15

    We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane, represent novel therapeutic targets in multiple myeloma. In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130(Cas) phosphorylation and multiple myeloma cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130(Cas) phosphorylation and VEGF-triggered multiple myeloma cell migration. The proteasome inhibitor bortezomib both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF-induced multiple myeloma cell migration. Bortezomib also decreased VEGF secretion in the bone marrow microenvironment and inhibited VEGF-triggered tyrosine phosphorylation of caveolin-1, migration, and survival in human umbilical vascular endothelial cells. Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered multiple myeloma cell migration and identify caveolin-1 in multiple myeloma cells and human umbilical vascular endothelial cells as a molecular target of bortezomib.

  9. Doxorubicin-induced cardiotoxicity in mice; protection by silymarin

    Directory of Open Access Journals (Sweden)

    Heba Abdelnasser Aniss a, Ashraf El Metwally Said b, Ibrahim Helmy El Sayed c, Camelia AdLy

    2012-07-01

    Full Text Available Background: despite its vast utility in clinical oncology, the use of doxorubicin is limited by a potentially fatal cardiomyopathy and congestive heart failure. Free radical formation and antioxidants depletion are mechanisms proposed for this cardiomyopathy. The aim of this study is to compare the potential antioxidative protective effect of silymarin on doxorubicin-induced cardiotoxicity in experimental mice. Materials and methods: four groups (ten animals in each group of experimental mice were used as follows: Group 1, mice received only saline (intraperitoneally and served as a negative control group; Group 2, mice received doxorubicin (intraperitoneally, 5 mg/kg body weight in three equal injections over a period of two weeks for a cumulative dose of 15 mg/kg body weight; Group 3, mice orally administrated silymarin (200 mg/day/kg body weight respectively, through an intragastric feeding tube over a period of three weeks; Group 4, mice treated orally with silymarin plus intraperitoneally doxorubicin administration with the same protocol of groups 3 and 4. Serum lactate dehydrogenase (LDH, creatine phosphokinase (CPK, aspartate aminotransferase (ASAT, alanine aminotransferase (ALAT, malondialdehyde (MDA, total nitric oxide (NO, cardiac reduced glutathione (GSH, superoxide dismutase (SOD, glutathione peroxidase (GPx and catalase (CAT were measured in all tested groups. Results: doxorubicin elevated the activities of LDH, CPK, AST, ALT, MDA and NO in the cardiac tissue. Cardiac antioxidant enzymes activities SOD and CAT also increased while GPx activity was decreased. Pre-co-treatment with silymarin prevented the changes induced by doxorubicin administration. These findings demonstrate the cardio-protective effect of silymarin on cardiac antioxidant status during doxorubicin induced cardiac damage in mice. Conclusion: silymarin could be recommended for further investigation as potentially new indication for clinical application.

  10. Dexrazoxane exacerbates doxorubicin-induced testicular toxicity.

    Science.gov (United States)

    Levi, Mattan; Tzabari, Moran; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2015-10-01

    Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5  mg/kg DXR, 100  mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.

  11. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    DEFF Research Database (Denmark)

    Vangsted, A. J.; Soeby, K.; Klausen, T.W.;

    2010-01-01

    Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored...

  12. Evaluation of dexamethasone pulse therapy in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Ahmad Q

    2003-03-01

    Full Text Available The treatment of systemic sclerosis, a multisystem disorder, is for from satisfactory. Dexamethasone pulse therapy was started in 25 patients of systemic sclerosis and of the 10 patients who successfully completed the treatment, the results have been quite encouraging. Adverse effects to the pulse were minimal.

  13. 77 FR 32010 - New Animal Drugs; Altrenogest; Dexamethasone; Florfenicol

    Science.gov (United States)

    2012-05-31

    ... HUMAN SERVICES Food and Drug Administration 21 CFR Parts 510, 516, 520, 522, and 558 New Animal Drugs; Altrenogest; Dexamethasone; Florfenicol AGENCY: Food and Drug Administration, HHS. ] ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug regulations to...

  14. Dexamethasone in adults with community-acquired bacterial meningitis

    NARCIS (Netherlands)

    D. van de Beek; J. de Gans

    2006-01-01

    Bacterial meningitis in adults is a severe disease with high fatality and morbidity rates. Experimental studies have shown that the inflammatory response in the subarachnoid space is associated with an unfavourable outcome. In these experiments, corticosteroids, and in particular dexamethasone, were

  15. Effect of dexamethasone on fetal hepatic glutamine-glutamate exchange

    NARCIS (Netherlands)

    M. Timmerman (Michelle); C. Teng; R.B. Wilkening; P.V. Fennessey (Paul); F.C. Battaglia (Frederick); G. Meschia

    2000-01-01

    textabstractIntravenous infusion of dexamethasone (Dex) in the fetal lamb causes a two- to threefold increase in plasma glutamine and other glucogenic amino acids and a decrease of plasma glutamate to approximately one-third of normal. To explore the underlying mechanis

  16. Ethanol-induced hypothermia in rats is antagonized by dexamethasone

    Directory of Open Access Journals (Sweden)

    Carreño C.F.T.

    1997-01-01

    Full Text Available The effect of dexamethasone on ethanol-induced hypothermia was investigated in 3.5-month old male Wistar rats (N = 10 animals per group. The animals were pretreated with dexamethasone (2.0 mg/kg, ip; volume of injection = 1 ml/kg 15 min before ethanol administration (2.0, 3.0 and 4.0 g/kg, ip; 20% w/v and the colon temperature was monitored with a digital thermometer 30, 60 and 90 min after ethanol administration. Ethanol treatment produced dose-dependent hypothermia throughout the experiment (-1.84 ± 0.10, -2.79 ± 0.09 and -3.79 ± 0.15oC for 2.0, 3.0 and 4.0 g/kg ethanol, respectively, 30 min after ethanol but only the effects of 2.0 and 3.0 g/kg ethanol were significantly antagonized (-0.57 ± 0.09 and -1.25 ± 0.10, respectively, 30 min after ethanol by pretreatment with dexamethasone (ANOVA, P<0.05. These results are in agreement with data from the literature on the rapid antagonism by glucocorticoids of other effects of ethanol. The antagonism was obtained after a short period of time, suggesting that the effect of dexamethasone is different from the classical actions of corticosteroids

  17. Cessation of dexamethasone exacerbates airway responses to methacholine in asthmatic mice.

    Science.gov (United States)

    Stengel, Peter W; Nickell, Laura E; Wolos, Jeffrey A; Snyder, David W

    2007-06-01

    In asthmatic mice, dexamethasone (30.0 mg/kg) was administered orally once daily on Days 24-27. One hour after dexamethasone on Day 25-27, the mice were exposed to ovalbumin aerosols. Twenty-eight days after the initial ovalbumin immunization, we found that dexamethasone reduced methacholine-induced pulmonary gas trapping and inhibited bronchoalveolar lavage eosinophils and neutrophils. However, five days after the last dose of dexamethasone and last ovalbumin aerosol exposure in other asthmatic mice, the airway obstructive response to methacholine was exacerbated in dexamethasone-treated mice compared to vehicle-treated mice on Day 32. Further, eosinophils, but not neutrophils, were still inhibited after cessation of dexamethasone. Thus, discontinuing dexamethasone worsened methacholine-induced pulmonary gas trapping of asthmatic mice in the absence of eosinophilic airway inflammation.

  18. Dexamethasone intravitreal implant in the treatment of diabetic macular edema

    Directory of Open Access Journals (Sweden)

    Dugel PU

    2015-07-01

    Full Text Available Pravin U Dugel,1,2 Francesco Bandello,3 Anat Loewenstein4 1Retinal Consultants of Arizona, Phoenix, AZ, 2Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 3Department of Ophthalmology, University Vita-Salute Scientific Institute San Raffaele, Milan, Italy; 4Department of Ophthalmology, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Abstract: Diabetic macular edema (DME resembles a chronic, low-grade inflammatory reaction, and is characterized by blood–retinal barrier (BRB breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for ≤6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048 from two large-scale, randomized Phase III trials indicated that dexamethasone intravitreal implant (0.35 mg and 0.7 mg administered at ≥6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA and macular edema. Significantly more patients showed a ≥15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%. Anatomical assessments showed rapid and sustained reductions in macular edema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effective in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of

  19. EFFECT OF DEXAMETHASONE FOR REDUCING POST - TONSILLECTOMY MORBIDITY

    Directory of Open Access Journals (Sweden)

    Hiremath

    2013-10-01

    Full Text Available ABSTRACT: BACKGROUND SURVEY: Vital healthcare resources are devoted to caring patients with prolonged hospitalization after routine, moderate risk surgery. Complications are assessed using a postoperative morbidity. Methods for reducing pain, nausea and vomiting after tonsillectomy are important to improve the standard of care our patients receive. OBJECTIVE: To determine the effects of a single dose of dexamethasone on post operative morbidity in patients undergoing tonsillectomy/adenotonsillectomy. DESIGN: It is a prospective double - blind randomized placebo controlled clinical investigation with ethical approval. METHODS : 60 patients (41 male and 19 female aged between 4 - 15 years of ASA I - II undergoing tonsillectomy /adenotonsillectomy were the participants in this study. Patients were randomized to receive a single dose of IV dexamethasone or Placebo (saline. Post operative pain was assessed using either objective pain scale (OPS or visual analogue scale (VAS. Ane sthetic and surgical techniques were standardized. RESULTS : Statistically significant relative decrease in incidence of post operative pain, nausea and vomiting was seen in those treated with dexamethasone. Even statistically significant differences were s een in tolerance to oral fluids and discharge from the hospital between two groups. Tramadol 1 mg/kg n the first 6 hours and oral paracetamol 10ug/kg in the next 6 - 24 hours were administered. If OPS > 6 or VAS> 40 occurred. Incidence of nausea, vomiting an d tonsillar bed oedema was noted. Pain scores were significantly less in dexamethasone group compared to control group. CONCLUSION : Dexamethasone given as a single dose of 0.15mg/kg at the time of induction of anesthesia is an effective safe and inexpensiv e method of reducing morbidity in tonsillectomy.

  20. Treatment of noninfectious posterior uveitis with dexamethasone intravitreal implant

    Directory of Open Access Journals (Sweden)

    Jane S Myung

    2010-12-01

    Full Text Available Jane S Myung, Grant D Aaker, Szilárd KissDepartment of Ophthalmology, Weill Cornell Medical Center, New York, NY, USAPurpose: To report our experience with dexamethasone 0.7 mg sustained-release intravitreal implant (Ozurdex®; Allergan, Inc, Irvine, CA in noninfectious posterior uveitis.Methods: A retrospective chart review of patients with noninfectious uveitis treated with sustained-release dexamethasone 0.7 mg intravitreal implant was performed. Complete ophthalmic examination including signs of inflammatory activity, visual acuity, fundus photography, fluorescein angiography, optical coherence tomography, and tolerability of the implant were assessed.Results: Six eyes of 4 consecutive patients treated with a total of 8 dexamethasone 0.7 mg sustained-release intravitreal implants for posterior noninfectious uveitis were included. Two patients presented with unilateral idiopathic posterior uveitis; 2 patients had bilateral posterior uveitis, one secondary to sarcoidosis and the other to Vogt-Koyanagi-Harada syndrome. All eyes showed clinical and angiographic evidence of decreased inflammation following implant placement. Mean follow-up time post-injection was 5.25 months. Four eyes received 1 and 2 eyes received 2 Ozurdex implants during the follow-up period. The duration of effect of the implant was 3 to 4 months. No serious ocular or systemic adverse events were noted during the follow-up period.Conclusions: In patients with noninfectious posterior uveitis, sustained-release dexamethasone 0.7 mg intravitreal implant may be an effective treatment option for controlling intraocular inflammation.Keywords: corticosteroids, dexamethasone implant, Ozurdex, uveitis

  1. Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells

    DEFF Research Database (Denmark)

    Aggerholm-Pedersen, Ninna; Demuth, Christina; Safwat, Akmal;

    2016-01-01

    growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8......) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI....... However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin....

  2. A network biology approach evaluating the anticancer effects of bortezomib identifies SPARC as a therapeutic target in adult T-cell leukemia cells

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2008-10-01

    Full Text Available Junko H Ohyashiki1, Ryoko Hamamura2, Chiaki Kobayashi2, Yu Zhang2, Kazuma Ohyashiki21Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan; 2First Department of Internal Medicine, Tokyo Medical University, Tokyo, JapanAbstract: There is a need to identify the regulatory gene interaction of anticancer drugs on target cancer cells. Whole genome expression profiling offers promise in this regard, but can be complicated by the challenge of identifying the genes affected by hundreds to thousands of genes that induce changes in expression. A proteasome inhibitor, bortezomib, could be a potential therapeutic agent in treating adult T-cell leukemia (ATL patients, however, the underlying mechanism by which bortezomib induces cell death in ATL cells via gene regulatory network has not been fully elucidated. Here we show that a Bayesian statistical framework by VoyaGene® identified a secreted protein acidic and rich in cysteine (SPARC gene, a tumor-invasiveness related gene, as a possible modulator of bortezomib-induced cell death in ATL cells. Functional analysis using RNAi experiments revealed that inhibition of the expression SPARC by siRNA enhanced the apoptotic effect of bortezomib on ATL cells in accordance with an increase of cleaved caspase 3. Targeting SPARC may help to treat ATL patients in combination with bortezomib. This work shows that a network biology approach can be used advantageously to identify the genetic interaction related to anticancer effects.Keywords: network biology, adult T cell leukemia, bortezomib, SPARC

  3. Cellular handling of a dexamethasone-anti-E-selectin immunoconjugate by activated endothelial cells : Comparison with free dexamethasone

    NARCIS (Netherlands)

    Kok, RJ; Asgeirsdottir, SA; Meijer, DKF; Molema, G

    2002-01-01

    Purpose. For selective inhibition of endothelial cell activation in chronic inflammation, we have developed a dexamethasone-anti-E-selectin immunoconjugate. The present study was performed to evaluate the cellular handling of this immunoconjugate by activated primary endothelial cells and to compare

  4. [Cellulitis due to Achromobacter xylosoxidans during bortezomib therapy for multiple myeloma].

    Science.gov (United States)

    Kikuchi, Taku; Mori, Takehiko; Kohashi, Sumiko; Yamane, Yusuke; Okayama, Mikio; Mashima, Eri; Murakami, Koichi; Shimizu, Takayuki; Kurihara, Yuichi; Ueda, Tomomi; Suzuki, Takeshi; Okamoto, Shinichiro

    2016-02-01

    Achromobacter xylosoxidans (A. xylosoxidans) is a non-fermentative gram-negative rod. This organism is reportedly a causative pathogen of bacteremia mainly in patients with hematological disorders. However, only one case of cellulitis due to A. xylosoxidans associated with hematological malignancy has been reported. An 80-year-old man developed cellulitis and subsequent bacteremia due to A. xylosoxidans during bortezomib therapy for multiple myeloma. Although his condition was serious enough to require intensive care, he fully recovered with appropriate antimicrobial agents and supportive care. The isolate was broadly resistant to antimicrobial agents, including cefepime, amikacin, and ciprofloxacin. Therefore, the identification and selection of appropriate antimicrobial agents were considered to have contributed to the successful outcome in this case. Physicians should recognize A. xylosoxidans as a possible pathogen causing cellulitis and secondary bacteremia, as well as being aware of its broad resistance to antimicrobial agents.

  5. Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells.

    Science.gov (United States)

    Smith, Alyson J; Dai, Haiming; Correia, Cristina; Takahashi, Rie; Lee, Sun-Hee; Schmitz, Ingo; Kaufmann, Scott H

    2011-05-20

    Previous studies have suggested that the BH3 domain of the proapoptotic Bcl-2 family member Noxa only interacts with the anti-apoptotic proteins Mcl-1 and A1 but not Bcl-2. In view of the similarity of the BH3 binding domains of these anti-apoptotic proteins as well as recent evidence that studies of isolated BH3 domains can potentially underestimate the binding between full-length Bcl-2 family members, we examined the interaction of full-length human Noxa with anti-apoptotic human Bcl-2 family members. Surface plasmon resonance using bacterially expressed proteins demonstrated that Noxa binds with mean dissociation constants (K(D)) of 3.4 nm for Mcl-1, 70 nm for Bcl-x(L), and 250 nm for wild type human Bcl-2, demonstrating selectivity but not absolute specificity of Noxa for Mcl-1. Further analysis showed that the Noxa/Bcl-2 interaction reflected binding between the Noxa BH3 domain and the Bcl-2 BH3 binding groove. Analysis of proteins expressed in vivo demonstrated that Noxa and Bcl-2 can be pulled down together from a variety of cells. Moreover, when compared with wild type Bcl-2, certain lymphoma-derived Bcl-2 mutants bound Noxa up to 20-fold more tightly in vitro, pulled down more Noxa from cells, and protected cells against killing by transfected Noxa to a greater extent. When killing by bortezomib (an agent whose cytotoxicity in Jurkat T-cell leukemia cells is dependent on Noxa) was examined, apoptosis was enhanced by the Bcl-2/Bcl-x(L) antagonist ABT-737 or by Bcl-2 down-regulation and diminished by Bcl-2 overexpression. Collectively, these observations not only establish the ability of Noxa and Bcl-2 to interact but also identify Bcl-2 overexpression as a potential mechanism of bortezomib resistance.

  6. PREPARATION AND CHARACTERIZATION OF DOXORUBICIN-LOADED MAGNETIC ANTICANCER NANOPARTICLES

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Doxorubicin(ADM)-loaded magnetic anticancer nanoparticles,using Fe3O4 as core, doxorubicin as model drug and polyvinylpyrrolidone (PVP) as matrix, were prepared by inverse emulsion polymerization. The experimental results showed that the average diameter of Fe3O4 particles was 19.8nm. The X-ray diffraction indicated that the prepared Fe3O4 particle was pure cubic Fe3O4. The results obtained by SEM showed the magnetic nanoparticles under optimal operating condition had a smooth spherical surface , LLS showed an average size of 78.7nm. And IR results demonstrated that they consisted of ADM, PVP and Fe3O4.

  7. Dexamethasone Treatment Reverses Cognitive Impairment but Increases Brain Oxidative Stress in Rats Submitted to Pneumococcal Meningitis

    Directory of Open Access Journals (Sweden)

    Tatiana Barichello

    2011-01-01

    Full Text Available Pneumococcal meningitis is associated with a significant mortality rate and neurologic sequelae. The animals received either 10 μL of saline or a S. pneumoniae suspension and were randomized into different groups: sham: placebo with dexamethasone 0.7 mg/kg/1 day; placebo with dexamethasone 0.2 mg/kg/7 days; meningitis groups: dexamethasone 0.7 mg/kg/1 day and dexamethasone 0.2 mg/kg/7 days. Ten days after induction we evaluated memory and oxidative stress parameters in hippocampus and cortex. In the step-down inhibitory avoidance task, we observed memory impairment in the meningitis group with dexamethasone 0.2 mg/kg/7 days. The lipid peroxidation was increased in hippocampus in the meningitis groups with dexamethasone and in cortex only in the meningitis group with dexamethasone 0.2 mg/kg/7 days. The protein carbonyl was increased in hippocampus in the meningitis groups with dexamethasone and in cortex in the meningitis groups with and without dexamethasone. There was a decrease in the proteins integrity in hippocampus in all groups receiving treatment with dexamethasone and in cortex in all groups with dexamethasone (0.7 mg/kg/1 day. The mitochondrial superoxide was increased in the hippocampus and cortex in the meningitis group with dexamethasone 0.2 mg/kg/7 days. Our findings demonstrate that dexamethasone reverted cognitive impairment but increased brain oxidative stress in hippocampus and cortex in Wistar rats ten days after pneumococcal meningitis induction.

  8. Grape seed and skin extract protects kidney from doxorubicin-induced oxidative injury.

    Science.gov (United States)

    Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safwen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

    2016-05-01

    The study investigated the protective effect of grape seed and skin extract (GSSE) against doxorubicin-induced renal toxicity in healthy rats. Animals were treated with GSSE or not (control), for 8 days, administered with doxorubicin (20mg/kg) in the 4th day, and renal function as well as oxidative stress parameters were evaluated. Data showed that doxorubicin induced renal toxicity by affecting renal architecture and plasma creatinine. Doxorubicin also induced an oxidative stress characterized by an increase in malondialdehyde (MDA), calcium and H(2)O(2) and a decrease in catalase (CAT) and superoxide dismutase (SOD). Unexpectedly doxorubicin increased peroxidase (POD) and decreased carbonyl protein and plasma urea. Treatment with GSSE counteracted almost all adverse effects induced by doxorubicin. Data suggest that doxorubicin induced an oxidative stress into rat kidney and GSSE exerted antioxidant properties, which seem to be mediated by the modulation of intracellular calcium.

  9. Successful use of combined high cut-off haemodialysis and bortezomib for acute kidney injury associated with myeloma cast nephropathy.

    LENUS (Irish Health Repository)

    Ward, F

    2012-05-01

    We present the case of a 58-year old female with de novo dialysis-dependent acute kidney injury (AKI) secondary to myeloma cast nephropathy. The patient underwent extended high cut-off haemodialysis (HCO-HD), in conjunction with bortezomib-based chemotherapy, and soon became dialysis independent with normal renal function. To our knowledge, this is the first time this treatment strategy has been employed successfully in an Irish centre.

  10. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma

    NARCIS (Netherlands)

    Perilongo, G.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Morland, B.; de Camargo, B.; Zsiros, J.; Roebuck, D.; Zimmermann, A.; Aronson, D.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.; Pritchard, J.; Scopinaro, M.; Czauderna, P.

    2009-01-01

    Background: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). Methods: Children with standard-risk hepato

  11. Toxicity of doxorubicin entrapped within long-circulating liposomes

    NARCIS (Netherlands)

    Daemen, T; Regts, J; Meesters, M; TenKate, MT; BakkerWoudenberg, IAJM; Scherphof, GL

    1997-01-01

    We studied the effect of doxorubicin entrapped within long-circulating liposomes (Dox-LCL) on the phagocytic capacity and bacterial blood clearance capacity of rat liver macrophages. Dox-LCL (125 nm in diameter) were composed of egg phosphatidylcholine (PC), cholesterol (CH) and poly(ethyleneglycol)

  12. Dexamethasone-cyclophosphamide pulse therapy in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Dhabhai Ravindra

    2005-01-01

    Full Text Available BACKGROUND AND AIMS: Therapy systemic lupus erythematosus (SLE has been generally discouraging. Methyl-prednisolone pulse therapy has been used for various connective tissue disorders. We used intravenous dexamethasone cyclophosphamide pulse therapy to treat SLE. METHODS: Fourteen patients (10 females and 4 males between the age of 15-48 years with definite or classical clinical criteria laid by American Rheumatism Association criteria were treated by Dexamethasone-Cyclophosphamide pulse (DCP therapy at our center. RESULTS: It was possible to induce a complete clinical remission with DCP therapy in most of the patients thereby offering them life free from disease and drugs. The side effects commonly observed with conventional daily dose regimen of corticosteroids were not present or were mild. CONCLUSIONS: Almost all patients had good response after 3-4 pulses to allow them a normal life style. Fever, malar rash and oral ulceration responded early but photosensitivity, discoid rash, alopecia and joint pains took some more time.

  13. Dexamethasone selectively suppresses microglial trophic responses to hippocampal deafferentation

    DEFF Research Database (Denmark)

    Woods, A G; Poulsen, F R; Gall, C M

    1999-01-01

    Hippocampal deafferentation increases the expression of insulin-like growth factor-1 by microglia, and of ciliary neurotrophic factor and basic fibroblast growth factor by astroglia in fields and periods of reactive axonal growth. Glucocorticoids attenuate lesion-induced hippocampal sprouting......, possibly by reducing trophic signals that stimulate growth. With an interest in this hypothesis, the present studies evaluated the influence of systemic treatment with the synthetic glucocorticoid dexamethasone on entorhinal lesion-induced increases in neurotrophic factor expression in young adult rat...... hippocampus. Daily dexamethasone injections almost completely blocked increases in insulin-like growth factor-1 messenger RNA content, but did not perturb increases in ciliary neurotrophic factor or basic fibroblast growth factor messenger RNA content, in the deafferented dentate gyrus molecular layer...

  14. Dexamethasone-induced catatonia in a patient with multiple myeloma.

    Science.gov (United States)

    Vanstechelman, Sylvie; Vantilborgh, Anna; Lemmens, Gilbert

    2016-12-01

    Catatonia is a complex neuropsychiatric syndrome, caused by different underlying metabolic, neurologic, psychiatric and toxic conditions. Although catatonia is often associated with psychiatric disorders such as schizophrenia or depression, in about 20 to 39% of the patients a somatic illness is found. Unfortunately, this diagnosis is often missed although catatonia is characterized by a specific symptom complex. We report a case of acute catatonia with psychotic features in a patient with multiple myeloma (MM), caused by systemic use of dexamethasone. Physicians should be aware of possible psychiatric side effects when prescribing high doses of dexamethasone. Further, MM patients on corticosteroids should be closely monitored for mild psychological and/or psychiatric symptoms since they may be predictive for the onset of catatonia.

  15. Dexamethasone Intravitreal Implant for Diabetic Macular Edema During Pregnancy

    DEFF Research Database (Denmark)

    Concillado, Michael; Lund-Andersen, Henrik; Mathiesen, Elisabeth R;

    2016-01-01

    PURPOSE: To describe the management of diabetic macular edema during pregnancy with the use of a dexamethasone slow-release intravitreal implant. DESIGN: Retrospective, observational, consecutive case series. METHODS: The study included 5 pregnant women who presented with diabetic macular edema...... injection. RESULTS: Diabetic macular edema involving the foveal center was observed between gestational weeks 9 and 23 in 10 eyes of 5 patients. Dexamethasone intravitreal implant injection was given 10 times in 9 eyes with a mean preinjection center field retinal thickness of 535 μm (range, 239-727 μm...... center field thickness and in 6 of 8 eyes by an increase in BCVA of 5 or more approxETDRS letters. A mild transient rise in intraocular pressure occurred in 3 out of 8 eyes. CONCLUSION: Diabetic macular edema involving the foveal center that presented during pregnancy responded promptly to intravitreal...

  16. Target Mechanism-Based Whole-Cell Screening Identifies Bortezomib as an Inhibitor of Caseinolytic Protease in Mycobacteria

    Science.gov (United States)

    Moreira, Wilfried; Ngan, Grace J. Y.; Low, Jian Liang; Poulsen, Anders; Chia, Brian C. S.; Ang, Melgious J. Y.; Yap, Amelia; Fulwood, Justina; Lakshmanan, Umayal; Lim, Jolander; Khoo, Audrey Y. T.; Flotow, Horst; Hill, Jeffrey; Raju, Ravikiran M.; Rubin, Eric J.

    2015-01-01

    ABSTRACT A novel type of antibacterial screening method, a target mechanism-based whole-cell screening method, was developed to combine the advantages of target mechanism- and whole-cell-based approaches. A mycobacterial reporter strain with a synthetic phenotype for caseinolytic protease (ClpP1P2) activity was engineered, allowing the detection of inhibitors of this enzyme inside intact bacilli. A high-throughput screening method identified bortezomib, a human 26S proteasome drug, as a potent inhibitor of ClpP1P2 activity and bacterial growth. A battery of secondary assays was employed to demonstrate that bortezomib indeed exerts its antimicrobial activity via inhibition of ClpP1P2: Down- or upmodulation of the intracellular protease level resulted in hyper- or hyposensitivity of the bacteria, the drug showed specific potentiation of translation error-inducing aminoglycosides, ClpP1P2-specific substrate WhiB1 accumulated upon exposure, and growth inhibition potencies of bortezomib derivatives correlated with ClpP1P2 inhibition potencies. Furthermore, molecular modeling showed that the drug can bind to the catalytic sites of ClpP1P2. This work demonstrates the feasibility of target mechanism-based whole-cell screening, provides chemical validation of ClpP1P2 as a target, and identifies a drug in clinical use as a new lead compound for tuberculosis therapy. PMID:25944857

  17. Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.

    Directory of Open Access Journals (Sweden)

    Adil Doganay Duru

    Full Text Available Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM that undergo autologous stem cell transplantation (ASCT. In this study, we aimed to identify the immunological and molecular consequences of del(8(p21 with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8(p21 responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8(p21 including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8(p21 to TRAIL/APO2L mediated apoptosis, in cells with del(8(p21 bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8(p21 to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8(p21.

  18. Effects of dexamethasone immunosuppression on turkey clostridial dermatitis.

    Science.gov (United States)

    Thachil, Anil J; Shaw, Daniel P; Nagaraja, Kakambi V

    2014-09-01

    Clostridia represents a group of anaerobic spore-forming bacteria ubiquitous in the poultry environment. They are widely distributed in soil and survive for many years as highly resistant, inactive spores. They enter the body through wounds and contaminated feed as active bacteria or spores. Multiplication of clostridial bacteria occurs only in the absence of oxygen or in environments with very low concentrations of oxygen. During active multiplication, the clostridial organisms produce several toxins that are responsible for most of the clinical signs seen in clostridial diseases. Immunosuppression is a problem for the poultry industry. In modern, intensive poultry-rearing conditions, stress due to high population densities pose a considerable challenge for the immune system, and infectious agents can exploit this situation to cause disease. Immunosuppression may predispose turkeys to clostridial infection, resulting in clostridial dermatitis and mortality. The purpose of this study was to determine whether immunosuppression predisposes turkeys to clostridial infection and causes clostridial dermatitis. We immunosuppressed 10-wk-old turkey poults with dexamethasone. The birds immunosuppressed and not immunosuppressed were then challenged with Clostridium perfringens, Clostridium septicum, or both and examined for the development of clostridial dermatitis. The dexamethasone-treated birds were found to be more susceptible to C. peifingens/C. septicum challenge and developed clostridial dermatitis than the no-dexamethasone-treated birds through the subcutaneous route. However, oral inoculation of the same agents did not cause any dermatitis lesions in either of the groups.

  19. Effects of thyroxine and dexamethasone on rat submandibular glands

    Energy Technology Data Exchange (ETDEWEB)

    Sagulin, G.B.; Roomans, G.M. (Karolinska Institutet, Huddinge (Sweden))

    1989-08-01

    Glucocorticoids and thyroxine are known to have a marked effect on the flow rate and protein composition of rat parotid saliva in hormonally intact animals. In the present study, the effects of a one-week treatment of male rats with dexamethasone and thyroxine were studied by electron microscopy and x-ray micro-analysis, and by measurement of the flow rate and determination of the chemical composition of pilocarpine-induced submandibular saliva. Thyroxine had the most extensive effects on the submandibular gland. The acinar cells were enlarged and filled with mucus; the cellular calcium concentration was significantly increased. The flow rate of the submandibular saliva was significantly reduced compared with that in saline-injected control animals. Thyroxine caused an increase in the concentrations of protein, total calcium, and potassium in the saliva. Dexamethasone had no significant effects on gland ultrastructure or on the elemental composition of the acinar cells; flow rate was not affected, but the concentrations of protein, calcium, and potassium were significantly increased. The effects of dexamethasone and thyroxine on the flow rate and protein composition of pilocarpine-induced rat submandibular saliva differ from those reported earlier for rat parotid saliva after simultaneous stimulation with pilocarpine and isoproterenol.

  20. Rhabdomyolysis secondary to drug interaction between atorvastatin, omeprazole, and dexamethasone

    Directory of Open Access Journals (Sweden)

    Elazzazy S

    2012-09-01

    Full Text Available Shereen Elazzazy,1 Saad S Eziada,2 Manal Zaidan11Pharmacy Department, 2Oncology Hematology Department, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarAbstract: Concomitant administration of atorvastatin, omeprazole, and dexamethasone has been shown to increase the serum concentration of serum hydroxymethylglutaryl coenzyme A which can be associated with elevation of creatine kinase and an increased risk of severe myopathy and rhabdomyolysis. In this paper, we report a case of a 60-year-old female patient with stage IV colon cancer and compromised hepatic function receiving palliative care who developed rhabdomyolysis while taking atorvastatin, omeprazole, and dexamethasone. Atorvastatin was stopped, and the dexamethasone dose was decreased. Her case was complicated by urosepsis cultures revealing an extended spectrum β-lactamase-producing strain of Escherichia coli, and she died on the second day after admission. Physicians should evaluate the risk/benefit ratio of continuing statins in palliative care patients, and pay special attention to the monitoring of patients on statins and P-glycoprotein inhibitors regardless of hepatic function.Keywords: statins, rhabdomyolysis, drug–drug interaction, P-glycoprotein inhibitors

  1. In vitro hemocompatibility and cytocompatibility of dexamethasone-eluting PLGA stent coatings

    Science.gov (United States)

    Zhang, Jiang; Liu, Yang; Luo, Rifang; Chen, Si; Li, Xin; Yuan, Shuheng; Wang, Jin; Huang, Nan

    2015-02-01

    Drug-eluting stents (DESs) have been an important breakthrough for interventional cardiology applications since 2002. Though successful in reducing restenosis, some adverse clinical problems still emerged, which were mostly caused by the bare-metal stents and non-biodegradable polymer coatings, associated with the delayed endothelialization process. In this study, dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) coatings were developed to explore the potential application of dexamethasone-eluting stents. Dexamethasone-eluting PLGA stents were prepared using ultrasonic atomization spray method. For other tests like stability and cytocompatibility and hemocompatibility tests, dexamethasone loaded coatings were deposited on 316L SS wafers. Fourier transform-infrared spectroscopy (FT-IR) results demonstrated that there was no chemical reaction between PLGA and dexamethasone. The balloon expansion experiment and surface morphology observation suggested that the stent coatings were smooth and uniform, and could also withstand the compressive and tensile strains imparted without cracking after stent expansion. The drug release behavior in vitro indicated that dexamethasone existed burst release within 1 day, but it presented linear release characteristics after 6 days. In vitro platelets adhesion, activation test and APTT test were also done, which showed that after blending dexamethasone into PLGA, the hemocompatibility was improved. Besides, dexamethasone and dexamethasone-loaded PLGA coatings could significantly inhibit the attachment and proliferation of smooth muscle cells.

  2. Doxorubicin Caused Apoptosis of Mesenchymal Stem Cells via p38, JNK and p53 Pathway

    Directory of Open Access Journals (Sweden)

    Fan Yang

    2013-11-01

    Full Text Available Background/Aims: Doxorubicin is a widely used chemotherapeutic agent, but its clinical use is restricted because of a high risk of cardiotoxicity. Bone marrow-derived mesenchymal stem cells (BMSCs may repair ischaemically damaged myocardium through transdifferentiation and paracrine action. The aim of this study is to investigate if doxorubicin causes the apoptosis of BMSCs and in turn impairs its healing ability. Methods: BMSCs were exposed to doxorubicin, and cell apoptosis was determined by western blot and stainings. Results: Doxorubicin reduced the survival ratio and caused the apoptosis of BMSCs, with the increase of intracellular ROS level and depolarization of mitochondrial membrane potential. The ROS scavenger NAC abrogated these consequences. Moreover, doxorubicin markedly activated phosphorylated ERK, p38 and JNK proteins in BMSCs. The specific inhibitors for p38 (SB203580 and JNK (SP600125 may abolish doxorubicin-induced apoptosis of BMSCs but the specific ERK inhibitor (PD98059 not, indicating p38 and JNK activation contribute to BMSCs apoptosis. Also, the phosphorylated and total p53 proteins were increased in doxorubicin-treated BMSCs. Proapoptotic cleaved caspases-3 was upregulated and antiapoptotic Bcl-2 protein was reduced in doxorubicin-treated BMSCs. At last, ELISA assay showed that doxorubicin treatment reduced the VEGF and IGF-1 released by BMSCs. Conclusion: Taken together, doxorubicin caused BMSCs apoptosis associated with p38, JNK and p53 pathways.

  3. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes.

    Science.gov (United States)

    Khan, Mahmood; Varadharaj, Saradhadevi; Shobha, Jagdish C; Naidu, Madireddi U; Parinandi, Narasimham L; Kutala, Vijay Kumar; Kuppusamy, Periannan

    2006-01-01

    Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.

  4. Dexamethasone intravitreal implant in the treatment of diabetic macular edema.

    Science.gov (United States)

    Dugel, Pravin U; Bandello, Francesco; Loewenstein, Anat

    2015-01-01

    Diabetic macular edema (DME) resembles a chronic, low-grade inflammatory reaction, and is characterized by blood-retinal barrier (BRB) breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana) injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours) and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for ≤6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048) from two large-scale, randomized Phase III trials indicated that dexamethasone intravitreal implant (0.35 mg and 0.7 mg) administered at ≥6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA) and macular edema. Significantly more patients showed a ≥15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%). Anatomical assessments showed rapid and sustained reductions in macular edema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effective in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of dexamethasone intravitreal implant in Phase III trials included cataract-related events (66.0% in phakic patients), intraocular pressure elevation ≥25 mmHg (29.7%), conjunctival hemorrhage (23.5%), vitreous hemorrhage (10.0%), macular fibrosis (8.3%), conjunctival hyperemia (7.2%), eye pain (6.1%), vitreous detachment (5.8%), and dry eye (5.8%); injection-related complications (eg, retinal tear/detachment, vitreous loss, endophthalmitis) were infrequent (implant offers a

  5. Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.

    Directory of Open Access Journals (Sweden)

    Bray Denard

    Full Text Available Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1, a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin.Mice transplanted with 6 lines of renal cell carcinoma (RCC were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin.Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis. From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC.Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

  6. Bortezomib-thalidomide-based regimens improved clinical outcomes without increasing toxicity as induction treatment for untreated multiple myeloma: a meta-analysis of phase III randomized controlled trials.

    Science.gov (United States)

    Huang, Hejing; Zhou, Lili; Peng, Lihui; Fu, Weijun; Zhang, Chunyang; Hou, Jian

    2014-09-01

    Novel agents thalidomide and bortezomib have significantly improved myeloma treatment. However, it remains unclear whether patients will benefit more from the combination therapy of these two agents. Our meta-analysis aims to compare the efficiency, and more importantly, the safety of bortezomib-thalidomide-based (VT-based) versus bortezomib-based or thalidomide-based (V-based/T-based) regimens as induction therapy in patients with previously untreated myeloma. Overall, five phase III RCTs including 1765 patients were identified. Compared with V-based or T-based regimens, VT-based regimens significantly improved CR (OR=2.22, 95% CI [1.44, 3.43]), ORR (OR=2.19, 95% CI [1.51, 3.19]) as well as PFS (HR=0.69, 95% CI [0.54, 0.88]), but not OS (HR=1.04, 95% CI [0.91, 1.19]). Notably, most expected side effects of bortezomib or thalidomide were comparable in both groups, including hematologic (anemia, neutropenia, thrombocytopenia), nonhematologic (peripheral neuropathy, deep venous thrombosis, infections, gastrointestinal events) side effects and discontinuation during or after induction therapy. These results suggest that combination of thalidomide and bortezomib might be a better first-line choice for patients with untreated myeloma.

  7. Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate

    Science.gov (United States)

    Kontsioti, Frieda; Konsta, Eugene; Vikentiou, Miriam; Spathis, Aris; Papageorgiou, Sotiris; Vasilatou, Diamantina; Gkontopoulos, Konstantinos; Mpazani, Efthimia; Karakitsos, Petros; Rigopoulos, Dimitrios; Dimitriadis, George

    2017-01-01

    Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) comprise the majority of CTCL, a heterogenous group of non-Hodgkins lymphomas involving the skin. The CTCL’s resistance to chemotherapy and the lack of full understanding of their pathogenesis request further investigation. With the view of a more targeted therapy, we evaluated in vitro the effectiveness of bortezomib and methotrexate, as well as their combination in CTCL cell lines, regarding apoptosis induction. Our data are of clinical value and indicate that the bortezomib/methotrexate combinational therapy has an inferior impact on the apoptosis of CTCL compared to monotherapy, with bortezomib presenting as the most efficient treatment option for SS and methotrexate for MF. Using PCR arrays technology, we also investigated the alterations in the expression profile of genes related to DNA repair pathways in CTCL cell lines after treatment with bortezomib or methotrexate. We found that both agents, but mostly bortezomib, significantly deregulate a large number of genes in SS and MF cell lines, suggesting another pathway through which these agents could induce apoptosis in CTCL. Finally, we show that SS and MF respond differently to treatment, verifying their distinct nature and further emphasizing the need for discrete treatment approaches. PMID:28107479

  8. The Cost-Effectiveness of Initial Treatment of Multiple Myeloma in the U.S. With Bortezomib Plus Melphalan and Prednisone Versus Thalidomide Plus Melphalan and Prednisone or Lenalidomide Plus Melphalan and Prednisone With Continuous Lenalidomide Maintenance Treatment

    OpenAIRE

    2013-01-01

    A detailed pharmacoeconomic analysis was conducted to estimate the incremental cost-effectiveness of bortezomib, melphalan, and prednisone versus thalidomide, melphalan, and prednisone versus lenalidomide, melphalan, and prednisone with lenalidomide maintenance as therapy for previously untreated transplant-ineligible multiple myeloma patients. Bortezomib, melphalan, and prednisone was found to be the cost-effective option in the U.S. setting.

  9. A comparison of dexamethasone, ondansetron, and dexamethasone plus ondansetron as prophylactic antiemetic and antipruritic therapy in patients receiving intrathecal morphine for major orthopedic surgery.

    LENUS (Irish Health Repository)

    Szarvas, Szilvia

    2012-02-03

    In a prospective, double-blinded, randomized trial, we evaluated the efficacy of IV (a) dexamethasone 8 mg, (b) ondansetron 8 mg, and (c) dexamethasone 8 mg plus ondansetron 4 mg for the prevention of postoperative nausea, vomiting (PONV), and pruritus in 130 (ASA physical status I to III) patients undergoing elective major orthopedic surgery after spinal anesthesia with hyperbaric 0.5% bupivacaine and intrathecal morphine. After spinal anesthesia, patients were randomized to one of three groups. Failure of PONV prophylaxis in the 24-h postoperative period occurred more frequently in patients who received dexamethasone alone (29 of 40; 73%) compared with those who received either ondansetron alone (23 of 47; 49%) (P = 0.02) or dexamethasone plus ondansetron together (19 of 43; 44%)(P = 0.01). There was no difference in the incidence of failure of prophylaxis of pruritus (70%, 72%, and 70% in dexamethasone 8 mg, ondansetron 8 mg, and dexamethasone 8 mg plus ondansetron 4 mg, respectively) (P > 0.1) in the 24-h postoperative period. We conclude that the administration of dexamethasone 8 mg with ondansetron 4 mg has no added benefit compared with ondansetron 8 mg alone in the prophylaxis of PONV and pruritus. IMPLICATIONS: Postoperative nausea and vomiting (PONV) and pruritus are common side effects after spinal opioid administration. In this study, dexamethasone 8 mg plus ondansetron 4 mg was as effective as ondansetron 8 mg. The administration of dexamethasone alone was associated with a frequent incidence of PONV, demonstrating a lack of efficacy. This has important cost implications.

  10. Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin

    Directory of Open Access Journals (Sweden)

    Jiang SP

    2013-08-01

    Full Text Available Sai-Ping Jiang,1,2,* Sai-Nan He,3,* Yun-Long Li,2,3 Da-Lin Feng,2 Xiao-Yang Lu,1 Yong-Zhong Du,2 He-Yong Yu,3 Fu-Qiang Hu,2 Hong Yuan2 1Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 3Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China *These authors contributed equally to this work Purpose: Safe and effective lipid nanoemulsion (LNE formulations for the antitumor delivery of doxorubicin is designed. Methods: LNEs composed of medium-chain triglyceride, soybean oil, lecithin, and doxorubicin are prepared by a solvent-diffusion method in an aqueous system. The effects of lipid material composition and polyethylene glycol (PEGylation on the size, drug encapsulation efficiency, and stability of LNEs are investigated. Based on in-vitro cytotoxicity and cellular uptake tests of A549 (human lung carcinoma cells, in-vivo biodistribution, antitumor activity, and cardiac toxicity are further examined using nude mouse bearing A549 tumor. Results: The LNE size decreases from 126.4 ± 8.7 nm to 44.5 ± 9.3 nm with increased weight ratio of medium-chain triglyceride to soybean oil from 1:4 to 3:2, whereas the encapsulation efficiency of doxorubicin is slightly reduced from 79.2% ± 2.1% to 71.2% ± 2.9%. The PEGylation of LNE by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(PEG2000] (DSPE-PEG 2000 does not significantly change the size and drug encapsulation efficiency. Three-month storage at room temperature and lyophilization process does not affect the drug encapsulation efficiency, whereas the size slightly increases to almost 100 nm. The in-vitro drug-release profiles of LNEs suggest that the present formulation can prolong drug release for 48 hours. LNEs can be internalized into tumor cells in vitro and efficiently accumulate in tumor tissues in vivo by passive targeting

  11. Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates

    Science.gov (United States)

    Zhang, Xuan; Chibli, Hicham; Kong, Dekun; Nadeau, Jay

    2012-07-01

    Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non-toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP-Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates.

  12. Controlled Release of Doxorubicin from Doxorubicin/γ-Polyglutamic Acid Ionic Complex

    Directory of Open Access Journals (Sweden)

    Bhavik Manocha

    2010-01-01

    Full Text Available Formation of drug/polymer complexes through ionic interactions has proven to be very effective for the controlled release of drugs. The stability of such drug/polymer ionic complexes can be greatly influenced by solution pH and ionic strength. The aim of the current work was to evaluate the potential of γ-polyglutamic acid (γ-PGA as a carrier for the anticancer drug, Doxorubicin (DOX. We investigated the formation of ionic complexes between γ-PGA and DOX using scanning electron microscopy, spectroscopy, thermal analysis, and X-ray diffraction. Our studies demonstrate that DOX specifically interacts with γ-PGA forming random colloidal aggregates and results in almost 100% complexation efficiency. In vitro drug release studies illustrated that these complexes were relatively stable at neutral pH but dissociates slowly under acidic pH environments, facilitating a pH-triggered release of DOX from the complex. Hydrolytic degradation of γ-PGA and DOX/γ-PGA complex was also evaluated in physiological buffer. In conclusion, these studies clearly showed the feasibility of γ-PGA to associate cationic drug such as DOX and that is may serve as a new drug carrier for the controlled release of DOX in malignant tissues.

  13. Prevention and treatment of doxorubicin-induced cardiotoxicity by dexrazoxane and schisandrin B in rabbits.

    Science.gov (United States)

    Che, Feifei; Liu, Yu; Xu, Caigang

    2011-12-01

    The cost of dexrazoxane, a drug used to provide protection from doxorubicin-induced cardiotoxicity, limits its use in low-income countries. We aimed to see whether schisandrin B, an inexpensive drug, could provide protection equivalent to that provided by dexrazoxane. New Zealand white rabbits were randomly divided into groups and treated with saline, doxorubicin, doxorubicin + dexrazoxane, or doxorubicin + schisandrin B. Doxorubicin-induced damage and the protective effects were studied by recording the echocardiographic parameters and serum levels of superoxide dismutase, malondialdehyde, cardiac troponin I, and brain natriuretic peptide and observing the histology and degree of apoptosis. Schisandrin B had dose-dependent effects in decreasing the magnitude of doxorubicin-induced indicators of cardiomyopathy to a degree that approximated the decrease produced by dexrazoxane treatment. Schisandrin B might be a useful, low-cost alternative drug for this application.

  14. Magnetic fluid hyperthermia enhances cytotoxicity of bortezomib in sensitive and resistant cancer cell lines.

    Science.gov (United States)

    Alvarez-Berríos, Merlis P; Castillo, Amalchi; Rinaldi, Carlos; Torres-Lugo, Madeline

    2014-01-01

    The proteasome inhibitor bortezomib (BZ) has shown promising results in some types of cancer, but in others it has had minimal activity. Recent studies have reported enhanced efficacy of BZ when combined with hyperthermia. However, the use of magnetic nanoparticles to induce hyperthermia in combination with BZ has not been reported. This novel hyperthermia modality has shown better potentiation of chemotherapeutics over other types of hyperthermia. We hypothesized that inducing hyperthermia via magnetic nanoparticles (MFH) would enhance the cytotoxicity of BZ in BZ-sensitive and BZ-resistant cancer cells more effectively than hyperthermia using a hot water bath (HWH). Studies were conducted using BZ in combination with MFH in two BZ-sensitive cell lines (MDA-MB-468, Caco-2), and one BZ-resistant cell line (A2780) at two different conditions, ie, 43°C for 30 minutes and 45°C for 30 minutes. These experiments were compared with combined application of HWH and BZ. The results indicate enhanced potentiation between hyperthermic treatment and BZ. MFH combined with BZ induced cytotoxicity in sensitive and resistant cell lines to a greater extent than HWH under the same treatment conditions. The observation that MFH sensitizes BZ-resistant cell lines makes this approach a potentially effective anticancer therapy platform.

  15. Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma.

    Science.gov (United States)

    Leshchenko, Violetta V; Kuo, Pei-Yu; Jiang, Zewei; Weniger, Marc A; Overbey, Jessica; Dunleavy, Kieron; Wilson, Wyndham H; Wiestner, Adrian; Parekh, Samir

    2015-09-29

    Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients.

  16. Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Kelley Salem

    2015-04-01

    Full Text Available Multiple myeloma (MM is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1 correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266 and the BTZ-resistant (BR lines (MM.1SBR, 8226BR were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1, and glutathione (GSH were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity.

  17. Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma.

    Science.gov (United States)

    Salem, Kelley; McCormick, Michael L; Wendlandt, Erik; Zhan, Fenghuang; Goel, Apollina

    2015-01-01

    Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper-zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity.

  18. Histopathological effects of doxorubicin on pancreas in male albino rats

    Directory of Open Access Journals (Sweden)

    I.A. Ali

    2015-06-01

    Full Text Available The aim of this study was to investigate the histopathological side effects of doxorubicin on pancreas tissue in male albino rats Rattus norvegicus. This study were used 55 adult rats (2.5-3.5 month of age. The rats divided into two groups, the first group include (35 rats. The second group were (20 rats. Microscopial examination of pancreas lesion demonstrated oedema around the acini, swelling of the epithelial cells of acini, occurance of cystic fibrosis (mucoviscidosis at the concentration of (4,5 mg/kg of body weight ,occurrence of small islets that form of few cells and exocrine-endocrine transformation. There were thickness in the walls of blood vessels, thrombus, congestion of blood vessels, we conclude, that doxorubicin had histopathological effect on pancreas in sub-acute doses more than chronic doses.

  19. The effect of thyroxin on hepatic redox equilibrium and lipid metabolism in rats treated with doxorubicin

    OpenAIRE

    Czuba Bartosz; Fituch Magdalena; Mandziuk Slawomir; Jodlowska-Jedrych Barbara; Matysiak Wlodzimierz; Halasa Justyna; Burdan Franciszek; Korga Agnieszka; Iwan Magdalena; Luszczewska-Sierakowska Iwona; Dudka Jarosław

    2014-01-01

    The main side effects of the administration of doxorubicin, a widely used anticancer drug, is the generation of a reactive oxygen species (ROS) in normal cells. As a result, redox disorders and secondary oxidative stress are developed. Doxorubicin ROS generation is attributed to enzymes that are produced abundantly in hepatocytes. Oxidative stress has been a well-known risk factor of doxorubicin-related toxicity. However, in addition, according to the data collected in the last decade, change...

  20. Signal transduction by erythrocytes on specific binding of doxorubicin immobilized on nanodispersed magnetite

    Energy Technology Data Exchange (ETDEWEB)

    Mykhaylyk, Olga [Institute Applied Problems Physics and Biophysics, NAS, Sluzhbova 3, UA-03142 Kyiv (Ukraine)]. E-mail: Olga.Mykhaylyk@gmx.net; Kotzuruba, Anatoliy [Institute of Biochemistry, NAS, Leontovicha 9, UA-01030 Kyiv (Ukraine); Dudchenko, Nataliya [Institute Applied Problems Physics and Biophysics, NAS, Sluzhbova 3, UA-03142 Kyiv (Ukraine); Toerok, Gyula [Research Institute for Solid State Physics and Optics, H-1525 Budapest, P.O. Box 49 (Hungary)

    2005-05-15

    Two specific binding sites for doxorubicin were revealed at the plasma membrane of human erythrocytes on investigation of the binding of doxorubicin magnetic nanoconjugates. Free and conjugated doxorubicins modulated signal transduction in erythrocytes in a similar way. Both up-regulated nitric oxide and cyclic GMP (cGMP) and down-regulated cyclic AMP (cAMP) production and stabilize the membranes of damaged erythrocytes.

  1. Bicontinuous cubic liquid crystalline nanoparticles for oral delivery of Doxorubicin

    DEFF Research Database (Denmark)

    Swarnakar, Nitin K; Thanki, Kaushik; Jain, Sanyog

    2014-01-01

    PURPOSE: The present study explores the potential of bicontinous cubic liquid crystalline nanoparticles (LCNPs) for improving therapeutic potential of doxorubicin. METHODS: Phytantriol based Dox-LCNPs were prepared using hydrotrope method, optimized for various formulation components, process...... variables and lyophilized. Structural elucidation of the reconstituted formulation was performed using HR-TEM and SAXS analysis. The developed formulation was subjected to exhaustive cell culture experiments for delivery potential (Caco-2 cells) and efficacy (MCF-7 cells). Finally, in vivo pharmacokinetics...

  2. Pegylated liposomal doxorubicin in the management of ovarian cancer

    Directory of Open Access Journals (Sweden)

    Gabriella Ferrandina

    2010-09-01

    Full Text Available Gabriella Ferrandina1,2, Giacomo Corrado1, Angelo Licameli1, Domenica Lorusso2, Gilda Fuoco1, Salvatore Pisconti3, Giovanni Scambia2 1Gynecologic Oncology Unit, Department of Oncology, Catholic University of Campobasso, Campobasso, Italy; 2Gynecologic Oncology Unit, Catholic University of Rome, Rome, Italy; 3Salvatore Pisconti, Oncology Unit, Taranto Hospital, Taranto, Italy Abstract: Among the pharmaceutical options available for treatment of ovarian cancer, much attention has been progressively focused on pegylated liposomal doxorubicin (PLD, whose unique formulation, which entraps conventional doxorubicin in a bilayer lipidic sphere ­surrounded by a polyethylene glycol layer, prolongs the persistence of the drug in the ­circulation and potentiates intratumor drug accumulation. These properties enable this drug to sustain its very favorable toxicity profile and to be used safely in combination with other drugs. PLD has been already approved for treatment of advanced ovarian cancer patients failing first-line platinum-based treatment. Moreover, phase III trials have been already completed, and results are eagerly awaited, which hopefully will expand the range of PLD clinical application in this neoplasia both in front-line treatment, and in the salvage setting in combination with other drugs. Moreover, attempts are continuing to enable this drug to be combined with novel cytotoxic drugs and target-based agents. This review aims at summarizing the available evidence and the new perspectives for the clinical role of PLD in the management of patients with epithelial ovarian cancer.Keywords: pegylated liposomal doxorubicin, ovarian cancer, clinical trials

  3. Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin

    Directory of Open Access Journals (Sweden)

    Georges Said

    2012-01-01

    Full Text Available Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR. Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR and cell adhesion-mediated drug resistance (CAM-DR. Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR. The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR.

  4. 21 CFR 524.1484g - Neomycin sulfate-thiabendazole-dexamethasone solution.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Neomycin sulfate-thiabendazole-dexamethasone solution. 524.1484g Section 524.1484g Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... NEW ANIMAL DRUGS § 524.1484g Neomycin sulfate-thiabendazole-dexamethasone solution. (a)...

  5. Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia.

    Directory of Open Access Journals (Sweden)

    Laura B Ramsey

    Full Text Available Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002. Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.

  6. Pregabalin and dexamethasone improves post-operative pain treatment after tonsillectomy

    DEFF Research Database (Denmark)

    Mathiesen, O; Jørgensen, D G; Hilsted, K L;

    2011-01-01

    Post-tonsillectomy pain can be severe. We investigated the analgesic effect from combinations of paracetamol, pregabalin and dexamethasone in adults undergoing tonsillectomy.......Post-tonsillectomy pain can be severe. We investigated the analgesic effect from combinations of paracetamol, pregabalin and dexamethasone in adults undergoing tonsillectomy....

  7. Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Hassan, Memy H; Ghobara, Mohamed; Abd-Allah, Gamil M

    2014-08-01

    Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-α, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin-induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity.

  8. Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin

    Institute of Scientific and Technical Information of China (English)

    Rifki Febriansah; Dyaningtyas Dewi PP; Sarmoko; Nunuk Aries Nurulita; Edy Meiyanto; Agung Endro Nugroho

    2014-01-01

    Objective:To evaluate of hesperidin to overcome resistance of doxorubicin in MCF-7 resistant doxorubicin cells (MCF-7/Dox) in cytotoxicity apoptosis and P-glycoprotein (Pgp) expression in combination with doxorubicin. Methods:The cytotoxic properties, 50%inhibition concentration (IC50) and its combination with doxorubicin in MCF-7 cell lines resistant to doxorubicin (MCF-7/Dox) cells were determined using MTT assay. Apoptosis induction was examined by double staining assay using ethidium bromide-acridine orange. Immunocytochemistry assay was performed to determine the level and localization of Pgp. Results: Single treatment of hesperidin showed cytotoxic activity on MCF-7/Dox cells with IC50 value of 11 µmol/L. Thus, combination treatment from hesperidin and doxorubicin showed addictive and antagonist effect (CI>1.0). Hesperidin did not increase the apoptotic induction, but decreased the Pgp expressions level when combined with doxorubicin in low concentration. Conclusions: Hesperidin has cytotoxic effect on MCF-7/Dox cells with IC50 of 11 µmol/L. Hesperidin did not increased the apoptotic induction combined with doxorubicin. Co-chemotherapy application of doxorubicin and hesperidin on MCF-7/Dox cells showed synergism effect through inhibition of Pgp expression.

  9. High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage

    Directory of Open Access Journals (Sweden)

    Szabolcs Gergely

    2015-01-01

    Full Text Available Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge’s DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury.

  10. Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

    Science.gov (United States)

    Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

    2016-03-31

    The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

  11. Dexamethasone alleviates tumor-associated brain damage and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Zheng Fan

    Full Text Available Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA, a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc-; SLC7a11 and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage.

  12. Orbital fibroblast chemokine modulation: effects of dexamethasone and cyclosporin A

    OpenAIRE

    BURNSTINE, M.; Elner, S.; Elner, V.

    1998-01-01

    AIM—Orbital inflammation is common, but the mechanisms underlying leucocytic infiltration of orbital tissue are poorly understood. Human orbital fibroblasts (OF) express chemokines, interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1), when exposed to proinflammatory cytokines. The effects of dexamethasone (DEX) and cyclosporin A (CSA) on OF IL-8 and MCP-1 were examined.
METHODS—Cultured human OF were incubated with recombinant interleukin 1β (rIL-1β; 0.2, 2.0, 20 ng/ml) alone or i...

  13. Influence of phenylbutazone, mofebutazone and aspirin on the pharmacokinetics of dexamethasone in the rat.

    Science.gov (United States)

    Kassem, M A; Schulte, K E

    1981-01-01

    Phenylbutazone suppresses the C-6 hydroxylation, absorption rate, bioavailability, and renal and plasma clearanceè rates of dexamethasone administered orally to normal and oedemateous rats. It increases the half life and the volume of distribution. Aspirin exerts an effect which is less pronounced and involves the enhancement of the C-6 hydroxylation. Aspirin suppresses the half life and renal clearance of dexamethasone and enhances its hepatic clearance. Mofebutazone does not exert any pronounced influence. Also, unlike phenylbutazone, it does not interfere with the gastrointestinal absorption of dexamethasone. More rapid onset of absorption, decrease of half life and increase of the contribution of renal clearance to total plasma clearance of dexamethasone, are characteristics of the oedematous condition in the rat. The contribution of renal clearance to the elimination of dexamethasone is much greater in the rat than in human subjects. The presence of a third unconjugated metabolite of dexamethaone in the urine of rat has been demonstrated.

  14. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma

    OpenAIRE

    Gay, Francesca; Rajkumar, S. Vincent; Coleman, Morton; Kumar, Shaji; Mark, Tomer; Dispenzieri, Angela; Pearse, Roger; Gertz, Morie A.; Leonard, John; Lacy, Martha Q.; Cheng-Kiang, Selina; Roy, Vivek; Jayabalan, David S.; Lust, John A.; Witzig, Thomas E.

    2010-01-01

    The objective of this case–matched study was to compare the efficacy and the toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital–Cornell Medical Center were retrospectively compared to an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blin...

  15. Salinomycin enhances doxorubicin-induced cytotoxicity in multidrug resistant MCF-7/MDR human breast cancer cells via decreased efflux of doxorubicin.

    Science.gov (United States)

    Kim, Kwang-Youn; Kim, Sang-Hun; Yu, Sun-Nyoung; Park, Suel-Ki; Choi, Hyeun-Deok; Yu, Hak-Sun; Ji, Jae-Hoon; Seo, Young-Kyo; Ahn, Soon-Cheol

    2015-08-01

    Salinomycin is a monocarboxylic polyether antibiotic, which is widely used as an anticoccidial agent. The anticancer property of salinomycin has been recognized and is based on its ability to induce apoptosis in human multidrug resistance (MDR). The present study investigated whether salinomycin reverses MDR towards chemotherapeutic agents in doxorubicin-resistant MCF-7/MDR human breast cancer cells. The results demonstrated that doxorubicin-mediated cytotoxicity was significantly enhanced by salinomycin in the MCF-7/MDR cells, and this occurred in a dose-dependent manner. This finding was consistent with subsequent observations made under a confocal microscope, in which the doxorubicin fluorescence signals of the salinomycin-treated cells were higher compared with the cells treated with doxorubicin alone. In addition, flow cytometric analysis revealed that salinomycin significantly increased the net cellular uptake and decreased the efflux of doxorubicin. The expression levels of MDR-1 and MRP-1 were not altered at either the mRNA or protein levels in the cells treated with salinomycin. These results indicated that salinomycin was mediated by its ability to increase the uptake and decrease the efflux of doxorubicin in MCF-7/MDR cells. Salinomycin reversed the resistance of doxorubicin, suggesting that chemotherapy in combination with salinomycin may benefit MDR cancer therapy.

  16. Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

    Directory of Open Access Journals (Sweden)

    Maresha S Gay

    Full Text Available The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1, 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner.

  17. Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents.

    Directory of Open Access Journals (Sweden)

    M Estée Török

    Full Text Available BACKGROUND: Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown. METHODS: Vietnamese adults and adolescents with tuberculous meningitis recruited to a randomised, double-blind, placebo-controlled trial of adjunctive dexamethasone were followed-up at five years, to determine the effect of dexamethasone on long-term survival and neurological disability. RESULTS: 545 patients were randomised to receive either dexamethasone (274 patients or placebo (271 patients. 50 patients (9.2% were lost to follow-up at five years. In all patients two-year survival, probabilities tended to be higher in the dexamethasone arm (0.63 versus 0.55; p = 0.07 but five-year survival rates were similar (0.54 versus 0.51, p = 0.51 in both groups. In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07 but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36. The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7% and there was no significant association between dexamethasone treatment and disability status at five years (p = 0.32. CONCLUSIONS: Adjunctive dexamethasone appears to improve the probability of survival in patients with TBM, until at least two years of follow-up. We could not demonstrate a five-year survival benefit of dexamethasone treatment which may be confined to patients with grade 1 TBM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01317654.

  18. In vitro hemocompatibility and cytocompatibility of dexamethasone-eluting PLGA stent coatings

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jiang; Liu, Yang; Luo, Rifang; Chen, Si; Li, Xin; Yuan, Shuheng; Wang, Jin, E-mail: jinxxwang@263.net; Huang, Nan

    2015-02-15

    Highlights: • Biodegradable dexamethasone-eluting PLGA stent coatings were developed. • Stent coatings can withstand the compressive and tensile strains without cracking. • Stent coatings presented favorable release kinetic for the lesion site. • Stent coatings can effectively inhibit the adhesion and activation of platelets. • Stent coatings can effectively inhibit the proliferation of SMC. - Abstract: Drug-eluting stents (DESs) have been an important breakthrough for interventional cardiology applications since 2002. Though successful in reducing restenosis, some adverse clinical problems still emerged, which were mostly caused by the bare-metal stents and non-biodegradable polymer coatings, associated with the delayed endothelialization process. In this study, dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) coatings were developed to explore the potential application of dexamethasone-eluting stents. Dexamethasone-eluting PLGA stents were prepared using ultrasonic atomization spray method. For other tests like stability and cytocompatibility and hemocompatibility tests, dexamethasone loaded coatings were deposited on 316L SS wafers. Fourier transform-infrared spectroscopy (FT-IR) results demonstrated that there was no chemical reaction between PLGA and dexamethasone. The balloon expansion experiment and surface morphology observation suggested that the stent coatings were smooth and uniform, and could also withstand the compressive and tensile strains imparted without cracking after stent expansion. The drug release behavior in vitro indicated that dexamethasone existed burst release within 1 day, but it presented linear release characteristics after 6 days. In vitro platelets adhesion, activation test and APTT test were also done, which showed that after blending dexamethasone into PLGA, the hemocompatibility was improved. Besides, dexamethasone and dexamethasone-loaded PLGA coatings could significantly inhibit the attachment and

  19. Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

    Directory of Open Access Journals (Sweden)

    Denise Niewerth

    2016-09-01

    Full Text Available Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML and acute lymphocytic leukaemia (ALL. Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1 and AML (COG-AAML07P1. Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12 obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001. These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028 between patients who did (n = 4 and did not reach complete remission (CR (n = 8, although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.

  20. Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lai, H.C. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Yeh, Y.C. [Graduate Institute of Natural Healing Sciences, Nanhua University, Chiayi, Taiwan (China); Wang, L.C. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Ting, C.T.; Lee, W.L. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Lee, H.W. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Wang, K.Y. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine, Chung-Shan Medical University, Taichung, Taiwan (China); Wu, A. [College of Biological Science, University of California, Davis (United States); Su, C.S. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Liu, T.J., E-mail: trliu@vghtc.gov.tw [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China)

    2011-12-15

    Background: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. Methods: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 {mu}M), propofol (1 {mu}M), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. Results: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-{delta} was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. Conclusions: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application. -- Highlights: Black-Right-Pointing-Pointer We evaluate how propofol prevents doxorubicin-induced toxicity in cardiomyocytes. Black-Right-Pointing-Pointer Propofol reduces doxorubicin-imposed nitrative and oxidative stress. Black-Right-Pointing-Pointer Propofol suppresses mitochondrion-, p53- and PKC-related apoptotic signaling. Black-Right-Pointing-Pointer Propofol ameliorates apoptosis and

  1. Biodegradable polyurethane nanocomposites containing dexamethasone for ocular route

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues da Silva, Gisele [Federal University of Sao Joao Del Rei, School of Pharmacy, Divinopolis, Minas Gerais (Brazil); Silva-Cunha, Armando da [Federal University of Minas Gerais, School of Pharmacy, Belo Horizonte, Minas Gerais (Brazil); Behar-Cohen, Francine [INSERM, Physiopathology of ocular diseases: Therapeutic innovations, Institut des Cordeliers, Paris (France); Laboratoire d' Innovations Therapeutiques, Fondation Rothschild, Paris (France); Universite Rene Descartes, Hotel Dieu University Hospital, Paris (France); Ayres, Eliane [Federal University of Minas Gerais, Department of Metallurgical and Materials Engineering, Belo Horizonte, Minas Gerais (Brazil); Orefice, Rodrigo L., E-mail: rorefice@demet.ufmg.br [Federal University of Minas Gerais, Department of Metallurgical and Materials Engineering, Belo Horizonte, Minas Gerais (Brazil)

    2011-03-12

    The treatment of posterior segment ocular diseases, such as uveitis, by using eye drops and oral drugs is usually not effective due to the body's natural barriers to drug penetration. In this study, ocular implants to treat uveitis were synthesized by incorporating dexamethasone acetate, an important type of corticoid used in the treatment of some uveitis, into a biodegradable polyurethane containi clay nanoparticles. Biodegradable polyurethane nanocomposites having poly(caprolactone) oligomers as soft segments were obtained by delaminating clay particles within a polyurethane aqueous dispersion. The drug was incorporated into the polymer by dispersing it in the waterborne polyurethane followed by a drying step. Nanoparticles derived from clay were demonstrated to be able to tailor the mechanical properties of polyurethanes to achieve values that can match the properties of ocular soft tissues. Infrared spectra (FTIR) showed that the presence of clay particles was able to change the microphase separation process typical of polyurethanes. X-ray diffraction and small angle x-ray scattering (SAXS) results were explored to show that the incorporation of both dexamethasone acetate and nanocomponents derived from clay led to a less defined two-phase polyurethane. The presence of clay nanoparticles increased the rate of drug release measured in vitro. Human retinal pigment epithelial cells (ARPE-19) were cultured in contact with polyurethanes and polyurethane nanocomposites, and the viability of them (evaluated by using MTT assay after 7 days) showed that no toxic components were released from polyurethanes containing no drugs during the test.

  2. An NMR Study of the Bortezomib Degradation under Clinical Use Conditions

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    Adele Bolognese

    2009-01-01

    Full Text Available The (R-3-methyl-1-((S-3-phenyl-2-(pyrazine-2-carboxamidopropanamidobutyl-boronic acid, bortezomib (BTZ, which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. Commercial BTZ samples, reconstituted according to the reported commercial instructions and stored at 4∘C, were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material, the N-(1-(1-hydroxy-3-methylbutylamino-1-oxo-3-phenylpropan-2-yl pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration and the (S-N-(1-(3-methylbutanamido-1-oxo-3-phenylpropan-2-ylpyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration, identified on the basis of their chemical and spectroscopic properties. The BTZ1 and BTZ2 finding suggests that, under the common condition of use and at 4∘C, commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process.

  3. Uptake of dexamethasone incorporated into liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation.

    Science.gov (United States)

    Chono, Sumio; Morimoto, Kazuhiro

    2006-09-01

    To confirm the efficacy of dexamethasone incorporated into liposomes in the treatment of atherosclerosis, the uptake of dexamethasone-liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation in these cells were investigated in-vitro. Dexamethasone-liposomes were prepared with egg yolk phosphatidylcholine, cholesterol and dicetylphosphate in a lipid molar ratio of 7/2/1 by the hydration method. This was adjusted to three different particle sizes to clarify the influence of particle size on the uptake by the macrophages and foam cells, and the inhibitory effect on cellular cholesterol ester accumulation. The distribution of particle sizes of dexamethasone-liposomes were 518.7+/-49.5 nm (L500), 202.2+/-23.1 nm (L200), and 68.6+/-6.5 nm (L70), respectively. For each size, dexamethasone concentration and dexamethasone/lipid molar ratio in dexamethasone-liposome suspension were 1 mg dexamethasone mL-1 and 0.134 mol dexamethasone mol-1 total lipids, respectively. The zeta potential was approximately -70 mV for all sizes. Dexamethasone-liposomes or free dexamethasone were added to the macrophages in the presence of oxidized low density lipoprotein (oxLDL) and foam cells, and then incubated at 37 degrees C. The uptake amount of dexamethasone by the macrophages and foam cells after a 24-h incubation was L500>L200>free dexamethasone>L70. The macrophages in the presence of oxLDL and foam cells were incubated with dexamethasone-liposomes or free dexamethasone for 24 h at 37 degrees C to evaluate the inhibitory effect on the cellular cholesterol ester accumulation. The cellular cholesterol ester level in the macrophages treated with oxLDL was significantly increased compared with that in macrophages without additives. L500, L200 and free dexamethasone significantly inhibited this cholesterol ester accumulation. L500, L200 and free dexamethasone also significantly reduced cellular cholesterol ester accumulation in foam cells. In

  4. Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells.

    Science.gov (United States)

    Manni, Sabrina; Brancalion, Alessandra; Mandato, Elisa; Tubi, Laura Quotti; Colpo, Anna; Pizzi, Marco; Cappellesso, Rocco; Zaffino, Fortunato; Di Maggio, Speranza Antonia; Cabrelle, Anna; Marino, Filippo; Zambello, Renato; Trentin, Livio; Adami, Fausto; Gurrieri, Carmela; Semenzato, Gianpietro; Piazza, Francesco

    2013-01-01

    CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

  5. Human cytosolic sulfotransferase SULT1C4 mediates the sulfation of doxorubicin and epirubicin.

    Science.gov (United States)

    Luo, Lijun; Zhou, Chunyang; Hui, Ying; Kurogi, Katsuhisa; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh

    2016-04-01

    Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate-conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin.

  6. Autophagy is involved in doxorubicin induced resistance of human myeloma cell line RP-MI8226

    Institute of Scientific and Technical Information of China (English)

    潘耀柱

    2013-01-01

    Objective To explore the role of autophagy in doxorubicin (DOX) -induced resistance of human myeloma cell line RPMI8226.Methods We established doxorubicin induced resistant subline of myeloma cell line RPMI8226/DOX by drug concentration step-elevation method.Resistant index of DOX was measured by MTT

  7. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.

    Science.gov (United States)

    Liu, Yan; Asnani, Aarti; Zou, Lin; Bentley, Victoria L; Yu, Min; Wang, You; Dellaire, Graham; Sarkar, Kumar S; Dai, Matthew; Chen, Howard H; Sosnovik, David E; Shin, Jordan T; Haber, Daniel A; Berman, Jason N; Chao, Wei; Peterson, Randall T

    2014-12-10

    Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.

  8. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Issam Salouege

    2014-01-01

    Conclusion: We have evaluated the protective effect of trimetazidine on an animal model of doxorubicin-induced cardiotoxicity and hepatotoxicity. The evaluation of these effects were assessed by several means; tissular distribution of doxorubicin, histological examination, assessment of liver function, and EF LV by scintigraphy that characterizes the originality of this study.

  9. The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis.

    Science.gov (United States)

    Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia

    2013-10-01

    Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

  10. Correction to: Direct effects of doxorubicin on skeletal muscle contribute to fatigue

    NARCIS (Netherlands)

    Norren, van K.; Helvoort, van A.; Agriles, J.M.; Tuijl, van S.; Arts, K.; Gorselink, M.; Laviano, A.; Kegler, D.; Haagsman, H.P.; Beek, van der E.M.

    2009-01-01

    Chemotherapy-induced fatigue is a multidimensional symptom. Oxidative stress has been proposed as a working mechanism for anthracycline-induced cardiotoxicity. In this study, doxorubicin (DOX) was tested on skeletal muscle function. Doxorubicin induced impaired ex vivo skeletal muscle relaxation fol

  11. Study of histamine wheal suppression by dexamethasone with and without iontophoresis

    Directory of Open Access Journals (Sweden)

    Sreerekha

    2006-01-01

    Full Text Available Background: Iontophoresis increases the penetration of drugs into the skin by electric current. The ability of topical steroids to reduce the size of the histamine wheal was used to assess the efficacy of topical dexamethasone delivered with and without iontophoresis. Aim: To determine the wheal suppressing ability of dexamethasone delivered with and without iontophoresis. Methods: A template with three squares of 3 x 3 cm was placed on both forearms of 20 volunteers and the edges marked. A gauze piece soaked in 2 ml of dexamethasone solution was placed on the flexor aspect of the left forearm and the electrode, an aluminum foil was placed on it and connected to the negative pole (since dexamethasone is negatively charged. An electric current was passed for 15 minutes. Similarly, on the right forearm, a dexamethasone soaked gauze piece was placed without iontophoresis. Histamine wheal suppression was assessed at the end of 30 min, 1 hr and 2 hrs, on both sides. Statistical analysis was done using an independent t-test. Results: There was a statistically significant difference in wheal suppression at 30 min ( p =0.006 on the left hand where iontophoresis was used. Conclusion: Our experiment showed that topical dexamethasone with iontophoresis has the maximum effect at the end of 30 minutes and is more effective than dexamethasone without iontophoresis.

  12. Involvement of basolateral amygdala GABAA receptors in the effect of dexamethasone on memory in rats

    Institute of Scientific and Technical Information of China (English)

    Lotfollah KHAJEHPOUR; Acieh ALIZADEH-MAKVANDI; Mahnaz KESMATI; Hooman ESHAGH-HAROONI

    2011-01-01

    In this study we investigated whether GABAA receptors of the basolateral amygdala (BLA) interact with the effect of dexamethasone on the retrieval stage of memory.Adult male Wistar rats were bilaterally cannulated in the BLA by stereotaxic surgery.The animals were trained in step-through apparatus by induction of electric shock (1.5 mA,3 s) and were tested for memory retrieval after 1 d.The time of latency for entering the dark compartment of the instrument and the time spent by rats in this chamber were recorded for evaluation of the animals' retrieval in passive avoidance memory.Administration of dexamethasone (0.3 and 0.9 mg/kg,subcutaneously (s.c.)),immediately after training,enhanced memory retrieval.This effect was reduced by intra-BLA microinjection of muscimol (0.125,0.250 and 0.500 μg/rat),when administered before 0.9 mg/kg of dexamethasone.Microinjection of bicuculline (0.75 μg/rat,intra-BLA) with an ineffective dose of dexamethasone (0.1 mg/kg,s.c.) increased memory retrieval.However,the same doses of muscimol and bicuculline without dexamethasone did not affect memory processes.Our data support reports that dexamethasone enhances memory retrieval.It seems that GABAA receptors of the BLA mediate the effect of dexamethasone on memory retrieval in rats.

  13. Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups.

    Directory of Open Access Journals (Sweden)

    Winfried Neuhaus

    Full Text Available Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4. Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.

  14. [Effect of dexamethasone on indomethacin-induced gastric erosion formation upon duration of the hormonal action].

    Science.gov (United States)

    Podvigina, T T; Morozova, O Iu; Bagaeva, T R; Filaretova, L P

    2009-07-01

    The aim of the study was to verify a dependence of dexamethasone effect on the gastric erosion formation upon duration of the hormonal action. Gastric erosions were induced by indometha cin (35 mg/kg, sc) in male rats after 24-hour fasting. The rats were given a single injection of dexamethasone at a dose of 1 mg/kg and they underwent the ulcerogenic stimulus (indomethacin) at va rious time points after the hormonal injection (1, 6, 12, 18, 24 hours as well as 3, 5, 7 days). The control rats were given dexamethasone vehicle. In 4 hours after indomethacin injection gastric erosions, corticosterone and blood glucose levels, as well as body and thymus weights were examined. The results obtained demonstrate a dependence ofdexamethasone effect on the gastric erosion formation upon duration of its action: dexamethasone attenuated or aggravated indomethacin-induced gastric erosions depending on the time of its injection. Gastroprotective action of dexamethasone was observed in the case of its injection 1, 6, and 12 hours before indomethacin. The further increase in the time interval caused transformation of gastroprotective action of dexamethasone against ulcerogenic effect. The data obtained suggest that a disturbance of carbohydrate regulation accompanied with the signs of catabolic effects of the glucocorticoid may be responsible for the ulcerogenic action of dexamethasone.

  15. Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

    Science.gov (United States)

    Neeson, Paul J; Hsu, Andy K; Chen, Yin R; Halse, Heloise M; Loh, Joanna; Cordy, Reece; Fielding, Kate; Davis, Joanne; Noske, Josh; Davenport, Alex J; Lindqvist-Gigg, Camilla A; Humphreys, Robin; Tai, Tsin; Prince, H Miles; Trapani, Joseph A; Smyth, Mark J; Ritchie, David S

    2015-09-01

    There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8(+) T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.

  16. Therapeutic effect of bortezomib for primary plasma cell leukemia followed by auto/allo stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Ozasa R

    2012-07-01

    Full Text Available Ryotaro Ozasa, Masaaki Hotta, Hideaki Yoshimura, Takahisa Nakanishi, Takeshi Tamaki, Shinya Fujita, Naoto Nakamichi, Michihiko Miyaji, Kazuyoshi Ishii, Tomoki Ito, Shosaku NomuraFirst Department of Internal Medicine, Kansai Medical University, Osaka, JapanAbstract: Plasma cell leukemia (PCL is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.Keywords: plasma cell leukemia, multiple myeloma, bortezomib, stem cell transplantation

  17. Effect of dexamethasone on voltage-gated Na+ channel in cultured human bronchial smooth muscle cells.

    Science.gov (United States)

    Nakajima, Toshiaki; Jo, Taisuke; Meguro, Kentaro; Oonuma, Hitoshi; Ma, Ji; Kubota, Nami; Imuta, Hiroyuki; Takano, Haruhito; Iida, Haruko; Nagase, Takahide; Nagata, Taiji

    2008-06-06

    Voltage-gated Na(+) channel (I(Na)) encoded by SCN9A mRNA is expressed in cultured human bronchial smooth muscle cells. We investigated the effects of dexamethasone on I(Na), by using whole-cell voltage clamp techniques, reverse transcriptase/polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Acute application of dexamethasone (10(-6) M) did not affect I(Na). However, the percentage of the cells with I(Na) was significantly less in cells pretreated with dexamethasone for 48 h, and the current-density of I(Na) adjusted by cell capacitance in cells with I(Na) was also decreased in cells treated with dexamethasone. RT-PCR analysis showed that alpha and beta subunits mRNA of I(Na) mainly consisted of SCN9A and SCN1beta, respectively. Treatment with dexamethasone for 24-48 h inhibited the expression of SCN9A mRNA. The inhibitory effect of dexamethasone was concentration-dependent, and was observed at a concentration higher than 0.1 nM. The effect of dexamethasone on SCN9A mRNA was not blocked by spironolactone, but inhibited by mifepristone. The inhibitory effects of dexamethasone on SCN9A mRNA could not be explained by the changes of the stabilization of mRNA measured by using actinomycin D. These results suggest that dexamethasone inhibited I(Na) encoded by SCN9A mRNA in cultured human bronchial smooth muscle cells by inhibiting the transcription via the glucocorticoid receptor.

  18. Dexamethasone mediates protection against acute pancreatitis via upregulation of pancreatitis-associated proteins

    Institute of Scientific and Technical Information of China (English)

    Emad Kandil; Yin-Yao Lin; Martin H Bluth; Hong Zhang; Gabriel Levi; Michael E Zenilman

    2006-01-01

    AIM:To examine the influence of dexamethasone on pancreatitis-associated protein (PAP) gene expression using both in vitro and in vivo models of acute pancreatitis and to study how PAP gene expression correlates with severity of pancreatitis.METHODS:In vifro, IL-6 stimulated pancreas acinar AR42J cells were cultured with increasing concentrations of dexamethasone and assayed for PAP expression (RT-PCR). In vivo, pancreatitis was induced in rats by retrograde injection of 40 g/L taurocholate into the pancreatic duct. Animals were pretreated with dexamethasone (2 mg/kg) daily or saline for 4 d.Pancreata and serum were harvested after 24 h and gene expression levels of PAP Ⅰ , Ⅱ and Ⅲ were measured by RT-PCR. Severity of pancreatitis was based on serum amylase, pancreatic wet weight, and histopathological score.RESULTS:In vitro, dexamethasone and IL-6 induced a marked transcription of PAP Ⅰ, Ⅱ and Ⅲ genes in AR42J cells at 24 h (P < 0.05 for all comparisons). In vivo,pancreas mRNA levels of PAP Ⅰ, Ⅱ or Ⅲ increased by 2.6-fold, 1.9-fold, and 1.3-fold respectively after dexamethasone treatment, compared with saline treated animals. Serum amylase levels and edema were significantly lower in the dexamethasone group compared with the saline group. Histopathologic evaluation revealed less inflammation and necrosis in pancreata obtained from dexamethasone treated animals (P < 0.05).CONCLUSION:Dexamethasone significantly decreases the severity of pancreatitis. The protective mechanism of dexamethasone may be via upregulating PAP gene expression during injury.

  19. Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers

    Science.gov (United States)

    Jang, Kyungho; Kim, Min-Kyoung; Oh, Jaeseong; Lee, SeungHwan; Cho, Joo-Youn; Yu, Kyung-Sang; Choi, Tai Kiu; Lee, Sang-Hyuk; Lim, Kyoung Soo

    2017-01-01

    Purpose Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results Area under the plasma concentration–time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0–48h/oseltamivir AUC0–48h) was 0.92 (0.87–0.97). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatments. Conclusion Coadministration of dexamethasone with oseltamivir slightly decreased systemic exposure to oseltamivir and oseltamivir carboxylate in healthy volunteers. This result suggests that CES1 is inhibited by dexamethasone in humans. However, coadministration of oseltamivir and dexamethasone did not appear to have a clinically relevant effect on the PK of oseltamivir; based on these results, dexamethasone can be coadministered with oseltamivir. PMID

  20. Bortezomib for antibody mediated rejection treatment: experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City.

    Science.gov (United States)

    Leyva, Sergio; Marino-Vázquez, Lluvia A; Reyes-Loaeza, Jorge A; Vega, Olynka; Uribe-Uribe, Norma; Alberú, Josefina; Morales-Buenrostro, Luis E

    2009-01-01

    The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response neither to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal.

  1. 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 vitro

    DEFF Research Database (Denmark)

    Lund, Thomas; Søe, Kent; Abildgaard, Niels;

    2010-01-01

    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 recei...

  2. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

    Science.gov (United States)

    Larocca, A; Bringhen, S; Petrucci, M T; Oliva, S; Falcone, A P; Caravita, T; Villani, O; Benevolo, G; Liberati, A M; Morabito, F; Montefusco, V; Passera, R; De Rosa, L; Omedé, P; Vincelli, I D; Spada, S; Carella, A M; Ponticelli, E; Derudas, D; Genuardi, M; Guglielmelli, T; Nozzoli, C; Aghemo, E; De Paoli, L; Conticello, C; Musolino, C; Offidani, M; Boccadoro, M; Sonneveld, P; Palumbo, A

    2016-06-01

    This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

  3. Prospective longitudinal study on quality of life in relapsed/refractory multiple myeloma patients receiving second- or third-line lenalidomide or bortezomib treatment.

    Science.gov (United States)

    Leleu, X; Kyriakou, C; Vande Broek, I; Murphy, P; Bacon, P; Lewis, P; Gilet, H; Arnould, B; Petrucci, M T

    2017-03-17

    Treatment advances for multiple myeloma (MM) that have prolonged survival emphasise the importance of measuring patients' health-related quality of life (HRQoL) in clinical studies. HRQoL/functioning and symptoms of patients with relapsed/refractory MM (RRMM) receiving second- or third-line lenalidomide or bortezomib treatment were measured in a prospective European multicentre, observational study at different time points. At baseline, patients in the lenalidomide cohort were frailer than in the bortezomib cohort with more rapid disease progression at study entry (more patients with Eastern Cooperative Oncology Group performance status >2, shorter time from diagnosis, more chronic heart failure, higher serum creatinine levels, more patients with dialysis required). About 40% of the patients receiving lenalidomide discontinued the study in Life Core domains of Diarrhoea and Global Health Status/QoL had worsened in the lenalidomide and bortezomib cohorts, respectively. A clinically meaningful deterioration in HRQoL was more often observed for patients who discontinued the study prior to 6 months in the bortezomib cohort than in the lenalidomide cohort.

  4. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma.

    OpenAIRE

    Perilongo, G.; Maibach, R; Shafford, E.; Brugieres, L; Brock, P; Morland, B.; de Camargo, B; Zsiros, J.; Roebuck, D; Zimmermann, A; Aronson, D.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.

    2009-01-01

    BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we...

  5. Development and physicochemical characterization of dexamethasone-loaded polymeric nanocapsule suspensions

    Directory of Open Access Journals (Sweden)

    Rossana Barcellos Friedrich

    2008-01-01

    Full Text Available The influence of drug concentration, oil phase, and surfactants on the characteristics of dexamethasone-loaded nanocapsules was investigated. The best formulations were obtained at dexamethasone concentrations of 0.25 and 0.50 mg.mL-1 (encapsulation efficiency: 80-90%; mean size: 189-253 nm. The type of oil phase influenced only the stability of dexamethasone-loaded nanocapsules. The association of polysorbate 80 and sorbitan monooleate provided a more stable formulation. Sunflower oil and sorbitan sesquioleate used for the first time as oil phase and surfactant for nanocapsules, respectively, have allowed obtaining suspensions with low mean size and narrow size distribution.

  6. Visible-light system for detecting doxorubicin contamination on skin and surfaces.

    Science.gov (United States)

    Van Raalte, J; Rice, C; Moss, C E

    1990-05-01

    A portable system that uses fluorescence stimulated by visible light to identify doxorubicin contamination on skin and surfaces was studied. When activated by violet-blue light in the 465-nm range, doxorubicin fluoresces, emitting orange-red light in the 580-nm range. The light source to stimulate fluorescence was a slide projector with a filter to selectively pass short-wave (blue) visible light. Fluorescence was both observed visually with viewing spectacles and photographed. Solutions of doxorubicin in sterile 0.9% sodium chloride injection were prepared in nine standard concentrations ranging from 2 to 0.001 mg/mL. Droplets of each admixture were placed on stainless steel, laboratory coat cloth, pieces of latex examination glove, bench-top absorbent padding, and other materials on which antineoplastics might spill or leak. These materials then were stored for up to eight weeks and photographed weekly. The relative ability of water, household bleach, hydrogen peroxide solution, and soap solution to deactivate doxorubicin was also measured. Finally, this system was used to inspect the antineoplastic-drug preparation and administration areas of three outpatient cancer clinics for doxorubicin contamination. Doxorubicin fluorescence was easily detectable with viewing spectacles when a slide projector was used as the light source. The photographic method was sensitive for doxorubicin concentrations from 2.0 to 0.001 mg/mL. Immersion of study materials in bleach for one minute eliminated detectable fluorescence. Doxorubicin contamination is detectable for at least eight weeks in the ambient environment. Probable doxorubicin contamination was detected in two of the three clinics surveyed. A safe, portable system that uses fluorescence stimulated by visible light is a sensitive method for detecting doxorubicin on skin and surfaces.

  7. Acute retinal necrosis following intravitreal dexamethasone (Ozurdex® implant

    Directory of Open Access Journals (Sweden)

    Murat Kucukevcilioglu

    2015-04-01

    Full Text Available A 52-year-old woman undergoing azathioprine treatment for rheumatoid arthritis developed acute retinal necrosis a month after intravitreal dexamethasone (Ozurdex ® implantation for posterior uveitis in the left eye. Varicella zoster virus (VZV DNA was detected in the anterior chamber and vitreous samples on polymerase chain reaction (PCR analysis. Retinal detachment occurred despite systemic and intravitreal antiviral therapy. Favorable structural and functional outcomes were achieved after retinal surgery with silicone oil. To the authors’ knowledge, this is the first reported case of acute retinal necrosis following placement of an Ozurdex® implant. Physicians practicing Ozurdex® implantations should be aware of this unusual but devastating complication. Extra caution and frequent follow-up are required in all immunocompromised patients receiving Ozurdex® implantation.

  8. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Vogel Ulla

    2010-08-01

    Full Text Available Abstract Background The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Methods Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion, *6, and CYP2D6 gene duplication. Results In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

  9. Subcutaneous bortezomib in multiple myeloma patients induces similar therapeutic response rates as intravenous application but it does not reduce the incidence of peripheral neuropathy.

    Directory of Open Access Journals (Sweden)

    Jiri Minarik

    Full Text Available Subcutaneous (SC application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM patients treated using either intravenous (IV or subcutaneous (SC route of administration.During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly - 63% or twice weekly - 27% in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration.The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥ 3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN. PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥ 2 was present in 20% vs 18% and PN grade ≥ 3 was present in 6% vs 4%.We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.

  10. High throughput chemical library screening identifies a novel p110-δ inhibitor that potentiates the anti-myeloma effect of bortezomib.

    Science.gov (United States)

    Malek, Ehsan; Driscoll, James J

    2016-06-21

    Multiple myeloma (MM) remains an incurable plasma cell malignancy and drug resistance persists as the major cause of treatment failure leading to fatal outcomes. The phosphatidyl-inositol-3-kinase (PI3K) pathway is constitutively hyperactivated in MM to promote disease progression and drug resistance. While inhibiting PI3K induces apoptosis in MM and is predicted to increase tumor susceptibility to anticancer therapy, early-generation pan-PI3K inhibitors display poor clinical efficacy as well as intolerable side effects. Here, we found that PI3K activity is significantly upregulated in MM cell lines and patient tumor cells resistant to bortezomib and that the majority of PI3K activity in MM cells is dependent upon the p110-δ isoform. Genetic or pharmacologic inhibition of p110-δ substantially reduced myeloma viability and enhanced cellular sensitivity to bortezomib. Chemical library screens then identified a novel compound, DT97, that potently inhibited p110-δ kinase activity and induced apoptosis in MM cells. DT97 was evaluated in the NCI-60 panel of human cancer cell types and anticancer activity was greatest against MM, leukemia and lymphoma cells. Co-treatment with DT97 and bortezomib synergistically induced apoptosis in MM patient cells and overcame bortezomib-resistance. Although bone marrow stromal cells (BMSCs) promote MM growth, the pro-survival effects of BMSCs were significantly reduced by DT97 treatment. Co-treatment with bortezomib and DT97 reduced the growth of myeloma xenotransplants in murine models and prolonged host survival. Taken together, the results provide the basis for further clinical evaluation of p110-δ inhibitors, as monotherapy or in synergistic combinations, for the benefit of MM patients.

  11. Induction of taxol metabolism in the rat by dexamethasone

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, C.D.; Gondi, K.N.; Walle, T.

    1994-12-31

    The antitumor drug taxol was metabolized to two major metabolites (RM1 and RM2) in adult male and female rat liver microsomes. The male rats produced RM1 2.6 fold faster than the females, and they produced RM2 3 fold faster than the females. This correlated well with the sex differences noticed in liver microsomal cytochrome P450 (CYP) 3A content (4.4 fold greater in male) and 6{beta}-hydroxylation of testosterone (2.4 fold greater in male). Taxol was metabolized to three major metabolites (RM1, RM2, and RM3) in adult male and female rat liver microsomes from rats pretreated with dexamethasone. Production of RM1 and RM2 was increased in these rats (2.3 and 3.3 fold respectively in males; 6.5 and 8.7 fold respectively in females) as compared to the untreated rats. These results compared well with the induction of CYP 3A proteins (3.5 fold in male, 10 fold in female) and induction of 6{beta}-hydroxylation (1.9 fold in males, 3.8 fold in females). RM3, which was produced only by the rats pretreated with dexamethasone, had a retention time of 0.58 relative to taxol which corresponds to 6{alpha}- hydroxytaxol, the major human metabolite of taxol. This study indicates that taxol metabolism in the rat is likely due to CYP 3A enzymes. Although the evidence points toward CYP 3A1 as the major isoform involved, it does not rule out others. The findings also suggest that CYP 3A1 is responsible for the induced metabolite, RM3.

  12. Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.

    Science.gov (United States)

    Trapani, Valentina; Luongo, Francesca; Arduini, Daniela; Wolf, Federica I

    2016-03-21

    Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.

  13. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Jacevic, Vesna; Djordjevic, Aleksandar; Srdjenovic, Branislava; Milic-Tores, Vukosava; Segrt, Zoran; Dragojevic-Simic, Viktorija; Kuca, Kamil

    2017-03-16

    Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

  14. Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

    Institute of Scientific and Technical Information of China (English)

    Ling-jie XU; Liang JIN; Hong PAN; Ao-zhen ZHANG; Gang WEI; Ping-ping LI; Wei-yue LU

    2006-01-01

    Aim: To investigate the effects of deferiprone on doxorubicin-induced cardiotoxicity and determine its protection on cardiac contractility in vivo at tissue level. Methods: Spontaneously-beating isolated atria from rats were pretreated with deferiprone for 10 min at 1.2 mmol/L or 0.3 mmol/L, respectively before co-incubation with doxorubicin (DOX) at 0.03 mmol/L for 60 min. Contractility (dF/dt) was assessed every 10 min during the incubation. After that, the tissues around the sinuatrial nodes were fixed for ultrastructural study; succinate dehydrogenase (SDH) and Cu, Zn superoxide dismutase (Cu, Zn-SOD) activity, as well as malondialdehyde (MDA) level of the atria were assayed. Results: Treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices. Conversely, with the presence of deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Cu, Zn-SOD activity increased by 12.97%-12.11%, the MDA level decreased by 29.12%-39.82% and succinate dehydrogenase (SDH) activity was ameliorated by 25.15%-34.76%. Conclusion : Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone is able to protect mitochondrial function and structure form damage induced by DOX. This cardiac protective potential of deferiprone could be due to its defense capability against oxidative damage.

  15. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar, David; Strom, Joshua; Chen, Qin M., E-mail: qchen@email.arizona.edu

    2014-04-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA.

  16. Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

    Science.gov (United States)

    Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

    2016-01-01

    Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells.

  17. Molecular Mechanism of Bovine Trabecular Meshwork Cells Apoptosis Induced by Dexamethasone and Protection by Pilocarpine

    Institute of Scientific and Technical Information of China (English)

    Yajuan Gu; Shujun Zeng; Pengxin Qiu; Yuping Wu; Dawei Peng; Guangmei Yan

    2005-01-01

    Purpose: To study the molecular mechanism of trabecular meshwork cells apoptosis induced by dexamethasone and the protection of pilocarpine.Methods: Determining mRNA expression with reverse transcription-polymerase chain reaction (RT-PCR), protein expression with Western blots and the percentage of apoptotic cells with fluorescent microscopy.Results: Dexamethasone up-regulated Fas proteins and affected Bax, caspase-8 and caspase-9 proteins in an action of first decrease then increase. Pre-treatment with pilocarpine decreased the four proteins expression, which were increased by dexamethasone. Pilocarpine self could decrease pro-apoptotic factors Bax, caspase-8 and caspase-9 proteins expression.Conclusion: Fas/FasL pathway participated in apoptotic process induced by dexamethasone in trabecular meshwork cells and the process was probably related with both caspase-8 and caspase-9 pathways. Pilocarpine protected the cells against apoptosis through down-regulating Fas, Bax, caspase-8 and caspase-9 proteins expression.

  18. Fentanyl, dexmedetomidine, dexamethasone as adjuvant to local anesthetics in caudal analgesia in pediatrics: A comparative study

    Directory of Open Access Journals (Sweden)

    Elham M. El-Feky

    2015-04-01

    Conclusion: Both caudal dexmedetomidine and caudal dexamethasone added to local anesthetics are good alternatives in prolongation of postoperative analgesia compared to caudal local anesthetic alone or added to caudal fentanyl. Also they showed less side effects compared to caudal fentanyl.

  19. Intraoperative High-Dose Dexamethasone in Cardiac Surgery and the Risk of Rethoracotomy

    NARCIS (Netherlands)

    van Osch, Dirk; Dieleman, Jan M.; Nathoe, Hendrik M.; Boasson, Marc P.; Kluin, Jolanda; Bunge, Jeroen J. H.; Nierich, Arno P.; Rosseel, Peter M.; Maaten, van der Joost; Hofland, Jan; Diephuis, Jan C.; de Lange, Fellery; Boer, Christa; van Dijk, Diederik

    2015-01-01

    Background. Cardiac surgery with the use of cardiopulmonary bypass is associated with a systemic inflammatory response. Intraoperative corticosteroids are administered to attenuate this inflammatory response. The recent Dexamethasone for Cardiac Surgery (DECS) trial could not demonstrate a beneficia

  20. Intraoperative High-Dose Dexamethasone in Cardiac Surgery and the Risk of Rethoracotomy

    NARCIS (Netherlands)

    van Osch, Dirk; Dieleman, Stefan; Nathoe, HM; Boasson, Marc P; Kluin, Jolanda; Bunge, Jeroen J H; Nierich, Arno P; Rosseel, Peter M; van der Maaten, Joost M; Hofland, Jan; Diephuis, Jan C; de Lange, Fellery; Boer, Christa; van Dijk, Diederik

    2015-01-01

    BACKGROUND: Cardiac surgery with the use of cardiopulmonary bypass is associated with a systemic inflammatory response. Intraoperative corticosteroids are administered to attenuate this inflammatory response. The recent Dexamethasone for Cardiac Surgery (DECS) trial could not demonstrate a beneficia

  1. [Modulation of the effects of dexamethasone in rat skeletal muscle by testosterone].

    Science.gov (United States)

    Trush, V V; Soboliev, V I

    2013-01-01

    In experiments on young females white rats by means of methods of electromyography and ergography we investigated the efficiency of a testosterone-propionate for smoothing of negative effects of dexamethasone on skeletal muscle. It has been established that the chronic injection of dexamethasone causes the decreasing of amplitude of contraction of forward tibial muscle on 29.7-59.3% (after 5-25 injections) and the lengthening of the latent period of muscle's excitation on 18.5-16.5% (after 15-25 injections), whereas the complex application of testosterone and dexamethasone prevents the changing of these parameters. At the same time testosterone didn't provide the smoothing of negative influence of dexamethasone on muscle's resistance to fatigue development.

  2. Gastrointestinal tract obstruction secondary to post-operative oedema: does dexamethasone administration help?

    Science.gov (United States)

    Atie, M; Khoma, O; Dunn, G; Falk, G L

    2016-08-23

    Oedema can occur in handled tissues following upper gastrointestinal surgery with anastomosis formation. Obstruction of the lumen may result in delayed return of enteric function. Intravenous steroid use may be beneficial. Three cases of delayed emptying following fundoplication, gastro-enteric and entero-enteric anastomoses are reviewed. Conservative management with supportive measures failed. Dexamethasone was administered to treat the oedematous obstruction. A literature review in PubMed, Cochrane database and Medline for English language publications on the use of dexamethasone in the treatment of acute post surgical oedema of the upper gastrointestinal was conducted. Administration of dexamethasone led to resolution of symptoms and successful outcome. No reports on the use of steroids in this context were identified in the literature. The use of dexamethasone may effectively treat intestinal obstruction due to inflammatory or oedematous cause in the early post-operative period.

  3. The association of perioperative dexamethasone, smoking and alcohol abuse with wound complications after laparotomy

    DEFF Research Database (Denmark)

    Dahl, Rikke M; Wetterslev, Jørn; Jorgensen, Lars N;

    2014-01-01

    perioperative administration of dexamethasone, pre-operative smoking or alcohol abuse is, however, uncertain. METHODS: This study was a post hoc analysis of data from the PROXI randomized trial in 1386 patients who underwent emergency or elective laparotomy. We assessed the associations of use of dexamethasone......, smoking status and alcohol abuse with the primary outcome, being a composite of SSI, anastomotic leak, wound dehiscence, burst abdomen and 30-day mortality. RESULTS: The primary outcome occurred in 21% of patients receiving dexamethasone versus 28% of patients not receiving dexamethasone...... abdomen (3.8% vs 2.4%, P = 0.04). In alcohol abusers, the primary outcome occurred in 48%, compared with 25% in patients who did not abuse alcohol (P = 0.0006). Burst abdomen occurred more commonly in alcohol abusers (15% vs 2.3%, P 

  4. Dexamethasone and diclofenac confirmation by LC-MS-MS as herbal product adulterants

    Directory of Open Access Journals (Sweden)

    Lourdes Garza-Ocañas

    2013-09-01

    Full Text Available Objective. To confirm the presence of dexamethasone and diclofenac as adulterants of an herbal product. Materials and methods. For identificaction and confirmation of drugs a method of instrumental analysis by liquid chromatography coupled with high pressure tandem mass spectrometry was used. Results. The presence of dexamethasone and diclofenac was confirmed in samples of 11 bottles of Reumofan Plus obtained from patients and/or physicians. The methodology used, allowed separation of stereoisomers dexamethasone and betamethasone, the relative abundances of product ions 237.2 and 279.2 m / z spectrally differentiate the compounds. Conclusions. The presence of dexamethasone and diclofenac was confirmed in samples of a product marketed as “100% natural” obtained from patients and / or physicians in a period from January to December, 2011.

  5. Dexamethasone prolongs local analgesia after subcutaneous infiltration of bupivacaine microcapsules in human volunteers

    DEFF Research Database (Denmark)

    Holte, Kathrine; Werner, Mads U; Lacouture, Peter G;

    2002-01-01

    BACKGROUND: The addition of small amounts of dexamethasone to extended-release formulations of bupivacaine in microcapsules has been found to prolong local analgesia in experimental studies, but no clinical data are available. METHODS: In a double-blinded study, 12 healthy male volunteers were...... randomized to receive simultaneous subcutaneous injections of bupivacaine microcapsules with dexamethasone and bupivacaine microcapsules without dexamethasone in each calf. Local analgesia was assessed with a validated human pain model; main parameters evaluated were thermal, mechanical, and pain detection...... curve [AUC]) were considered best estimate of analgesia. Safety evaluations were performed daily for the first week and at 2 weeks, 6 weeks, and 6 months after injection. RESULTS: The addition of dexamethasone significantly prolonged local analgesia of bupivacaine microcapsules without influence...

  6. Intratympanic injection of dexamethasone for treatment of tinnitus in patients with sudden sensorineural hearing loss

    OpenAIRE

    Yoshida, Tadao; Teranishi, Masaaki; Iwata, Tomoyuki; Otake, Hironao; Nakashima, Tsutomu

    2012-01-01

    The purpose of this study is to test the effectiveness of intratympanic dexamethasone injections as a treatment for severe tinnitus in idiopathic sudden sensorineural hearing loss (SNHL). We studied 37 patients who received intratympanic dexamethasone injections and 14 control patients who did not receive it, with severe tinnitus after onset of unilateral sudden SNHL. Hearing level did not change during this study in any patient. The relationship between the duration of tinnitus and effective...

  7. Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation.

    LENUS (Irish Health Repository)

    Butler, Joseph S

    2010-09-01

    The Wnt\\/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in bone development and remodeling. The objectives of this study were firstly, to determine the effects of dexamethasone exposure on Wnt\\/β-catenin signaling at an intracellular and transcriptional level, and secondly, to assess the phenotypic effects of silencing the Wnt antagonist, Dickkopf-1 (Dkk1) in the setting of dexamethasone exposure.

  8. ANTIDIABETIC AND HYPOLIPIDEMIC ACTIVITY OF GYMNEMA SYLVESTRE IN DEXAMETHASONE INDUCED INSULIN RESISTANCE IN ALBINO RATS

    OpenAIRE

    Hemanth Kumar V, Nagendra Nayak IM , Shobha V Huilgol, Saeed M Yendigeri , Narendar K

    2015-01-01

    Background: Gymnema sylvestre plant was widely used for medicinal purpose. The plant leaves were traditionally used to treat diabetes. Aim: To determine the antidiabetic and hypolipidemic activity of Gymnema sylvestre in dexamethasone induced insulin resistance in Albino rats. Objectives: The present study was undertaken to evaluate antidiabetic and hypolipidemic activity of Gymnema sylvestre leaf aqueous extract against dexamethasone induced insulin resistance in Albino rats. Materials and M...

  9. Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice

    OpenAIRE

    Ghaisas, M. M.; Ahire, Y. S.; P R Dandawate; Gandhi, S.P; Mule, M.

    2011-01-01

    In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/...

  10. Antagonistic interactions between dexamethasone and fluoxetine modulate morphodynamics and expression of cytokines in astrocytes.

    Science.gov (United States)

    Henkel, A W; Alali, H; Devassy, A; Alawadi, M M; Redzic, Z B

    2014-11-07

    The "plasticity hypothesis" proposes that major depression is caused by morphological and biochemical modifications in neurons and astrocytes and those beneficial pharmacological effects of selective-serotonin-reuptake-inhibitors (SSRI) are at least partially associated with modifications of cellular communications between these cells. In this study we examined effects of the antidepressant fluoxetine on cultured astrocytes that were, in some cases, pretreated with dexamethasone, a cortisol analog known to trigger depressive disorder. Primary rat astrocytes were purified and treated with dexamethasone and the SSRI fluoxetine in physiological concentrations so that both drugs did not affect cell viability. Expression of interleukin-2 (IL-2) and glia-derived-neurotrophic-factor (GDNF) were analyzed and monitored and cell viability, apoptosis, cluster formation, particle-removing capacity and cell mobility were also monitored. Pre-studies without any drugs on mixed neuron-astrocyte co-cultures suggested that astrocytes interacted with neurons and other brain cells in vitro by actively assembling them into clusters. Treatment of purified astrocytes with dexamethasone significantly decreased their mobility compared to controls but had no effect on cluster formation. Dexamethasone-treated cells removed fewer extracellular particles derived from dead cells and cell debris. Both effects were abolished by simultaneous application of fluoxetine. Intracellular IL-2 increased, while GDNF amount expression was diminished following dexamethasone treatment. Simultaneous administration of fluoxetine reversed dexamethasone-triggered IL-2 elevation but had no effect on decreased GDNF concentration. These results suggest that mobility and growth factor equilibrium of astrocytes are affected by dexamethasone and by fluoxetine and that fluoxetine could reverse some changes induced by dexamethasone.

  11. Longstanding refractory pseudophakic cystoid macular edema resolved using intravitreal 0.7 mg dexamethasone implants

    DEFF Research Database (Denmark)

    Brynskov, Troels; Laugesen, Caroline Schmidt; Halborg, Jakob;

    2013-01-01

    Refractory pseudophakic cystoid macular edema (PCME) following cataract surgery has long posed a challenge to clinicians, but intravitreal injections with a sustained delivery 0.7 mg dexamethasone implant has emerged as a promising therapy for this condition.......Refractory pseudophakic cystoid macular edema (PCME) following cataract surgery has long posed a challenge to clinicians, but intravitreal injections with a sustained delivery 0.7 mg dexamethasone implant has emerged as a promising therapy for this condition....

  12. Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis.

    Science.gov (United States)

    Wang, Jianxia; Yuan, Zhixiang

    2013-09-01

    Ovarian cancer is one human malignancy which has response portly to doxorubicin. The anti-cancer activity of gambogic acid has been tested in in vitro and in vivo studies. In this study, we showed that gambogic acid, a natural compound, could potentiate the anticancer activity of doxorubicin in ovarian cancer through ROS-mediated apoptosis. Platinum-resistant human ovarian cancer cell line (SKOV-3) was treated with gambogic acid, doxorubicin, or the combination of both to investigate cell proliferation and apoptosis. We found that the combination of gambogic acid and doxorubicin causes synergistic loss of cell viability in SKOV-3 cells and this synergistic effect correlated with increased cellular ROS accumulation. Moreover, in vivo results showed that gambogic acid and doxorubicin combination resulted in a synergistic suppressing effect on tumor growth in ovarian cancer mice model. Taken together, the results suggested that doxorubicin in combination with gambogic acid might provide a promising therapeutic strategy to enhance chemosensitivity of ovarian cancer to doxorubicin.

  13. Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy

    Directory of Open Access Journals (Sweden)

    Ninna Aggerholm-Pedersen

    2016-01-01

    Full Text Available Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin.

  14. Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

    Science.gov (United States)

    Tay, Zoey; Eng, Ru Jun; Sajiki, Kenichi; Lim, Kim Kiat; Tang, Ming Yi; Yanagida, Mitsuhiro; Chen, Ee Sin

    2013-01-01

    Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

  15. Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice.

    Science.gov (United States)

    Zhao, Xiaoyan; Zhang, Jie; Tong, Nannan; Chen, Youran; Luo, Yonghuang

    2012-01-01

    Doxorubicin, a very potent and often used anti-cancer drug, is largely limited due to the dose-related toxic effects. The present study investigated whether berberine, a natural product alkaloid, can reduce the liver injury induced by doxorubicin. Mice of either gender were randomly divided into four groups: the control group, doxorubicin group, berberine group, and berberine+doxorubicin group. In the tests, body weight, general condition and mortality of the mice were observed, and serum alanine aminotransferase and aspartate transaminase levels were determined to evaluate liver function. Furthermore, the liver was excised for determination of the weight changes, as well as histopathological analysis in the tissues. Mortality rate and significant decline in body weight, and increased plasma alanine aminotransferase and aspartate transaminase activities were observed in doxorubicin-treated mice. These changes were significantly prevented by pretreatment with berberine. Histopathological studies showed that doxorubicin caused structural injuries, such as vascular congestion, inflammatory cell infiltration, hepatocellular degeneration and necrosis, fibrosis in the liver. These histopathological changes were largely attenuated by berberine pretreatment. These findings indicate that berberine has the hepatoprotective effect on doxorubicin-induced liver injury in mice.

  16. Doxorubicin liposome-loaded microbubbles for contrast imaging and ultrasound-triggered drug delivery.

    Science.gov (United States)

    Escoffre, Jean-Michel; Mannaris, Christophoros; Geers, Bart; Novell, Anthony; Lentacker, Ine; Averkiou, Michalakis; Bouakaz, Ayache

    2013-01-01

    Targeted drug delivery under image guidance is gaining more interest in the drug-delivery field. The use of microbubbles as contrast agents in diagnostic ultrasound provides new opportunities in noninvasive image-guided drug delivery. In the present study, the imaging and therapeutic properties of novel doxorubicin liposome-loaded microbubbles are evaluated. The results showed that at scanning settings (1.7 MHz and mechanical index 0.2), these microbubbles scatter sufficient signal for nonlinear ultrasound imaging and can thus be imaged in real time and be tracked in vivo. In vitro therapeutic evaluation showed that ultrasound at 1 MHz and pressures up to 600 kPa in combination with the doxorubicin liposomeloaded microbubbles induced 4-fold decrease of cell viability compared with treatment with free doxorubicin or doxorubicin liposome-loaded microbubbles alone. The therapeutic effectiveness is correlated to an ultrasound-triggered release of doxorubicin from the liposomes and an enhanced uptake of the free doxorubicin by glioblastoma cells. The results obtained demonstrate that the combination of ultrasound and the doxorubicin liposome-loaded microbubbles can provide a new method of noninvasive image-guided drug delivery.

  17. The role of milk thistle extract in breast carcinoma cell line (MCF-7 apoptosis with doxorubicin.

    Directory of Open Access Journals (Sweden)

    Hussein Rastegar

    2013-09-01

    Full Text Available Breast cancer is the most commonly diagnosed invasive malignancy and first leading cause of cancer-related deaths in Iranian women. Based on silymarin's unique characteristics, its application in chemotherapy combined with doxorubicin can be effective to enhance the efficacy together with a reduced toxicity on normal tissues. The present study focus on evaluate the efficacy of silymarin in combination with doxorubicin, on viability and apoptosis of estrogen-dependent breast carcinoma cell line (MCF-7. After being cultured, MCF-7 cells were divided into 8 groups and treated as follows: 1st group received 75 μg silymarin, groups 2, 3, and 4 were treated with 10, 25, and 50 nM doxorubicin, respectively, and groups 5, 6, and 7 respectively received 10, 25, and 50 nM doxorubicin as well as 75 μg silymarin. Viability percentage and apoptosis of the cells were assessed with Trypan Blue staining after 16, 24, and 48 hours. Silymarin has a synergistic effect on the therapeutic potential of doxorubicin. Use of silymarin in combination with doxorubicin can be more effective on the therapeutic potential of doxorubicin and decreases its dose-limiting side effects.

  18. Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells.

    Science.gov (United States)

    Zhang, Rong; Saito, Ryuta; Shibahara, Ichiyo; Sugiyama, Shinichiro; Kanamori, Masayuki; Sonoda, Yukihiko; Tominaga, Teiji

    2016-01-01

    Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma-bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications.

  19. Resistant mechanisms of doxorubicin%多柔比星的耐药机制

    Institute of Scientific and Technical Information of China (English)

    冼志荣; 张国君

    2013-01-01

    Doxorubicin is widely used in chemotherapy of breast cancer and many other cancers.How ever,doxorubicin resistance restricts its use to some extent.The mechanisms of doxorubicin resistance may involve transport protein,apoptosis protein,DNA repair function,enzyme and other factors.Researches about reversing doxorubicin resistance are ongoing and provide some effective therapeutic regimens to overcome doxorubicin resistance clinically.But the specific mechanism of doxorubicin resistance is yet to be elucidated.It is expected that more reasonable and effective counter-measures will be put forward to improve the theraputical effect of doxorubicin.%多柔比星广泛应用于乳腺癌等肿瘤的化疗中,但因耐药使其应用受到一定限制.多柔比星耐药的产生机制可能涉及转运蛋白、凋亡蛋白、DNA修复功能、酶等因素.逆转多柔比星耐药的研究也在持续进行,为临床上克服多柔比星耐药提供了有效方案.但具体机制仍有待进一步阐释,并期待提出更合理的策略以提高疗效.

  20. Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue.

    Science.gov (United States)

    Biondo, Luana Amorim; Lima Junior, Edson Alves; Souza, Camila Oliveira; Cruz, Maysa Mariana; Cunha, Roberta D C; Alonso-Vale, Maria Isabel; Oyama, Lila Missae; Nascimento, Claudia M Oller; Pimentel, Gustavo Duarte; Dos Santos, Ronaldo V T; Lira, Fabio Santos; Rosa Neto, José Cesar

    2016-01-01

    White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.

  1. Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

    Directory of Open Access Journals (Sweden)

    Zoey Tay

    Full Text Available Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

  2. The effect of thyroxin on hepatic redox equilibrium and lipid metabolism in rats treated with doxorubicin

    Directory of Open Access Journals (Sweden)

    Czuba Bartosz

    2014-12-01

    Full Text Available The main side effects of the administration of doxorubicin, a widely used anticancer drug, is the generation of a reactive oxygen species (ROS in normal cells. As a result, redox disorders and secondary oxidative stress are developed. Doxorubicin ROS generation is attributed to enzymes that are produced abundantly in hepatocytes. Oxidative stress has been a well-known risk factor of doxorubicin-related toxicity. However, in addition, according to the data collected in the last decade, changes in thyroxin status can propagate ROS generation, and, thus, initiate the doxorubicin hepatic effect. Moreover, both compounds have an impact on the cell metabolism. The aim of the study was to verify the thesis that thyroxin can modulate the effect of doxorubicin with regard to redox status and lipid metabolism disorders. In our work, we determined the ratio of NADP+/ NADPH and NAD+/NADH in liver homogenates, blood ketone bodies and triglycerides in the liver and blood in rats treated with doxorubicin and thyroxin. Our results indicate that thyroxin has an insignificant effect on NAD+/NADH, NADP+/NADPH ratios and on hepatic and blood triglycerides. Moreover, thyroxin administration normalized the level of blood ketone bodies that was disturbed by doxorubicin.

  3. Doxorubicin toxicity can be ameliorated during antioxidant L-carnitine supplementation.

    Science.gov (United States)

    Alshabanah, Othman A; Hafez, Mohamed M; Al-Harbi, Mohamed M; Hassan, Zeinab K; Al Rejaie, Salim S; Asiri, Yosef A; Sayed-Ahmed, Mohamed M

    2010-01-01

    Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 were intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12, and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increase the biochemical levels of alanine transaminase , alkaline phosphatase, total bilirubin, total carnitine, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p carnitine supplementation completely reverse the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.

  4. Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.

    Directory of Open Access Journals (Sweden)

    Miho Nara

    Full Text Available Side population (SP cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11 express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3 express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM, polycomb (e.g., EZH2, EPC1 and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5 more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680 and a proteasome inhibitor (bortezomib with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3 and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.

  5. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

    2017-02-28

    Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.

  6. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro.

    Science.gov (United States)

    Spallarossa, Paolo; Garibaldi, Silvano; Altieri, Paola; Fabbi, Patrizia; Manca, Valeria; Nasti, Sabina; Rossettin, Pierfranco; Ghigliotti, Giorgio; Ballestrero, Alberto; Patrone, Franco; Barsotti, Antonio; Brunelli, Claudio

    2004-10-01

    The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a beta-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V-FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-alpha and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (P carvedilol) and HE (P carvedilol reduced the number of positive fluorescent cells (P Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-alpha. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (P carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (P preventing doxorubicin-induced ROS generation and cardiac apoptosis. Our results suggest that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes.

  7. Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes

    Science.gov (United States)

    Pascual-Figal, Domingo; Fernández-Belda, Francisco; Lax, Antonio

    2017-01-01

    The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced

  8. Comparing Betamethasone and Dexamethasone Effects on Concentration of Male Reproductive Hormones in Mice

    Directory of Open Access Journals (Sweden)

    Jalalaldin Gooyande

    2014-01-01

    Full Text Available Most of chemical drugs have side effects on various parts of body. It is necessary to identify these effects to better use of drugs. Betamethasone and Dexamethasone are two of the most usual drugs in human and animal medication. The effect of these drugs on concentration of male reproductive hormones of mice was the goal of this study. Eighteen matured male mice were divided into eight groups including control, placebo and six treatment groups. Placebo group was received physiological serum only and treatments were Betamethasone (0.1, 0.5 and 1 mg/kg and Dexamethasone (0.1, 0.5 and 1 mg/kg which were injected in peritoneum every other day and for twenty days. After 20 days, blood samples were taken and FSH, LH and testosterone levels were measured using Eliza test method. Obtained data were analyzed using one way analysis of variance and mean comparison was done using Duncan's multiple ranges test and SPSS program. Results showed that 0.5 mg/kg of Betamethasone and all levels of dexamethasone caused significant increase in FSH concentration. For LH hormone, 1 mg/kg of Betamethasone and 0.1 mg/kg of Dexamethasone caused significant decrease whereas 1 mg/kg of Dexamethasone increased it significantly. Testosterone was increased significantly by 1 mg/kg of Dexamethasone. So, mentioned drugs are effective on hormone action of reproductive system dose dependently and probable effect of them must be considered in time of using.

  9. Mesenchymal stem cell infusion on skin wound healing of dexamethasone immunosuppressed wistar rats

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    Betânia Souza Monteiro

    Full Text Available ABSTRACT: To evaluate the therapeutic contribution of MSC intravenous infusion to surgical wound healing in dexamethasone-immunosuppressed rats, thirty-five rats were randomly divided into 2 groups: in the Control Group (CG, five rats received normal saline as 0.2ml subcutaneous (SC injections every 24 hours, for 30 consecutive days and, in the Dexamethasone Group (DG, 30 rats were given 0.2mL subcutaneous dexamethasone (0.1mg kg-1 every 24 hours, for 30 consecutive days. After 30 days, all rats underwent surgery to create an experimental skin wound. The 30 animals of the DG group were divided into two equal groups, which received different treatments: the dexamethasone group (DG received a single application of 0.5ml normal saline, via the intravenous route (IV, 48 hours after wound creation; and the Mesenchymal Stem Cells Dexamethasone group (MSCDG received MSC transplantation at a concentration of 9x106 cells in a single IV application, 48 hours after wound creation. The surgical wounds of CG rats closed on average 14.75 days after creation and DG rats had wounds closed within 22 days; whereas, the surgical wounds of MSCDG rats were closed in 14 days. MSC infusion in dexamethasone-immunosuppressed patients contributed positively to epithelial healing in less time.

  10. Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats

    DEFF Research Database (Denmark)

    Thomsen, Karen Louise; Møller, Holger Jon; Graversen, Jonas Heilskov

    2016-01-01

    AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/...... the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.......AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg....../kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also...

  11. Comparative study of preoperative use of oral gabapentin, intravenous dexamethasone and their combination in gynaecological procedure

    Directory of Open Access Journals (Sweden)

    Neha Agrawal

    2015-01-01

    Full Text Available Background: We studied the effects of oral gabapentin and intravenous (I.V. dexamethasone given together or separately 1 h before the start of surgery on intraoperative hemodynamics Postoperative analgesia and postoperative nausea vomiting (PONV in patients undergoing gynaecological procedure. Materials and Methods: Patients were randomly divided into three groups: Group 1 (gabapentin, n = 46 received 400 mg gabapentin, Group 2 (dexamethasone, n = 46 received 8 mg dexamethasone and Group 3 (gabapentin plus dexamethasone, n = 46 received both 400 mg gabapentin and 8 mg dexamethasone I.V. 1 h before the start of surgery. Standard induction and maintenance of anesthesia were accomplished. Visual analog scale for pain was recorded for 12 h. Side effects were noted. Results: Hemodynamics at various time interval (0, 5, 10, 15, 20, 25 and 30 min of laryngeal mask airway insertion and PONV were found significantly lower in Group 3 than in Group 1 and Group 2 (P 3 was significantly longer in Group 3 (510.00 ± 61.64 min than in Group 1 (352.83 ± 80.61 min and in Group 2 (294.78 ± 60.76 min, (P < 0.05. Conclusion: The present study concludes that the combination of oral Gabapentin and I.V. dexamethasone has significantly less hemodynamic changes, better postoperative analgesia and less incidence of PONV than individual administration of each drug.

  12. Apoferritin Modified Magnetic Particles as Doxorubicin Carriers for Anticancer Drug Delivery

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    Vojtech Adam

    2013-06-01

    Full Text Available Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF. The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution.

  13. Serious stomatitis and esophagitis: a peculiar mucous reaction induced by pegylated liposomal doxorubicin.

    Science.gov (United States)

    Ma, Han; Chen, Meilan; Liu, Junru; Li, Ying; Li, Juan

    2015-01-01

    Pegylated liposomal doxorubicin is an important antineoplastic agent with activity in a variety of solid tumors. It has a totally different profile of pharmacokinetics and toxicity compared with doxorubicin. It rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in many kinds of mucocutaneous reactions, including palmar-plantar erythrodysesthesia, diffuse follicular rash, intertrigo-like eruption, new formation of melanotic macules, stomatitis and radiation recall dermatitis. We present a rare case of multiple myeloma who immediately developed serious stomatitis and esophatitis associated with minor palmar-plantar erythrodysesthesia after a single course of pegylated liposomal doxorubicin.

  14. Is there a role for ‘modified VAD’ in the treatment of multiple myeloma?

    Science.gov (United States)

    Agazzi, A; Sammassimo, S; Laszlo, D; Liptrott, SJ; Cascio, R; Alietti, A; Rabascio, C; Mancuso, P; Pruneri, G; Martinelli, G

    2009-01-01

    VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma. PMID:22276003

  15. Is there a role for 'modified VAD' in the treatment of multiple myeloma?

    Science.gov (United States)

    Agazzi, A; Sammassimo, S; Laszlo, D; Liptrott, Sj; Cascio, R; Alietti, A; Rabascio, C; Mancuso, P; Pruneri, G; Martinelli, G

    2009-01-01

    VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma.

  16. Peri-operative dexamethasone therapy and post-operative psychosis in patients undergoing major oral and maxillofacial surgery

    OpenAIRE

    Chethan Manohara Koteswara; Pritish Patnaik

    2014-01-01

    A broad array of behavioral symptoms, including psychosis, can transpire post-operatively following a variety of surgeries. It is difficult to diagnose the exact cause of post-operative psychosis. We report three cases, which developed psychosis post-operatively after undergoing major oral and maxillofacial surgeries. All the three patients were administered dexamethasone peri-operatively. Dexamethasone is used to prevent or reduce post-operative edema. The exact dose of dexamethasone, which ...

  17. Dexamethasone and Long-Term Outcome of Tuberculous Meningitis in Vietnamese Adults and Adolescents

    Science.gov (United States)

    Török, M. Estée; Bang, Nguyen Duc; Chau, Tran Thi Hong; Yen, Nguyen Thi Bich; Thwaites, Guy E.; Thi Quy, Hoang; Dung, Nguyen Huy; Hien, Tran Tinh; Chinh, Nguyen Tran; Thi Thanh Hoang, Hoang; Wolbers, Marcel; Farrar, Jeremy J.

    2011-01-01

    Background Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown. Methods Vietnamese adults and adolescents with tuberculous meningitis recruited to a randomised, double-blind, placebo-controlled trial of adjunctive dexamethasone were followed-up at five years, to determine the effect of dexamethasone on long-term survival and neurological disability. Results 545 patients were randomised to receive either dexamethasone (274 patients) or placebo (271 patients). 50 patients (9.2%) were lost to follow-up at five years. In all patients two-year survival, probabilities tended to be higher in the dexamethasone arm (0.63 versus 0.55; p = 0.07) but five-year survival rates were similar (0.54 versus 0.51, p = 0.51) in both groups. In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07) but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36). The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7%) and there was no significant association between dexamethasone treatment and disability status at five years (p = 0.32). Conclusions Adjunctive dexamethasone appears to improve the probability of survival in patients with TBM, until at least two years of follow-up. We could not demonstrate a five-year survival benefit of dexamethasone treatment which may be confined to patients with grade 1 TBM. Trial Registration ClinicalTrials.gov NCT01317654 NCT01317654?term = tuberculous+meningitis&rank = 3 PMID:22174748

  18. The effects of sympathectomy and dexamethasone in rats ingesting sucrose

    Directory of Open Access Journals (Sweden)

    2006-03-01

    Full Text Available Both high-sucrose diet and dexamethasone (D treatment increase plasma insulin and glucose levels and induce insulin resistance. We showed in a previous work (Franco-Colin, et al. Metabolism 2000; 49:1289-1294 that combining both protocols for 7 weeks induced less body weight gain in treated rats without affecting mean daily food intake. Since such an effect may be explained by an increase in caloric expenditure, possibly due to activation of the sympathetic nervous system by sucrose ingestion, in this work, and using 10% sucrose in the drinking water, male Wistar rats were divided into 4 groups. Two groups were sympathectomized using guanethidine (Gu treatment for 3 weeks. One of these groups of rats received D in the drinking water. Of the 2 groups not receiving Gu, one was the control (C and the other received D. After 8 weeks a glucose tolerance test was done. The rats were sacrificed and liver triglyceride (TG, perifemoral muscle lipid, and norepinephrine (NE levels in the liver spleen, pancreas, and heart were determined. Gu-treated rats (Gu and Gu+D groups showed less than 10% NE concentration compared to C and D rats, less daily caloric intake and body-weight gain, more sucrose intake, and better glucose tolerance. The area under the curve after glucose administration correlated significantly with the mean body weight gain of the rats, except for D group. Groups D (D and Gu+D also showed less caloric intake and body-weight gain but higher liver weight and TG concentration and lower peripheral muscle mass. The combination of Gu+D treatments showed some peculiar results: negative body weight gain, a fatty liver, and low muscle mass. Though the glucose tolerance test had the worst results for the D group, it showed the best results in the Gu+D group. There were significant interactions for Guan X Dex by two-way ANOVA test for the area under the curve in the glucose tolerance test, muscle mass, and muscle lipids. The results suggest that

  19. Overnight Dexamethasone Suppression Test in the Diagnosis of Cushing's Disease

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    Fatemeh Esfahanian

    2010-08-01

    Full Text Available Realizing the cause of Cushing's Syndrome (CS is one of the most challenging processes in clinical endocrinology. The long high dose dexamethasone suppression test (standard test is costly and need an extended inpatient stay. In this study we want to show the clinical utility of the overnight 8 mg dexamethasone suppression test (DST for differential diagnosis of CS in a referral center. Retrospectively from 2002-2005 we selected the patients of endocrinology ward in Imam hospital who were admitted with the diagnosis of Cushing syndrome and had 8 mg DST (modified test along with classic DST. In modified test a decrease in an 8 AM serum cortisol level of 50% or more is thought to indicate suppression and we compared the results of modified test with standard test. This test had been done on 42 patients: 10 male (23% and 32 female (76%. The mean age of patients was 31.39 (15-63, 32 with proven pituitary Cushing's disease, 7 with primary adrnal tumors and 3 with ectopic ACTH syndrome. The standard test according to 50% suppression of UFC had 90.62% sensitivity, and according to 90% suppression had 43.75% sensitivity. The sensitivity of this test was 71.85% for serum cortisol suppression. The modified test (8 mg overnight DST had 78% sensitivity. All of these tests had 100% specificity for the diagnosis of Cushing's disease. The positive predictive vale (PPV of all of these tests was 100%. The negative predictive value (NPV of modified test for the diagnosis of Cushing's disease was 58.82%. In standard test the NPV of serum cortisol was 52.6%, UFC 50% had 76.9% NPV and UFC 90% had 35.7% NPV. The results of serum cortisol suppression in modified test is better than standard test. Although 50% suppression of UFC in standard test had greater sensitivity than modified test, collecting of urine is difficult, time consuming and needing hospitalization, so we advice modified test that is much simpler and more convenient instead of standard test in the first

  20. A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review

    Directory of Open Access Journals (Sweden)

    Yik Hoe Ngan

    2016-01-01

    Full Text Available Cancer remains a major cause of hospitalization and death every year. From time to time, new formulations of anticancer drugs are available in the market and draw the concern of healthcare professionals in terms of the superiority, toxicology, and cost-effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, which is a highly potent chemotherapeutic agent, comes with three formulations (pegylated liposomal, nonpegylated liposomal and nonliposomal conventional formulations. English-language literature in relation to the three formulations has been reviewed to inform the healthcare professionals regarding the differences between these formulations. In terms of efficacy, there is only one study supporting the superiority of liposomal doxorubicin, but there are more data which supports the non-inferiority of liposomal doxorubicin in comparison to conventional non-liposomal doxorubicin. It is emphasized that liposomal doxorubicin promotes better toxicology profile than nonliposomal conventional doxorubicin with an increased cost. The cost-effectiveness of liposomal doxorubicin is not well defined as there are very limited studies in this area. Apart from that, this review highlights the interpatient variability in regards to the clearance and volume of distribution following the administration of liposomal doxorubicin. In conclusion, further studies will be required to better define the superiority of liposomal formulation of doxorubicin regarding the efficacy and dose standardization of liposomal doxorubicin should be sought in the near future.

  1. Creatine supplementation reduces doxorubicin-induced cardiomyocellular injury.

    Science.gov (United States)

    Santacruz, Lucia; Darrabie, Marcus D; Mantilla, Jose Gabriel; Mishra, Rajashree; Feger, Bryan J; Jacobs, Danny O

    2015-04-01

    Heart failure is a common complication of doxorubicin (DOX) therapy. Previous studies have shown that DOX adversely impacts cardiac energy metabolism, and the ensuing energy deficiencies antedate clinical manifestations of cardiac toxicity. Brief exposure of cultured cardiomyocytes to DOX significantly decreases creatine transport, which is the cell's sole source of creatine. We present the results of a study performed to determine if physiological creatine supplementation (5 mmol/L) could protect cardiomyocytes in culture from cellular injury resulting from exposure to therapeutic levels of DOX. Creatine supplementation significantly decreased cytotoxicity, apoptosis, and reactive oxygen species production caused by DOX. The protective effect was specific to creatine and depended on its transport into the cell.

  2. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies.

    Science.gov (United States)

    Jin, Xun; Zhang, Peilan; Luo, Li; Cheng, Hao; Li, Yunzu; Du, Ting; Zou, Bingwen; Gou, Maling

    Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer.

  3. Gamma irradiation reduces the immunological toxicity of doxorubicin, anticancer drug

    Science.gov (United States)

    Kim, Jae-Hun; Sung, Nak-Yun; Raghavendran, H. Balaji; Yoon, Yohan; Song, Beom-Seok; Choi, Jong-il; Yoo, Young-Choon; Byun, Myung-Woo; Hwang, Young-Jeong; Lee, Ju-Woon

    2009-07-01

    Doxorubicin (DOX) is a widely used anticancer agent, but exhibits some immunological toxicity to patients during chemotherapy. The present study was conducted to evaluate the effect of gamma irradiation on the immunological response and the inhibition activity on in vivo tumor mass of DOX. The results showed that DOX irradiated at 10 and 20 kGy reduce the inhibition of mouse peritoneal macrophage proliferation and induce the release of cytokines (TNF-α and IL-6) when compared with non-irradiated DOX. The cytotoxicity against human breast (MCF-7), murine colon adenocarcinoma (Colon 26) and human monocytic (THP-1) tumor cell were not significantly different between non-irradiated and irradiated DOX ( Pproducts by gamma irradiation.

  4. DEXAMETHASONE DOWNREGULATES EXPRESSION OF TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS (TREM-1: EVIDENCE FOR A TNFα-RELATED EFFECT

    Directory of Open Access Journals (Sweden)

    Ira eMihailidou

    2013-11-01

    Full Text Available Objectives To investigate the effect of dexamethasone on triggering receptor expressed on myeloid cells-1 (TREM-1.Methods Lethal infection was induced by Pseudomonas aeruginosa in 96 mice, both wild-type and TNF-/-; mice were pre-treated either with saline or with dexamethasone/hydrocortisone. TREM-1 on neutrophil membranes was measured after sacrifice. Monocytes of the U937 human cell line were challenged by LPS and heat-killed P.aeruginosa with the sequential addition of dexamethasone, hydrocortisone, TNFα and anti-TNF. Expression of TREM-1 and release of soluble TREM-1 (sTREM-1 in supernatants were measured.Results Pre-treatment with dexamethasone prolonged animal survival; this was not shown with hydrocortisone pre-treatment. Mice pre-treated with dexamethasone showed decreased expression of TREM-1 on neutrophils. LPS and P.aeruginosa induced the expression of TREM-1 and the release of sTREM-1 by U937 monocytes; that was decreased upon addition of dexamethasone but not of hydrocortisone. The effect of dexamethasone was enhanced upon addition of TNFα and lost in the presence of anti-TNF. The effect was also lost in TNF-/- mice. Gene expression of TREM-1 by U937 monocytes was decreased after treatment with dexamethasone.Conclusions TREM-1/sTREM-1 is a novel site of action of dexamethasone. This action is related with down-regulation of gene expression and is modulated by TNFα.

  5. Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells

    Science.gov (United States)

    Hong, Wei; Shi, Hong; Qiao, Mingxi; Gao, Xiang; Yang, Jie; Tian, Chunlian; Zhang, Dexian; Niu, Shengli; Liu, Mingchun

    2017-01-01

    Even though a tremendous number of multifunctional nanocarriers have been developed to tackle heterogeneous cancer cells, little attention has been paid to elucidate how to rationally design a multifunctional nanocarrier. In this study, three individual functions (active targeting, stimuli-triggered release and endo-lysosomal escape) were evaluated in doxorubicin (DOX)-sensitive MCF-7 cells and DOX-resistant MCF-7/ADR cells by constructing four kinds of micelles with active-targeting (AT-M), passive targeting, pH-triggered release (pHT-M) and endo-lysosomal escape (endoE-M) function, respectively. AT-M demonstrated the strongest cytotoxicity against MCF-7 cells and the highest cellular uptake of DOX due to the folate-mediated endocytosis. However, AT-M failed to exhibit the best efficacy against MCF-7/ADR cells, while endoE-M exhibited the strongest cytotoxicity against MCF-7/ADR cells and the highest cellular uptake of DOX due to the lowest elimination of DOX from the cells. This was attributed to the carrier-facilitated endo-lysosomal escape of DOX, which avoided exocytosis by lysosome secretion, resulting in an effective accumulation of DOX in the cytoplasm. The enhanced elimination of DOX from the MCF-7/ADR cells also accounted for the remarkable decrease in cytotoxicity against the cells of AT-M. Three micelles were further evaluated with MCF-7 cells and MCF-7/ADR-resistant cells xenografted mice model. In accordance with the in vitro results, AT-M and endoE-M demonstrated the strongest inhibition on the MCF-7 and MCF-7/ADR xenografted tumor, respectively. Active targeting and active targeting in combination with endo-lysosomal escape have been demonstrated to be the primary function for a nanocarrier against doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells, respectively. These results indicate that the rational design of multifunctional nanocarriers for cancer therapy needs to consider the heterogeneous cancer cells and the primary function needs

  6. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  7. Intratympanic dexamethasone injection vs methylprednisolone for the treatment of refractory sudden sensorineural hearing loss

    Science.gov (United States)

    Berjis, Nezamoddin; Soheilipour, Saeed; Musavi, Alireza; Hashemi, Seyed Mostafa

    2016-01-01

    Background: During the past years various drugs have been used for sudden sensorineural hearing loss (SSNHL) treatment including steroids that are shown to be beneficial. Directed delivery of high doses of steroids into the inner ear is suggested for its potential and known as intratympanic steroids therapy (IST). Despite the use of dexamethasone and methylprednisolone as the traditional treatments, there are still debates about the optimal dosage, preferred drug, and the route of administration. Materials and Methods: We performed a randomized clinical trial study in which 50 patients suffering from SSNHL and resistant to standard therapy were employed. Each patient took 0.5 ml methylprednisolone (40 mg/mg) along with bicarbonate or dexamethasone (4 mg/mL) through direct intratympanic injection. This method was performed and scheduled once every 2 days for three times only for the dexamethasone receiving group. Hearing test was carried out and the results were analyzed according to a four-frequency (0.5, 1.0, 2.0, 3.0 kHz) pure tone average (PTA) and Siegel's criteria. Results: According to Siegel's criteria, three out of 25 (12%) dexamethasone receiving patients were healed in 1 and 4 (16%), 9 (32%) were respectively recovered in Siegel's criteria 2, 3, and 9 (32%) showed no recovery. In the group receiving methylprednisolone, recovery was found in 6 (24%), 8 (32%), 7 (28%) patients in the Siegel's criteria 1, 2, 3, respectively, and in 4 (16%) patients no recovery was recorded. In methylprednisolone group, hearing was significantly improved compared to the dexamethasone group (P hearing improvement rate was 84% in methylprednisolone receiving patients showing a significantly higher improvement than 64% in the dexamethasone group. Conclusions: Topical intratympanic treatment with methylprednisolone is safe and an effective treatment approach for those SSNHL cases that are refractory to the common therapies by Dexamethasone. PMID:27403406

  8. Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus.

    Science.gov (United States)

    Duffy, B A; Chun, K P; Ma, D; Lythgoe, M F; Scott, R C

    2014-03-01

    Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus.

  9. Intratympanic dexamethasone injection vs methylprednisolone for the treatment of refractory sudden sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Nezamoddin Berjis

    2016-01-01

    Full Text Available Background: During the past years various drugs have been used for sudden sensorineural hearing loss (SSNHL treatment including steroids that are shown to be beneficial. Directed delivery of high doses of steroids into the inner ear is suggested for its potential and known as intratympanic steroids therapy (IST. Despite the use of dexamethasone and methylprednisolone as the traditional treatments, there are still debates about the optimal dosage, preferred drug, and the route of administration. Materials and Methods: We performed a randomized clinical trial study in which 50 patients suffering from SSNHL and resistant to standard therapy were employed. Each patient took 0.5 ml methylprednisolone (40 mg/mg along with bicarbonate or dexamethasone (4 mg/mL through direct intratympanic injection. This method was performed and scheduled once every 2 days for three times only for the dexamethasone receiving group. Hearing test was carried out and the results were analyzed according to a four-frequency (0.5, 1.0, 2.0, 3.0 kHz pure tone average (PTA and Siegel′s criteria. Results: According to Siegel′s criteria, three out of 25 (12% dexamethasone receiving patients were healed in 1 and 4 (16%, 9 (32% were respectively recovered in Siegel′s criteria 2, 3, and 9 (32% showed no recovery. In the group receiving methylprednisolone, recovery was found in 6 (24%, 8 (32%, 7 (28% patients in the Siegel′s criteria 1, 2, 3, respectively, and in 4 (16% patients no recovery was recorded. In methylprednisolone group, hearing was significantly improved compared to the dexamethasone group (P < 0.05. The general hearing improvement rate was 84% in methylprednisolone receiving patients showing a significantly higher improvement than 64% in the dexamethasone group. Conclusions: Topical intratympanic treatment with methylprednisolone is safe and an effective treatment approach for those SSNHL cases that are refractory to the common therapies by Dexamethasone.

  10. Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala.

    Science.gov (United States)

    Sawamura, Takehito; Klengel, Torsten; Armario, Antonio; Jovanovic, Tanja; Norrholm, Seth D; Ressler, Kerry J; Andero, Raül

    2016-02-01

    Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

  11. Effects of dexamethasone on the glucogenic capacity of fetal, pregnant, and non-pregnant adult sheep.

    Science.gov (United States)

    Franko, K L; Giussani, D A; Forhead, A J; Fowden, A L

    2007-01-01

    Fetal glucocorticoids have an important role in the pre-partum maturation of physiological systems essential for neonatal survival such as glucogenesis. Consequently, in clinical practice, synthetic glucocorticoids, like dexamethasone, are given routinely to pregnant women threatened with pre-term delivery to improve the viability of their infants. However, little is known about the effects of maternal dexamethasone treatment on the glucogenic capacity of either the fetus or mother. This study investigated the effects of dexamethasone treatment using a clinically relevant dose and regime on glycogen deposition and the activities of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver and kidney of pregnant ewes and their fetuses, and of non-pregnant ewes. Dexamethasone administration increased the glycogen content of both the fetal and adult liver within 36 h of beginning treatment. It also increased G6Pase activity in the liver and kidney of the fetuses but not of their mothers or the non-pregnant ewes. Neither hepatic nor renal PEPCK activity was affected by dexamethasone in any group of animals. These changes in glycogen content and G6Pase activity were accompanied by rises in the plasma glucose and insulin concentrations and by a fall in the plasma cortisol level in the fetus and both groups of adult animals. In addition, dexamethasone treatment raised fetal plasma tri-iodothyronine (T(3)) concentrations and reduced maternal levels of plasma T(3) and thyroxine, but had no effect on thyroid hormone concentrations in the non-pregnant ewes. These findings show that maternal dexamethasone treatment increases the glucogenic capacity of both the mother and fetus and has major implications for glucose availability both before and after birth.

  12. Study on Preparation and Release of Dexamethasone Hyaluronan Microspheres

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Hyaluronan (HA), the consistent glycosaminoglycans in extracellular matrix, is a kind of biomaterials with wonderful biocompatibility. To develop drug release system (DDS) with HA as drug carrier is a new hotspot in the field of pharmaceutics. In this paper, we applied technique of ultrosound and reversed phase (Water/Oil) emulsification to develop dexamethasone (DEX)-HA-STMP cross-linking microspheres (DEX-HA MS) with STMP as cross-linker. DEX-HA MS has a wonderful shape and property of dispersion. There is a negative correlation between diameter of DEX-HA MS and the content of cross-linker, or the content of emulsifier, and a positive correlation between the diameter and CHA. When CHA≤1% ,DEX/HA≤1/10(g/g),there is a positive correlation between the factors mentioned below and drug loading (DL%)/loading efficiency (LE%) ,the content of STMP, the content of emulsifier, CHA and the content of DEX. DEX-HA-MS can realize function of slow release. In vitro drug release experiment shows that cumulative release (CR%) of DEX-HA MS fits in with pervasion-corrosion equation, and there is a negative correlation between the content of STMP, CHA and CR% , a positive correlation between emulsifier and CR%. When DEX/HA ≤1/5 (g/g) there is a negative correlation between the content of DEX and CR%.

  13. Self-assembled rosette nanotubes encapsulate and slowly release dexamethasone

    Directory of Open Access Journals (Sweden)

    Chen Y

    2011-05-01

    Full Text Available Yupeng Chen1,2, Shang Song2, Zhimin Yan3, Hicham Fenniri3, Thomas J Webster2,41Department of Chemistry, Brown University, Providence, RI, USA; 2School of Engineering, Brown University, Providence, RI, USA; 3National Institute for Nanotechnology and Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada; 4Department of Orthopedics, Brown University, Providence, RI, USAAbstract: Rosette nanotubes (RNTs are novel, self-assembled, biomimetic, synthetic drug delivery materials suitable for numerous medical applications. Because of their amphiphilic character and hollow architecture, RNTs can be used to encapsulate and deliver hydrophobic drugs otherwise difficult to deliver in biological systems. Another advantage of using RNTs for drug delivery is their biocompatibility, low cytotoxicity, and their ability to engender a favorable, biologically-inspired environment for cell adhesion and growth. In this study, a method to incorporate dexamethasone (DEX, an inflammatory and a bone growth promoting steroid into RNTs was developed. The drug-loaded RNTs were characterized using diffusion ordered nuclear magnetic resonance spectroscopy (DOSY NMR and UV-Vis spectroscopy. Results showed for the first time that DEX can be easily and quickly encapsulated into RNTs and released to promote osteoblast (bone-forming cell functions over long periods of time. As a result, RNTs are presented as a novel material for the targeted delivery of hydrophobic drugs otherwise difficult to deliver.Keywords: nanotubes, drug delivery, self-assembly, physiological conditions

  14. Effect of autophagy induced by dexamethasone on senescence in chondrocytes

    Science.gov (United States)

    Xue, Enxing; Zhang, Yu; Song, Bing; Xiao, Jun; Shi, Zhanjun

    2016-01-01

    The aim of the current study was to explore the effects of dexamethasone (DXM) on autophagy and senescence in chondrocytes. Collagen II and aggrecan were examined in normal chondrocytes isolated from Sprague-Dawley rats. Following stimulation with DXM, LysoTracker Red staining, monodansylcadaverine (MDC) staining, green fluorescent protein-red fluorescent protein-light chain 3 (LC3) and western blotting were used to detect autophagy levels in the chondrocytes. Mechanistic target of rapamycin (mTOR) pathway-associated molecules were investigated by western blotting. Cell senescence was analyzed by senescence-associated (SA)-β-galactosidase (β-gal) staining. A dose-dependent increase in the number of autophagic vacuoles was observed in the DXM-treated chondrocytes, as demonstrated by LysoTracker Red and MDC staining. A dose-dependent increase in autophagosome formation was observed in the DXM-treated chondrocytes. Expression of LC3-II and beclin-1 was increased by DXM, in particular in the cells treated with DXM for 4 days. However, P62 expression was reduced as a result of treatment. SA-β-gal staining indicated that DXM increased cell senescence. Notably, DXM-induced cell senescence was exacerbated by the autophagic inhibitor 3-MA. Autophagy induced by DXM protected chondrocytes from senescence, and it is suggested that the mTOR pathway may be involved in the activation of DXM-induced autophagy. PMID:27572674

  15. Dexamethasone-suppression adrenal scintigraphy in hyperandrogenism: concise communication

    Energy Technology Data Exchange (ETDEWEB)

    Gross, M.D.; Freitas, J.E.; Swanson, D.P.; Woodbury, M.C.; Schteingart, D.E.; Beierwaltes, W.H.

    1981-01-01

    To assess the contribution of adrenal-derived androgens in women with hirsutism, adrenal scintigrams under dexamethasone suppression (DS) were performed on 35 women with increasing facial or body hair and irregular or absent menses. Based upon the DS regimen chosen (8 mg/d for 2 days or 4 md/d for 7 days before the injection of 6..beta..-(/sup 131/I)iodomethylnorcholesterol), three imaging patterns were identified. The first was the absence of uptake before 3 days (8-mg DS) or before 5 days (4-mg DS) after injection. This imaging pattern was seen in 17 of the 35 patients studied and was considered normal. The second pattern was bilateral uptake earlier than 3 days (8-mg DS regimen) or 5 days (4-mg DS) after injection. This was seen in 13 of the 35 patients and was interpreted as bilateral early visualization. Adrenal-vein catheterization performed on six patients with this pattern showed increased adrenal-vein testosterone. The third pattern, observed in five patients, was unilateral early visualization, which in four cases investigated to date was the result of an adrenocortical adenoma. This study confirms the adrenal cortex as a source of androgens in women with hirsutism and hyperandrogenism and demonstrates that DS adrenal scintigraphy can be utilized to identify those women in whom adrenal-derived androgens contribute to their hyperandrogenism.

  16. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.

    Science.gov (United States)

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-10-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.

  17. Molecular Modification of Metadherin/MTDH Impacts the Sensitivity of Breast Cancer to Doxorubicin.

    Directory of Open Access Journals (Sweden)

    Zhenchuan Song

    Full Text Available Breast cancer is a leading cause of death in women and with an increasing worldwide incidence. Doxorubicin, as a first-line anthracycline-based drug is conventional used on breast cancer clinical chemotherapy. However, the drug resistances limited the curative effect of the doxorubicin therapy in breast cancer patients, but the molecular mechanism determinants of breast cancer resistance to doxorubicin chemotherapy are not fully understood. In order to explore the association between metadherin (MTDH and doxorubicin sensitivity, the differential expressions of MTDH in breast cancer cell lines and the sensitivity to doxorubicin of breast cancer cell lines were investigated.The mRNA and protein expression of MTDH were determined by real-time PCR and Western blot in breast cancer cells such as MDA-MB-231, MCF-7, MDA-MB-435S, MCF-7/ADR cells. Once MTDH gene was knocked down by siRNA in MCF-7/ADR cells and overexpressed by MTDH plasmid transfection in MDA-MB-231 cells, the cell growth and therapeutic sensitivity of doxorubicin were evaluated using MTT and the Cell cycle assay and apoptosis rate was determined by flow cytometry.MCF-7/ADR cells revealed highly expressed MTDH and MDA-MB-231 cells had the lowest expression of MTDH. After MTDH gene was knocked down, the cell proliferation was inhibited, and the inhibitory rate of cell growth and apoptosis rate were enhanced, and the cell cycle arrest during the G0/G1 phase in the presence of doxorubicin treatment. On the other hand, the opposite results were observed in MDA-MB-231 cells with overexpressed MTDH gene.MTDH gene plays a promoting role in the proliferation of breast cancer cells and its high expression may be associated with doxorubicin sensitivity of breast cancer.

  18. Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

    OpenAIRE

    Carmela Pisano; Sabrina Chiara Cecere; Marilena Di Napoli; Carla Cavaliere; Rosa Tambaro; Gaetano Facchini; Cono Scaffa; Simona Losito; Antonio Pizzolorusso; Sandro Pignata

    2013-01-01

    Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then rece...

  19. Treatment of experimental extravasation of amrubicin, liposomal doxorubicin, and mitoxantrone with dexrazoxane

    DEFF Research Database (Denmark)

    Langer, Seppo W; Thougaard, Annemette V; Sehested, Maxwell;

    2012-01-01

    Dexrazoxane is an established treatment option in extravasation of the classic anthracyclines such as doxorubicin, epirubicin, and daunorubicin. However, it is not known whether the protection against the devastating tissue injuries extends into extravasation with new types of anthracyclines, the......, the anthracenediones, or the liposomal pegylated anthracycline formulations. We therefore tested the antidotal efficacy of dexrazoxane against extravasation of amrubicin, mitoxantrone, and liposomal pegylated doxorubicin in mice....

  20. The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle

    OpenAIRE

    2013-01-01

    The combined loss of muscle strength and constant fatigue are disabling symptoms for cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and premature fatigue along with an increase in reactive oxygen species (ROS). As mitochondria represent a primary source of oxidant generation in muscle, we hypothesized doxorubicin could negatively effect mitochondria by inhibiting respiratory capacity, leading to an incr...

  1. Doxorubicin Toxicity can be Ameliorated during Antioxidant L-Carnitine Supplementation

    Directory of Open Access Journals (Sweden)

    Othman A. Alshabanah

    2010-01-01

    Full Text Available Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 was intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p., to obtain treatments with cumulative doses of 6, 12 and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p. for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg and L-carnitine (200 mg/kg. High cumulative dose of doxorubicin (18 mg/kg significantly increases the biochemical levels of alanine transaminase, alkaline phosphatase, total bilirubin, thiobarbituric acid reactive substances (TBARs, total nitrate/nitrite (NOx p < 0.05 and decrease in glutathione (GSH , superoxide dismutase (SOD, glutathione peroxidase (GSHP x, glutathione-s-transferase (GST, glutathione reductase (GR and catalase (CAT activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reversed the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.

  2. Successful Use of Cyclophosphamide as an Add-On Therapy for Multiple Myeloma Patients with Acquired Resistance to Bortezomib or Lenalidomide

    Directory of Open Access Journals (Sweden)

    Shigeki Ito

    2013-01-01

    Full Text Available Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma.

  3. cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas

    DEFF Research Database (Denmark)

    Manfè, Valentina; Biskup, Edyta; Willumsgaard, Ayalah;

    2013-01-01

    improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc...... and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where...

  4. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.

    Science.gov (United States)

    Ghosh, Asish K; Rai, Rahul; Park, Kitae E; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D; Vaughan, Douglas E

    2016-11-08

    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.

  5. Bortezomib and Fenretinide Induce Synergistic Cytotoxicity in Mantle Cell Lymphoma Via Apoptosis, Cell Cycle Dysregulation, and IκBα Kinase Down-regulation

    Science.gov (United States)

    Cowan, Andrew J.; Frayo, Shani L.; Press, Oliver W.; Palanca-Wessels, Maria C.; Pagel, John M.; Green, Damian J.; Gopal, Ajay K.

    2015-01-01

    Background Mantle cell lymphoma (MCL) remains incurable for most patients and proteasome inhibitors like bortezomib induce responses in a minority of patients with relapsed disease. Fenretinide is a retinoid that has shown preclinical activity in B-cell lymphomas. We hypothesized that these agents could yield augmented anti-tumor activity. Methods Mantle cell lymphoma lines (Granta-519, Jeko-1, Rec-1) were treated with escalating concentrations of bortezomib and fenretinide singly and in combination. Cytotoxicity was assessed using the MTT assay. Flow cytometric methods assessed apoptosis and necrosis with annexin V-FITC/propidium iodide and G1 and G2 cell cycle changes with DAPI staining. Changes in Cyclin D1, Cyclin B, IκBα, and IKKα expression were quantified by Western blot. Results Cytotoxicity was mediated via apoptosis; both agents showed observed vs expected cytotoxicity in Granta-519 of 92.2% vs 55.1%, in Jeko-1 of 87.6% vs 36.3%, and in Rec-1 of 63.2% vs 29.8%. Isobolographic analysis confirmed synergy in Jeko-1 and Rec-1. Bortezomib induced G2 phase arrest with a 1.7 fold-increase over control, and fenretinide resulted in G1 phase arrest, with an increase of 1.3 fold over control. In combination G2 phase arrest predominated, with a 1.4 fold-increase compared to control, and reduced expression of Cyclin D1 to 24%, Cyclin B to 52% and 64%, Cyclin D3 to 25% and 43%, IκBα to 23% and 46%, and IκBα kinase to 34% and 44%. Conclusions Bortezomib and fenretinide exhibit synergistic cytotoxicity against MCL cell lines. This activity is mediated by IκBα kinase modulation, decreased cyclin expression, cell cycle dysregulation, and apoptotic cell death. PMID:26237500

  6. Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-cell Neoplasms

    Science.gov (United States)

    Holkova, Beata; Perkins, E. Brent; Ramakrishnan, Viswanathan; Tombes, Mary Beth; Shrader, Ellen; Talreja, Neha; Wellons, Martha D.; Hogan, Kevin T.; Roodman, G. David; Coppola, Domenico; Kang, Loveleen; Dawson, Jana; Stuart, Robert K.; Peer, Cody; Figg, William D.; Kolla, Sarah; Doyle, Austin; Wright, John; Sullivan, Daniel M.; Roberts, John D.; Grant, Steven

    2011-01-01

    Purpose A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximally tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B cell malignancies (multiple myeloma, indolent and mantle cell lymphoma). Experimental Design Patients received bortezomib by IV push on days 1, 4, 8 and 11. Patients also received alvocidib on days 1 and 8 by 30 min bolus infusion followed by a 4 hour continuous infusion. Treatment was on a 21 day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3+3 design until the MTD was identified based upon DLTs. Pharmacokinetic studies and pharmacodynamic studies were performed. Results Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30 min bolus and 4 hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common non-hematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate 44%). Pharmacokinetic results were typical for alvocidib, and pharmacodynamic studies yielded variable results. Conclusions The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin’s lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. PMID:21447728

  7. An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome

    DEFF Research Database (Denmark)

    Wibroe, Peter P; Ahmadvand, Davoud; Oghabian, Mohammad Ali;

    2016-01-01

    In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two...... follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We...

  8. Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Jang K

    2017-03-01

    Full Text Available Kyungho Jang,1,2,* Min-Kyoung Kim,3,4,* Jaeseong Oh,1 SeungHwan Lee,1 Joo-Youn Cho,1 Kyung-Sang Yu,1 Tai Kiu Choi,3 Sang-Hyuk Lee,3,4 Kyoung Soo Lim4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Medical School, Jeonju, 3Department of Psychiatry, 4Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea *These authors contributed equally to this work Purpose: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1 to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results: Area under the plasma concentration–time curve (AUC of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval of the metabolic ratio

  9. The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis

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    Jing Lu

    2015-01-01

    Full Text Available The International Staging System (ISS is the most important prognostic system for multiple myeloma (MM. It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p<0.001, and the median progression-free survival (PFS was 30/29.5/25 months (p=0.072, respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system.

  10. Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.

    Science.gov (United States)

    Bucur, Octavian; Stancu, Andreea Lucia; Goganau, Ioana; Petrescu, Stefana Maria; Pennarun, Bodvael; Bertomeu, Thierry; Dewar, Rajan; Khosravi-Far, Roya

    2013-01-01

    Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.

  11. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone.

    Science.gov (United States)

    Shende, Vishvesh H; McArthur, Simon; Gillies, Glenda E; Opacka-Juffry, Jolanta

    2015-01-01

    The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume) showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

  12. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone

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    Vishvesh H. Shende

    2015-01-01

    Full Text Available The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

  13. Intratympanic injection of dexamethasone for treatment of tinnitus in patients with sudden sensorineural hearing loss

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    Tadao Yoshida

    2012-01-01

    Full Text Available The purpose of this study is to test the effectiveness of intratympanic dexamethasone injections as a treatment for severe tinnitus in idiopathic sudden sensorineural hearing loss (SNHL. We studied 37 patients who received intratympanic dexamethasone injections and 14 control patients who did not receive it, with severe tinnitus after onset of unilateral sudden SNHL. Hearing level did not change during this study in any patient. The relationship between the duration of tinnitus and effectiveness of treatment was investigated in sudden SNHL. We used a visual analogue scale to evaluate 51 patients with severe tinnitus at the stage of stable hearing level after idiopathic sudden sensorineural hearing loss. Forty-one per cent of patients showed significant improvement after treatment. The average period between onset of sudden sensorineural hearing loss and initiation of intratympanic dexamethasone injection was significantly shorter (207 days in the improved group than in the unchanged group (482 days (P<0.001. In control group, one of 14 patients presented significant improvement spontaneously. Intratympanic dexamethasone treatment may be effective in treatment of severe tinnitus after sudden SNHL at the stage of stable hearing level, and the shorter the period from onset of sudden deafness to the start of intratympanic dexamethasone treatment, the greater the improvement in tinnitus that can be expected.

  14. Dexamethasone inhibits the differentiation of rat tendon stem cells into tenocytes by targeting the scleraxis gene.

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    Chen, Wan; Tang, Hong; Zhou, Mei; Hu, Chao; Zhang, Jiqiang; Tang, Kanglai

    2015-08-01

    Glucocorticoid-induced tendon rupture is very common in clinical practice, and the overall outcome of surgical suture repair is rather poor. The mechanism remains unclear, and effective treatments are still lacking. In the present study, we investigated the effect of dexamethasone on the differentiation of rat tendon stem cells (TSCs) to tenocytes and the underlying molecular mechanisms and found that dexamethasone inhibits the differentiation of TSCs to tenocytes by analyzing the development of long, spindle-shaped cells and detecting the expression of tenocyte markers type I collagen and tenomodulin (TNMD) at both the mRNA and protein levels. We also discovered that after treatment with dexamethasone, the scleraxis expression level is downregulated in vitro and in human specimen. Chromatin immunoprecipitation (ChIP)-PCR showed that dexamethasone promotes glucocorticoid receptor interacted with the TGGAAGCC sequence located between -734 and -726 base pairs (bp) upstream of the start codon of the scleraxis gene. Furthermore, TSCs were transfected with scleraxis knockdown or overexpression plasmids, and the results indicated that scleraxis plays a pivotal role in the differentiation of TSCs to tenocytes. In conclusion, dexamethasone inhibits the differentiation of TSCs to tenocytes by inhibiting the scleraxis gene.

  15. Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis.

    Science.gov (United States)

    Whitcup, Scott M; Robinson, Michael R

    2015-11-01

    Uveitis is a group of ocular inflammatory disorders that can lead to severe vision loss. Despite advances in anti-inflammatory therapy, many patients are resistant to or intolerant of existing treatments. A biodegradable, sustained-release implant, dexamethasone intravitreal implant 0.7 mg (Ozurdex), has been developed to deliver dexamethasone to target tissues in the posterior segment of the eye, minimizing systemic drug exposure and limiting side effects. The implant releases dexamethasone over a period of up to 6 months as the poly(D,L-lactide-co-glycolide) polymer matrix of the implant is metabolized to carbon dioxide and water. The implant is placed in the vitreous of the eye with a single-use applicator in a sutureless, office-based procedure. Treatment with a single dexamethasone intravitreal implant in patients with noninfectious intermediate or posterior uveitis has been shown to produce significant improvements in intraocular inflammation and best-corrected visual acuity with treatment benefit sustained for 6 months. Dexamethasone intravitreal implant has also been shown to reduce central retinal thickness and improve best-corrected visual acuity in patients with macular edema of various etiologies. The implant has been approved for treatment of noninfectious uveitis involving the posterior segment, diabetic macular edema, and macular edema associated with branch and central retinal vein occlusion.

  16. Synergistic anti-proliferative and pro-apoptotic activity of combined therapy with bortezomib, a proteasome inhibitor, with anti-epidermal growth factor receptor (EGFR) drugs in human cancer cells.

    Science.gov (United States)

    Cascone, Tina; Morelli, Maria Pia; Morgillo, Floriana; Kim, Woo-Young; Rodolico, Gabriella; Pepe, Stefano; Tortora, Giampaolo; Berrino, Liberato; Lee, Ho-Young; Heymach, John V; Ciardiello, Fortunato

    2008-09-01

    The proteasome plays a pivotal role in the turnover of regulatory transduction proteins induced by activated cell membrane growth factor receptors. The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. Proteasome inhibition may sensitize human cancer cell lines to EGFR inhibitors. We investigated the growth inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in combination with anti-EGFR drugs, such as gefitinib, vandetanib, and cetuximab in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent growth inhibition in a nine cancer cell line panel (IC(50) values, range 6-42 nM). A significant synergistic growth inhibitory effect was observed with the combination of bortezomib and each EGFR inhibitor in all cell lines (combination index, CI, range 0.10-0.55), which was accompanied by a significant induction in apoptosis by the combined treatment with bortezomib, cetuximab and vandetanib. In HCT-116 colon cancer and A549 lung adenocarcinoma cells, bortezomib plus EGFR inhibitor treatment induced a more effective inhibition of EGFR-activated down-stream signals, including a marked suppression in activated, phosphorylated Akt (P-Akt). In contrast, overexpression of a constitutively active P-Akt protected A549 cells by cell growth inhibition and apoptosis following treatment with bortezomib and EGFR inhibitors. The combined treatment with bortezomib and EGFR inhibitors has a synergistic growth inhibitory and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent autocrine growth pathway through to a more efficient and sustained inhibition of Akt.

  17. HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

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    Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.; Lee, Helen; Leonard, Shannon C.; Klinz, Stephan G.; Noble, Charles O. [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States); Lücker, Petra B.; Zandstra, Peter W. [University of Toronto, 160 College Street, Office 1116, Toronto, Ontario M5S 3E1 (Canada); Drummond, Daryl C.; Olivier, Kenneth J.; Nielsen, Ulrik B.; Niyikiza, Clet; Agresta, Samuel V. [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States); Wickham, Thomas J., E-mail: twickham@merrimackpharma.com [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States)

    2012-07-01

    Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free doxorubicin

  18. Analysis of Efficacy of DICE (Dexamethasone, Ifosfamide,Cisplatin and Etoposide) Regimen on Recurrent and Refractory Intermediate and High Grade Non-Hodgkin's Lymphoma

    Institute of Scientific and Technical Information of China (English)

    Lei Yang; Zhucheng Song; Xiaohong Xu; Jinzhi Wei; Qinghe Tan; Zhirong Cong; Chunlei Peng

    2009-01-01

    OBJECTIVE Thus far there is no standard salvage regimen for patients with recurrent and refractory intermediate and high grade non-Hodgkin's lymphoma (NHL). This study intends to investigate the therapeutic efficacy of the DICE (dexamethasone, isofosfamide, cisplatin and etoposide) regimen on the recurrent and refractory NHL, and to observe the related adverse effects. METHODS Clinical records of 22 patients with recurrent and refractory NHL, who failed to achieve a remission from the CHOP [cyclophosphamide, hydroxydaunomycin/doxorubicin (adriamycin), oncovin, prednisone] regimen within 2 to 6 cycles of treatment, were reviewed. DICE, as a salvage regimen with a median course of treatment of 4 cycles (ranging from 2 to 7 cycles), was now used, and evaluation of the therapeutic efficacy and adverse effect of DICE was conducted in all the patients. Of the 22 NHL cases, 8 were of T-cell origin and the other 14 B-cell origin. Salvage treatment was performed in the patients, with appraisal, prevention and treatment of the toxic reactions. RESULTS Following DICE treatment in the 22 patients, the total effective rate of the regimen was 63.6%, and the complete remission (CR) rate was 40.9%. The effective rates of DICE on the T and B-cell sourced NHL were 75.0% and 57.1%, and the CR rate were 37.5%, 42.9%, respectively (P > 0.05). An increase of the lactate dehydrogenase (LDH) level accompanied by a giant lump was the short-term effect on patients with recurrence (mean P < 0.05) who were drug resistant. Myelosuppression, digestive system reaction and alopecia were the commonly-seen complications in the patients who Received DICE regimen. All patients recovered after treatment, and no chemotherapy-related death occurred. CONCLUSION DICE regimen is effective in treating refractory and recurrent NHL.

  19. Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension.

    Science.gov (United States)

    Tain, Y L; Sheen, J M; Chen, C C; Yu, H R; Tiao, M M; Kuo, H C; Huang, L T

    2014-05-01

    Glucocorticoids are administered to premature infants to accelerate pulmonary maturation. In experimental model, prenatal dexamethasone (DEX) results in reduced nephron number and adulthood hypertension. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), can cause oxidative stress and is involved in the development of hypertension. L-citrulline can be converted to l-arginine (the substrate for NOS) in the body. Thus we intended to determine if maternal L-citrulline therapy can prevent prenatal DEX-induced programmed hypertension by restoration ADMA/nitric oxide (NO) balance, alterations of renin-angiotensin system (RAS) and sodium transporters, and epigenetic regulation by histone deacetylases (HDACs). Male offspring were assigned to four groups: control, pregnancy rats received intraperitoneal DEX (0.2 mg/kg body weight) daily on gestational days 15 and 16 (DEX), pregnancy rats received 0.25% L-citrulline in drinking water during the entire pregnancy and lactation period (CIT), and DEX + CIT. We found DEX group developed hypertension at 16 weeks of age, which was prevented by maternal L-citrulline therapy. Prenatal DEX exposure increased plasma ADMA concentrations and reduced renal NO production. However, L-citrulline reduced plasma ADMA level and increased renal level of NO in DEX + CIT group. Next, prenatal DEX-induced programmed hypertension is related to increased mRNA expression of angiotensin and angiotensin II type 1 receptor, and class I HDACs in the kidney. Prenatal DEX exposure increased renal protein abundance of Na(+)/Cl(-) cotransporter (NCC), which was prevented by L-citrulline therapy. The beneficial effects of L-citrulline therapy include restoration of ADMA/NO balance and alteration of NCC, to prevent the prenatal DEX-induced programmed hypertension.

  20. Effectiveness of intratympanic dexamethasone for refractory sudden sensorineural hearing loss.

    Science.gov (United States)

    Erdur, Omer; Kayhan, Fatma Tulin; Cirik, Ahmet Adnan

    2014-06-01

    The purpose of this study was to investigate the effectiveness of intratympanic steroids in patients with idiopathic sudden sensorineural hearing loss who did not respond to initial systemic steroid therapy. This retrospective study involved 51 patients, who did not respond to systemic steroids as a first-line treatment. Initial systemic steroid therapy consisted of administration of methylprednisolon intravenously (250 mg) at the first day and followed by orally (1 mg/kg) tapering for 14 days. Twenty-one patients accepted intratympanic treatment, and the remaining 30 patients who refused intratympanic treatment were evaluated as the control group. Steroids (dexamethasone drops, 1 mg/mL) were administered through a ventilation tube. Hearing was assessed immediately before treatment and 2 months after treatment. Recovery of hearing was defined as an improvement of >20 dB in the pure tone average. We tested 250, 500, 1,000, 2,000, 4,000, and 8,000 Hz frequencies for the pure tone audiometric evaluation. Statistically Student's t test, Mann-Whitney U test, Chi-squared and Fisher's exact tests were used. The pure tone average improved in 47.6% of the intratympanic group and in 10% of the control group (p = 0.002), with pure tone average improvements of 19.9 ± 16.5 and 4.76 ± 9.6 dB in the intratympanic and control groups, respectively. When the hearing threshold at each frequency was analyzed, improvements at all frequencies were significantly greater in the intratympanic steroid group when compared with the control group (p sudden sensorineural hearing loss in patients, who are refractory to primary systemic steroid therapy.

  1. Observation on the compatible stability of injected cefoxitin sodium and dexamethasone

    Institute of Scientific and Technical Information of China (English)

    Yan-Qing Xie

    2015-01-01

    Objective:To observe the compatible stability of cefoxitin sodium in 0.9% sodium chloride injection and dexamethasone sodium phosphate. Methods:The cefoxitin sodium was compatible with dexamethasone sodium phosphate in 0.9% sodium chloride injection at 25℃. HPLC was used to determine the change of cefoxitin sodium content in the compatible liquids within 0-6 h. The appearance of pharmaceutical liquids was observed, and the change of PH value was detected.Results:No obvious change of cefoxitin sodium content in the compatible liquids within 0-6 h, and no change of PH value, appearance, and characteristics were observed. The insoluble particles conformed to the specifications.Conclusions:Cefoxitin sodium can be compatible with dexamethasone sodium phosphate in 0.9% sodium chloride injection within 6 h.

  2. Thalidomide-based induction regimens are as effective as bortezomib-based regimens in elderly patients with multiple myeloma with cereblon expression.

    Science.gov (United States)

    Jung, Sung-Hoon; Choi, Hyun-Jung; Shin, Myung-Geun; Lee, Seung-Shin; Hwang, Eu Chang; Jung, Tae-Young; Cho, Min-Seok; Yang, Deok-Hwan; Ahn, Jae-Sook; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Lee, Je-Jung

    2016-10-01

    Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs and is considered a biomarker for the prediction of outcomes after thalidomide- or lenalidomide-based treatments. In this study, we evaluated CRBN expression in bone marrow (BM) tissue at diagnosis and investigated the relationship between CRBN expression and treatment outcomes after thalidomide- or bortezomib-based front-line therapies in 89 elderly patients with multiple myeloma (MM). CRBN expression at the time of diagnosis was evaluated with immunohistochemical (IHC) staining for myeloma cells in paraffin wax-embedded BM tissue. CRBN-immunostained slides were scored by intensity and diffuseness, and a total score of >6 was defined as CRBN-positive (CRBN(+)). Thirty-eight patients (45.2 %) were CRBN(+). Among patients treated with thalidomide-based regimens, CRBN(+) patients showed a better treatment response than did CRBN-negative patients (35.0 vs. 11.8 % complete response rate, respectively; HR = 4.038, P = 0.137). During a median follow-up of 31.8 months, patients treated with bortezomib-based regimens had a longer time to progression (TTP) than did patients treated with thalidomide-based regimens (15.6 vs. 13.2 months, respectively; P = 0.047), but early mortality occurred frequently in patients treated with bortezomib-based regimens. Additionally, there was no significant difference in survival outcomes between thalidomide- and bortezomib-based regimens in CRBN(+) patients (median TTP, 13.8 vs. 15.6 months, respectively; P = 0.842 and median OS, 39.3 vs. 30.1 months, respectively; P = 0.074). These data suggest that thalidomide-based regimens are as effective as bortezomib-based regimens in elderly patients with MM who are CRBN(+). Thus, CRBN positivity, by IHC staining, may be useful in deciding appropriate treatment options in elderly patients with MM.

  3. Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer.

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    Mahavir B Chougule

    Full Text Available BACKGROUND: The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC. METHODS: TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. RESULTS: Noscapine inhibited growth of MDA-MB-231 and MDA-MB-468 cells with the IC(50 values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59 were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150-550 mg/kg/day compared to controls. Noscapine (300 mg/kg, Doxorubicin (1.5 mg/kg and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups. CONCLUSIONS: Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC.

  4. Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

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    Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

    2014-11-21

    Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

  5. Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells.

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    Thomas Efferth

    Full Text Available BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART, a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS, a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms. CONCLUSIONS: Our studies raise the possibility to develop ART in

  6. The lateral habenula is a common target of cocaine and dexamethasone.

    Science.gov (United States)

    Zhang, Chun-Xiao; Zhang, Hong; Xu, Hai-Yan; Li, Ming-Xian; Wang, Shao

    2013-10-25

    The lateral habenular nucleus (LHb) receives projections from areas rich in dopaminergic neurons and sends efferent fibers to these areas, suggesting that the LHb has a role in dopaminergic reward-related activity. The LHb is also implicated in multiple stress reactions, including responses to painful stimuli. However, it is unclear whether the LHb facilitates glucocorticoid/cocaine interactions by serving as a common target of both. In this study we investigated the effect of cocaine and dexamethasone (a synthesized glucocorticoid) on pain-related neurons (pain-excitatory and pain-inhibitory). Cocaine treatment effectively increased the firing rate of 89.7% of pain-excitatory neurons (cocaine-up response) and decreased the firing rate of 81.8% of pain-inhibitory neurons (cocaine-down response) in the LHb, suggesting that LHb neurons respond to cocaine via different mechanisms. Dexamethasone enhanced the firing rate of the cocaine-up neurons, while cocaine-down neurons were not influenced, indicating that both drugs may elicit an electrophysiological response at the same LHb neuron. Effects of either cocaine or dexamethasone alone, or both combined, on FOS expression in the LHb were observed via immunohistochemistry. Single administration of either cocaine or dexamethasone increased the number of FOS-positive neurons in the LHb. Pretreatment with dexamethasone and then cocaine markedly enhanced the number of FOS-positive neurons in the LHb relative to cocaine treatment alone, suggesting that stress and addictive drugs exert a synergistic effect on the LHb. We conclude that the LHb responds to cocaine via more than one mechanism and is a common target of both cocaine and the dexamethasone.

  7. Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age-related changes in rat hippocampus.

    Science.gov (United States)

    Moore, Michelle; Piazza, Alessia; Nolan, Yvonne; Lynch, Marina A

    2007-10-01

    Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

  8. Autoradiographic localization of specific [3H]dexamethasone binding in fetal lung.

    Science.gov (United States)

    Beer, D G; Butley, M S; Cunha, G R; Malkinson, A M

    1984-10-01

    The cellular and subcellular localization of specific [3H]dexamethasone binding was examined in fetal mouse lung at various stages of development and in human fetal lung at 8 weeks of gestation using a rapid in vitro steroid incubation technique followed by thaw-mount autoradiography. Competition studies with unlabeled steroids demonstrate the specificity of [3H]dexamethasone labeling, and indicate that fetal lung mesenchyme is a primary glucocorticoid target during lung development. Quantitative binding studies, involving incubation of intact tissue with competing ligand and subsequent subcellular fractionation, show this to be specific, nuclear binding characteristic of glucocorticoid receptors. Autoradiographs of [3H]dexamethasone binding in lung tissue at early stages of development demonstrate that the mesenchyme directly adjacent to the more proximal portions of the bronchiolar network is heavily labeled. In contrast, the epithelium which will later differentiate into bronchi and bronchioles, is relatively unlabeled. Distal portions of the growing epithelium, destined to become alveolar ducts and alveoli, do show nuclear localization of [3H]dexamethasone. Because of the known importance of the mesenchyme in controlling lung development and the ability of glucocorticoids to stimulate lung development, these results suggest that many of the growth-promoting effects of glucocorticoids may be mediated through the mesenchyme. In addition, by utilizing a technique which allows the simultaneous examination of extracellular matrix components and [3H]dexamethasone binding, a relationship is observed between extensive mesenchymal [3H]dexamethasone binding and extensive extracellular matrix accumulation. Since glucocorticoids stimulate the synthesis of many extracellular matrix components, these results suggest a role for these hormones in affecting mesenchymal-epithelial interactions during lung morphogenesis.

  9. Increased Lipiodol uptake in hepatocellular carcinoma possibly due to increased membrane fluidity by dexamethasone and tamoxifen

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Stephanie, E-mail: stephanie.becker@rouen.fnclcc.f [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Department of Nuclear Medicine, Centre H. Becquerel, F-76038 Rouen (France); Ardisson, Valerie; Lepareur, Nicolas [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Sergent, Odile [European University of Brittany, F-35000 Rennes (France); UPRES EA SeRAIC, IFR 140, University of Rennes 1, F-35043 Rennes (France); Bayat, Sahar [INSERM U936 Department of Biostatistics, CHRU Pontchaillou, F-35033 Rennes (France); Noiret, Nicolas [European University of Brittany, F-35000 Rennes (France); Ecole Nationale Superieure de Chimie de Rennes, UMR CNRS 6226, F-35708 Rennes (France); Gaboriau, Francois; Clement, Bruno [INSERM U 991, Rennes, F-35033 France (France); Boucher, Evelyne [INSERM U 991, Rennes, F-35033 France (France); Department of Medical Oncology, Centre E. Marquis, F-35042 Rennes (France); Raoul, Jean-Luc [INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France); Department of Medical Oncology, Centre E. Marquis, F-35042 Rennes (France); Garin, Etienne [Department of Nuclear Medicine, Centre E. Marquis, F-35042 Rennes (France); INSERM U 991, Rennes, F-35033 France (France); European University of Brittany, F-35000 Rennes (France)

    2010-10-15

    Introduction: Lipiodol is used as a vector for chemoembolization or internal radiotherapy in unresectable hepatocellular carcinomas (HCCs). The aim of this study is to improve the tumoral uptake of Lipiodol by modulating membrane fluidizing agents to optimize the effectiveness of Lipiodol vectorized therapy. Methods: The effect of dexamethasone and tamoxifen on membrane fluidity was studied in vitro by electron paramagnetic resonance applied to rat hepatocarcinoma cell line N1S1. The tumoral uptake of Lipiodol was studied in vivo on rats with HCC, which had been previously treated by dexamethasone and/or tamoxifen, after intra-arterial administration of {sup 99m}Tc-SSS-Lipiodol. Results: The two molecules studied here exhibit a fluidizing effect in vitro which appears dependent on time and dose, with a maximum fluidity obtained after 1 hr at concentrations of 20 {mu}M for dexamethasone and 200 nM for tamoxifen. In vivo, while the use of dexamethasone or tamoxifen alone tends to lead to increased tumoral uptake of Lipiodol, this effect does not reach levels of significance. On the other hand, there is a significant increase in the tumoral uptake of {sup 99m}Tc-SSS-Lipiodol in rats pretreated by both dexamethasone and tamoxifen, with a tumoral uptake (expressed in % of injected activity per g of tumor) of 13.57{+-}3.65% after treatment, as against 9.45{+-}4.44% without treatment (P<.05). Conclusions: Dexamethasone and tamoxifen fluidify the N1S1 cells membrane, leading to an increase in the tumoral uptake of Lipiodol. These drugs could be combined with chemo-Lipiodol-embolization or radiolabeled Lipiodol, with a view to improving the effectiveness of HCCs therapy.

  10. Effects of dexamethasone on proliferation, differentiation and apoptosis of adult human osteoblasts in vitro

    Institute of Scientific and Technical Information of China (English)

    杨林; 陶天遵; 王新婷; 杜宁; 陈伟珍; 陶树清; 王志成; 吴丽萍

    2003-01-01

    Objective To observe the effects of dexamethasone on proliferation, differentiation and apoptosis of adult human osteoblasts in vitro. Methods Iliac trabecular bone specimens were obtained from adult patients undergoing necessary surgery. After the bone pieces were digested with collagenase-trypsin, osteoblasts were released and incubated at 37℃ in a relative humidity of 95% and 5% CO2. Then, the cells were purified, and their passages were given DMEM-F12 and fetal bovine serum medium. Subsequently, 10-8 mol/L dexamethasone was added into the culture medium to incubate the osteoblasts for three days, and the cells from control groups were incubated without any drugs. All cells were observed continually with phase contrast microscope and transmission electron microscope. Finally, apoptosis was detected by the use of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and biochemical indices, alkaline phosphatase (ALP) and osteocalcin (OCN) were used to determine the effects of dexamethasone on proliferation, differentiation and apoptosis of adult osteoblasts in vitro. Results In the adult osteoblasts obtained by collagenase-trypsin digestion, it achieved high survial, stable biochemical indices and excellent purification. Under the condition of dexamethasone 10-8 mol/L and osteoblasts 10 000/ml, there was significant promotion of ALP and OCN secretion without cell apoptosis.Conclusions Dexamethasone has a significant effect on the proliferation and differentiation of adult osteoblasts in vitro without apoptosis, and dexamethasone at the suggested concentration can be used as positive control in drug studies for osteoporosis treatment.

  11. Dexamethasone therapy for bacterial meningitis. Results of two double-blind, placebo-controlled trials.

    Science.gov (United States)

    Lebel, M H; Freij, B J; Syrogiannopoulos, G A; Chrane, D F; Hoyt, M J; Stewart, S M; Kennard, B D; Olsen, K D; McCracken, G H

    1988-10-13

    We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P less than 0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P less than 0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P less than 0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P less than 0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P less than 0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P less than 0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness.

  12. Prenatal dexamethasone augments the neurobehavioral teratology of chlorpyrifos: significance for maternal stress and preterm labor.

    Science.gov (United States)

    Levin, Edward D; Cauley, Marty; Johnson, Joshua E; Cooper, Ellen M; Stapleton, Heather M; Ferguson, P Lee; Seidler, Frederic J; Slotkin, Theodore A

    2014-01-01

    Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure 8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos' effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants.

  13. Dexamethasone reduces tachykinin but not ACh airway hyperreactivity after O[sub 3

    Energy Technology Data Exchange (ETDEWEB)

    Murlas, C.G.; Lang, Z.; Chodimella, V. (Rush Univ., Chicago, IL (United States))

    1993-01-01

    We investigated whether dexamethasone pretreatment affected the acute increase in airway reactivity produced by high-level ozone exposure. Reactivity to intravenous IV substance P (SP), IV acetylcholine (ACh), or aerosolized capsaicin (CAP) before and 1 hr after ozone exposure (3 ppm for 2 hr) was determined by measuring specific airway resistance in anesthetized, spontaneously breathing guinea pigs, half of whom had been pretreated for 2 days pre-ozone with dexamethasone (2 mg/kg intramuscularly [IM] daily). The amount of IV SP, IV ACh, or inhaled capsaicin necessary to increase baseline specific airway resistance by 100% (ED200ACh or ED200SP) or 35% (ED135CAP) was determined by interpolation from dose-response curves. Compared to their pre-ozone status on the day of exposure, we found that dexamethasone-pretreated animals manifested significantly less of an increase in airway reactivity postozone to IV SP or inhaled CAP than did untreated animals. Changes in logEDs of the pretreated group were 0.18 +/- 0.03 (mean +/- SE) for SP and 2.20 +/- 0.11 for CAP compared to 0.27 +/- 0.04 and 3.38 +/- 0.34, respectively, for the untreated groups post-ozone (p < 0.05 and n = 4 for each). In contrast, dexamethasone pretreatment had no effect on IV ACh reactivity postozone: changes in logED200ACh were 0.27 +/- 0.08 and 0.28 +/- 0.04 for the pretreated and untreated groups, respectively (n = 4). In animals pretreated with captopril to block possible dexamethasone stimulation of angiotensin-converting enzyme synthesis that could influence tachykinin reactivity, we found that the corticosteroid effect on post-ozone SP reactivity was as marked as that seen in animals without captopril (n = 4). These reactivity studies were consistent with the possibility that dexamethasone may ameliorate ozone-induced, tachykinin hyperreactivity by stimulating airway neutral endopeptidase (NEP).

  14. CR4056, a new analgesic I2 ligand, is highly effective against bortezomib-induced painful neuropathy in rats

    Directory of Open Access Journals (Sweden)

    Meregalli C

    2012-06-01

    Full Text Available Cristina Meregalli,1 Cecilia Ceresa,1 Annalisa Canta,1 Valentina Alda Carozzi,1 Alessia Chiorazzi,1 Barbara Sala,1 Norberto Oggioni,1 Marco Lanza,2 Ornella Letar,i2 Flora Ferrari,2 Federica Avezza,1 Paola Marmiroli,1 GianFranco Caselli,2 Guido Cavaletti11Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, 2Pharmacology and Toxicology Department, Rottapharm | Madaus Research Center, Monza, ItalyAbstract: Although bortezomib (BTZ is the frontline treatment for multiple myeloma, its clinical use is limited by the occurrence of painful peripheral neuropathy, whose treatment is still an unmet clinical need. Previous studies have shown chronic BTZ administration (0.20 mg/kg intravenously three times a week for 8 weeks to female Wistar rats induced a peripheral neuropathy similar to that observed in humans. In this animal model of BTZ-induced neurotoxicity, the present authors evaluated the efficacy of CR4056, a novel I2 ligand endowed with a remarkable efficacy in several animal pain models. CR4056 was administered in a wide range of doses (0.6–60 mg/kg by gavage every day for 2–3 weeks in comparison with buprenorphine (Bupre (28.8 µg/kg subcutaneously every day for 2 weeks and gabapentin (Gaba (100 mg/kg by gavage every day for 3 weeks. Chronic administration of BTZ reduced nerve conduction velocity and induced allodynia. CR4056, Bupre, or Gaba did not affect the impaired nerve conduction velocity. Conversely, CR4056 dose-dependently reversed BTZ-induced allodynia (minimum effective dose 0.6 mg/kg. The optimal dose found, 6 mg/kg, provided a constant pain relief throughout the treatment period and without rebound after suspension, being effective when coadministered with BTZ, starting before or after allodynia was established, or when administered alone after BTZ cessation. A certain degree of tolerance was seen after 7 days of administration, but only at the highest doses (20 and 60 mg/kg. Bupre was effective

  15. Randomized clinical trial of preoperative dexamethasone on postoperative nausea and vomiting after laparoscopy for suspected appendicitis

    DEFF Research Database (Denmark)

    Kleif, J; Kirkegaard, A; Vilandt, J;

    2017-01-01

    BACKGROUND: Few studies have investigated the effects of preoperative dexamethasone in acute surgical patients. This study examined the effects of 8 mg dexamethasone administered intravenously 30 min before surgery for suspected acute appendicitis. METHODS: A multicentre, parallel-group, double......-blind, placebo-controlled study was conducted at two university hospitals in Denmark. Adults undergoing laparoscopic surgery for suspected appendicitis were eligible for inclusion. Participants, healthcare staff and investigators were blinded until all data analysis had been done. The primary outcome...

  16. The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression.

    Science.gov (United States)

    Hagenbuchner, Judith; Ausserlechner, Michael J; Porto, Verena; David, Reinhard; Meister, Bernhard; Bodner, Martin; Villunger, Andreas; Geiger, Kathrin; Obexer, Petra

    2010-03-05

    Neuroblastoma is the most frequent extracranial solid tumor in children. Here, we report that the proteasome inhibitor bortezomib (PS-341, Velcade) activated the pro-apoptotic BH3-only proteins PMAIP1/Noxa and BBC3/Puma and induced accumulation of anti-apoptotic MCL1 as well as repression of anti-apoptotic BCL2L1/Bcl-xL. Retroviral expression of Bcl-xL, but not of MCL1, prevented apoptosis by bortezomib. Gene knockdown of Noxa by shRNA technology significantly reduced apoptosis, whereas Puma knockdown did not affect cell death kinetics. Immunoprecipitation revealed that endogenous Noxa associated with both, Bcl-xL and MCL1, suggesting that in neuronal cells Noxa can neutralize Bcl-xL, explaining the pronounced protective effect of Bcl-xL. Tetracycline-regulated Noxa expression did not trigger cell death per se but sensitized to bortezomib treatment in a dose-dependent manner. This implies that the induction of Noxa is necessary but not sufficient for bortezomib-induced apoptosis. We conclude that MCL1 steady-state expression levels do not affect sensitivity to proteasome-inhibitor treatment in neuronal tumor cells, and that both the repression of Bcl-xL and the activation of Noxa are necessary for bortezomib-induced cell death.

  17. Development and Characterization of Liposomal Doxorubicin Hydrochloride with Palm Oil

    Directory of Open Access Journals (Sweden)

    Bahareh Sabeti

    2014-01-01

    Full Text Available The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox. The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about −31 and −32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4 at 37°C. Comparing cytotoxicity and cellular uptake of LUV with CaelyxR on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.

  18. Development and characterization of liposomal doxorubicin hydrochloride with palm oil.

    Science.gov (United States)

    Sabeti, Bahareh; Noordin, Mohamed Ibrahim; Mohd, Shaharuddin; Hashim, Rosnani; Dahlan, Afendi; Javar, Hamid Akbari

    2014-01-01

    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.

  19. Interactions of human serum albumin with doxorubicin in different media

    Science.gov (United States)

    Gun'ko, Vladimir M.; Turov, Vladimir V.; Krupska, Tetyana V.; Tsapko, Magdalina D.

    2017-02-01

    Interactions of human serum albumin (10 wt% H2O and 0.3 wt% sodium caprylate) with doxorubicin hydrochloride (1 wt%) were studied alone or with addition of HCl (3.6 wt% HCl) using 1H NMR spectroscopy. A model of hydrated HSA/12DOX was calculated using PM7 method with COSMO showing large variations in the binding constant depending on structural features of DOX/HSA complexes. DOX molecules/ions displace bound water from narrow intramolecular voids in HSA that leads to diminution of freezing-melting point depression of strongly bound water (SBW). Structure of weakly bound water (WBW) depends much weaker on the presence of DOX than SBW because a major fraction of DOX is bound to adsorption sites of HSA. Addition of HCl results in strong changes in structure of macromolecules and organization of water in hydration shells of HSA (i.e., mainly SBW) and in the solution (i.e., WBW + non-bound bulk water).

  20. Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity.

    Science.gov (United States)

    Pizarro, Marcela; Troncoso, Rodrigo; Martínez, Gonzalo J; Chiong, Mario; Castro, Pablo F; Lavandero, Sergio

    2016-08-31

    Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.

  1. Facile biosynthesis, separation and conjugation of gold nanoparticles to doxorubicin

    Science.gov (United States)

    Kumar, S. Anil; Peter, Yves-Alain; Nadeau, Jay L.

    2008-12-01

    Particle shape and size determine the physicochemical and optoelectronic properties of nanoscale materials, including optical absorption, fluorescence, and electric and magnetic moments. It is thus desirable to be able to synthesize and separate various particle shapes and sizes. Biosynthesis using microorganisms has emerged as a more ecologically friendly, simpler, and more reproducible alternative to chemical synthesis of metal and semiconductor nanoparticles, allowing the generation of rare forms such as triangles. Here we show that the plant pathogenic fungus Helminthosporum solani, when incubated with an aqueous solution of chloroaurate ions, produces a diverse mixture of extracellular gold nanocrystals in the size range from 2 to 70 nm. A plurality are polydisperse spheres, but a significant number are homogeneously sized rods, triangles, pentagons, pyramids, and stars. The particles can be separated according to their size and shape by using a sucrose density gradient in a tabletop microcentrifuge, a novel and facile approach to nanocrystal purification. Conjugation to biomolecules can be performed without further processing, as illustrated with the smallest fraction of particles which were conjugated to the anti-cancer drug doxorubicin (Dox) and taken up readily into HEK293 cells. The cytotoxicity of the conjugates was comparable to that of an equivalent concentration of Dox.

  2. Erdosteine prevents doxorubicin-induced cardiotoxicity in rats.

    Science.gov (United States)

    Yagmurca, Murat; Fadillioglu, Ersin; Erdogan, Hasan; Ucar, Muharrem; Sogut, Sadik; Irmak, M Kemal

    2003-10-01

    The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.

  3. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies

    Directory of Open Access Journals (Sweden)

    Jin X

    2016-09-01

    Full Text Available Xun Jin,1 Peilan Zhang,1 Li Luo,1 Hao Cheng,1 Yunzu Li,1 Ting Du,1 Bingwen Zou,2 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China; 2Department of Thoracic Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of China Abstract: Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol (DPP nanoparticles to deliver doxorubicin (Dox for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer. Keywords: bladder cancer, drug delivery, nanoparticles, intravesical therapy

  4. Doxorubicin-induced alopecia is associated with sebaceous gland degeneration.

    Science.gov (United States)

    Selleri, Silvia; Seltmann, Holger; Gariboldi, Silvia; Shirai, Yuri F; Balsari, Andrea; Zouboulis, Christos C; Rumio, Cristiano

    2006-04-01

    Alopecia, accompanied by skin dryness, is one of the distressing side effects often occurring in chemotherapy-treated cancer patients. Little is known of the effects of chemotherapy on sebaceous glands, despite their importance in hair follicle homeostasis. This study investigates sebaceous gland morphology and the response of SZ95 sebaceous gland cell line to doxorubicin (DXR) treatment. The morphology of sebaceous glands during intraperitoneal DXR treatment was investigated by optical and electron microscopy in a 7-day-old rat model and further confirmed in an adult mouse model. Moreover, in vitro studies using the SZ95 sebaceous gland cell line were performed to assess the response of sebocytes to DXR in terms of cell proliferation, apoptosis, and necrosis. DXR treatment induced sebaceous gland regression and occasionally caused their complete disappearance. This observed damage and disappearance preceded DXR-induced hair loss. In vitro experiments using the SZ95 sebaceous gland cell line indicated that DXR treatment induced a differentiation process leading to premature sebocytes apoptosis. Owing to the importance of the sebaceous gland in hair follicle homeostasis, DXR-induced involution of this gland might be related to subsequent hair loss.

  5. Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

    Science.gov (United States)

    Li, Haoyu; Chen, Zhenghu; Hu, Ting; Wang, Long; Yu, Yang; Zhao, Yanling; Sun, Wenijing; Guan, Shan; Pang, Jonathan C.; Woodfield, Sarah E.; Liu, Qing; Yang, Jianhua

    2016-01-01

    Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients. PMID:27687684

  6. Melatonin attenuates doxorubicin-induced testicular toxicity in rats.

    Science.gov (United States)

    Lee, K-M; Lee, I-C; Kim, S-H; Moon, C; Park, S-H; Shin, D-H; Kim, S-H; Park, S-C; Kim, H-C; Kim, J-C

    2012-05-01

    This study investigated the protective effects of melatonin (MLT) against doxorubicin (DXR)-induced testicular toxicity and oxidative stress in rats. DXR was given as a single intraperitoneal dose of 10 mg kg(-1) body weight to male rats at 1 h after MLT treatment on day 6 of the study. MLT at 15 mg kg(-1) body weight was administered daily by gavage for 5 days before DXR treatment followed by an additional dose for 5 days. Sperm analysis, histopathological examination and biochemical methods were used for this investigation. DXR caused a decrease in the weight of seminal vesicles, epididymal sperm count and motility and an increase in the incidence of histopathological changes of the testis. In addition, an increased malondialdehyde (MDA) concentration and decreased glutathione content, glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase activities were observed. On the contrary, MLT treatment significantly ameliorated DXR-induced testicular toxicity in rats. Moreover, MDA concentration and GR, GST and SOD activities were not affected when MLT was administered in conjunction with DXR. These results indicate that MLT had a protective effect against DXR-induced testicular toxicity and that the protective effects of MLT may be due to both the inhibition of lipid peroxidation and increased antioxidant activity.

  7. A sensitive high performance liquid chromatography assay for the quantification of doxorubicin associated with DNA in tumor and tissues.

    Science.gov (United States)

    Lucas, Andrew T; O'Neal, Sara K; Santos, Charlene M; White, Taylor F; Zamboni, William C

    2016-02-01

    Doxorubicin, a widely used anticancer agent, exhibits antitumor activity against a wide variety of malignancies. The drug exerts its cytotoxic effects by binding to and intercalating within the DNA of tumor and tissue cells. However, current assays are unable to accurately determine the concentration of the intracellular active form of doxorubicin. Thus, the development of a sample processing method and a high-performance liquid chromatography (HPLC) methodology was performed in order to quantify doxorubicin that is associated with DNA in tumors and tissues, which provided an intracellular cytotoxic measure of doxorubicin exposure after administration of small molecule and nanoparticle formulations of doxorubicin. The assay uses daunorubicin as an internal standard; liquid-liquid phase extraction to isolate drug associated with DNA; a Shimadzu HPLC with fluorescence detection equipped with a Phenomenex Luna C18 (2μm, 2.0×100mm) analytical column and a gradient mobile phase of 0.1% formic acid in water or acetonitrile for separation and quantification. The assay has a lower limit of detection (LLOQ) of 10ng/mL and is shown to be linear up to 3000ng/mL. The intra- and inter-day precision of the assay expressed as a coefficient of variation (CV%) ranged from 4.01 to 8.81%. Furthermore, the suitability of this assay for measuring doxorubicin associated with DNA in vivo was demonstrated by using it to quantify the doxorubicin concentration within tumor samples from SKOV3 and HEC1A mice obtained 72h after administration of PEGylated liposomal doxorubicin (Doxil(®); PLD) at 6mg/kg IV x 1. This HPLC assay allows for sensitive intracellular quantification of doxorubicin and will be an important tool for future studies evaluating intracellular pharmacokinetics of doxorubicin and various nanoparticle formulations of doxorubicin.

  8. Molecular dynamics simulation of doxorubicin adsorption on a bundle of functionalized CNT.

    Science.gov (United States)

    Izadyar, Akram; Farhadian, Nafiseh; Chenarani, Naser

    2016-08-01

    In this study, molecular dynamics simulation is used to investigate the adsorption of an anticancer drug, doxorubicin, on bundles of functionalized single-walled carbon nanotubes (SWNTs) in an aqueous solution. Carboxylic group has been selected as the functional group. Molecular dynamics (MD) simulations are performed for both separated systems containing a SWNT bundle and a functionalized carbon nanotube bundle, and results are compared with existing experimental data. MD results show that doxorubicin can be adsorbed on CNTs using different methods such as entrapment within CNT bundle, attachment to the side wall of the CNT, and adsorption on the CNT inner cavity. For functionalized CNT, the adsorption of drugs on the functional groups is essential for predicting the enhancement of drug loading on the functionalized nanotubes. Furthermore, the adsorption behavior of doxorubicin on CNTs is fitted with Langmuir and Freundlich isotherm models. The results show that Langmuir model can predict the adsorption behavior of doxorubicin on CNTs more accurately than Freundlich model does. As predicted by this isotherm model, the adsorption process of doxorubicin on CNTs is relatively difficult, but it can be improved by increasing the functional groups on the CNTs surface.

  9. The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes

    Directory of Open Access Journals (Sweden)

    F. Misiti

    2003-12-01

    Full Text Available Anthracyclines, a class of antitumor drugs widely used for the treatment of solid and hematological malignancies, cause a cumulative dose-dependent cardiac toxicity whose biochemical basis is unclear. Recent studies of the role of the metabolites of anthracyclines, i.e., the alcohol metabolite doxorubicinol and aglycone metabolites, have suggested new hypotheses about the mechanisms of anthracycline cardiotoxicity. In the present study, human red blood cells were used as a cell model. Exposure (1 h at 37ºC of intact human red blood cells to doxorubicinol (40 µM and to aglycone derivatives of doxorubicin (40 µM induced, compared with untreated red cells: i a ~2-fold stimulation of the pentose phosphate pathway (PPP and ii a marked inhibition of the red cell antioxidant enzymes, glutathione peroxidase (~20% and superoxide dismutase (~60%. In contrast to doxorubicin-derived metabolites, doxorubicin itself induced a slighter PPP stimulation (~35% and this metabolic event was not associated with any alteration in glutathione reductase, glutathione peroxidase, catalase or superoxide dismutase activity. Furthermore, the interaction of hemoglobin with doxorubicin and its metabolites induced a significant increase (~22% in oxygen affinity compared with hemoglobin incubated without drugs. On the basis of the results obtained in the present study, a new hypothesis, involving doxorubicinol and aglycone metabolites, has been proposed to clarify the mechanisms responsible for the doxorubicin-induced red blood cell toxicity.

  10. Combinatorial Cytotoxic Effects of Damnacanthal and Doxorubicin against Human Breast Cancer MCF-7 Cells in Vitro

    Directory of Open Access Journals (Sweden)

    Muhammad Yusran Abdul Aziz

    2016-09-01

    Full Text Available Despite progressive research being done on drug therapy to treat breast cancer, the number of patients succumbing to the disease is still a major issue. Combinatorial treatment using different drugs and herbs to treat cancer patients is of major interest in scientists nowadays. Doxorubicin is one of the most used drugs to treat breast cancer patients. The combination of doxorubicin to other drugs such as tamoxifen has been reported. Nevertheless, the combination of doxorubicin with a natural product-derived agent has not been studied yet. Morinda citrifolia has always been sought out for its remarkable remedies. Damnacanthal, an anthraquinone that can be extracted from the roots of Morinda citrifolia is a promising compound that possesses a variety of biological properties. This study aimed to study the therapeutic effects of damnacanthal in combination with doxorubicin in breast cancer cells. Collectively, the combination of both these molecules enhanced the efficacy of induced cell death in MCF-7 as evidenced by the MTT assay, cell cycle, annexin V and expression of apoptosis-related genes and proteins. The effectiveness of doxorubicin as an anti-cancer drug was increased upon addition of damnacanthal. These results could provide a promising approach to treat breast cancer patients.

  11. Host-guest interaction of ZnBDC-MOF + doxorubicin: A theoretical and experimental study

    Science.gov (United States)

    Vasconcelos, Iane B.; Wanderley, Kaline A.; Rodrigues, Nailton M.; da Costa, Nivan B.; Freire, Ricardo O.; Junior, Severino A.

    2017-03-01

    The incorporation of drugs in biodegradable polymeric particles is one of many processes that controllably and significantly increase their release and action. In this paper, we describe the synthesis and physicochemical characterization of ZnBDC-MOF + doxorubicin (DOXO@ZnBDC) and the system's effectiveness in the sustained release of the drug doxorubicin. An experimental and theoretical study is presented of the interaction between the [Zn(BDC)(H2O)2]n MOF and the drug doxorubicin (DOXO). The synthesis was characterized by elemental analysis and X-ray powder diffraction (XRPD). The experimental incorporation was accomplished and analyzed by Fourier transform infrared spectroscopy (FTIR), XRPD and UV-Vis (ultraviolet-visible) spectrophotometry. Based on an analysis of the doxorubicin release profile, our results suggest that the drug delivery system showed slower release than other systems under development. Studies of cytotoxicity by the MTT method showed good results for the system developed with antineoplastic doxorubicin, and together with the other results of this study, suggest the successful development of a MOF-based drug delivery system.

  12. α-Tocopherol succinate improves encapsulation and anticancer activity of doxorubicin loaded in solid lipid nanoparticles.

    Science.gov (United States)

    Oliveira, Mariana S; Mussi, Samuel V; Gomes, Dawidson A; Yoshida, Maria Irene; Frezard, Frederic; Carregal, Virgínia M; Ferreira, Lucas A M

    2016-04-01

    This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and α-tocopheryl succinate (TS), a succinic acid ester of α-tocopherol that exhibits anticancer actions, evaluating the influence of TS on drug encapsulation efficiency. The SLN were characterized for size, zeta potential, entrapment efficiency (EE), and drug release. Studies of in vitro anticancer activity were also conducted. The EE was significantly improved from 30 ± 1% to 96 ± 2% for SLN without and with TS at 0.4%, respectively. In contrast, a reduction in particle size from 298 ± 1 to 79 ± 1 nm was observed for SLN without and with TS respectively. The doxorubicin release data show that SLN provide a controlled drug release. The in vitro studies showed higher cytotoxicity for doxorubicin-TS-loaded SLN than for free doxorubicin in breast cancer cells. These findings suggest that TS-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer.

  13. Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

    Science.gov (United States)

    Xu, Xiao Dong; Zhao, Yan; Zhang, Min; He, Rui Zhi; Shi, Xiu Hui; Guo, Xing Jun; Shi, Cheng Jian; Peng, Feng; Wang, Min; Shen, Min; Wang, Xin; Li, Xu; Qin, Ren Yi

    2017-01-01

    Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer. PMID:28208617

  14. Transcorneal iontophoresis of dendrimers: PAMAM corneal penetration and dexamethasone delivery.

    Science.gov (United States)

    Souza, Joel G; Dias, Karina; Silva, Silas A M; de Rezende, Lucas C D; Rocha, Eduardo M; Emery, Flavio S; Lopez, Renata F V

    2015-02-28

    Iontophoresis of nanocarriers in the eye has been proposed to sustain drug delivery and maintain therapeutic concentrations. Fourth generation polyamidoamine (PAMAM) dendrimers are semi-rigid nanoparticles with surface groups that are easily modified. These dendrimers are known to modulate tight junctions, increase paracellular transport of small molecules and be translocated across epithelial barriers, exhibiting high uptake by different cell lines. The first aim of this study was to investigate the effect of iontophoresis on PAMAM penetration and distribution into the cornea. The second aim was to evaluate, ex vivo and in vivo, the effect of these dendrimers in dexamethasone (Dex) transcorneal iontophoresis. Anionic (PAMAM G3.5) and cationic (PAMAM G4) dendrimers were labeled with fluorescein isothiocyanate (FITC), and their distribution in the cornea was investigated using confocal microscopy after ex vivo anodal and cathodal iontophoresis for various application times. The particle size distribution and zeta potential of the dendrimers in an isosmotic solution were determined using dynamic light scattering and Nanoparticle Tracking Analysis (NTA), where the movement of small particles and the formation of large aggregates, from 5 to 100 nm, could be observed. Transcorneal iontophoresis increased the intensity and depth of PAMAM-FITC fluorescence in the cornea, suggesting improved transport of the dendrimers across the epithelium toward the stroma. PAMAM complexes with Dex were characterized by (13)C-NMR, (1)H-NMR and DOSY. PAMAM G3.5 and PAMAM G4 increased the aqueous solubility of Dex by 10.3 and 3.9-fold, respectively; however, the particle size distribution and zeta potential remained unchanged. PAMAM G3.5 decreased the Dex diffusion coefficient 48-fold compared with PAMAM G4. The ex vivo studies showed that iontophoresis increased the amount of Dex that penetrated into the cornea by 2.9, 5.6 and 3.0-fold for Dex, Dex-PAMAM G4 and Dex-PAMAM G3

  15. Biphasic influence of dexamethasone exposure on embryonic vertebrate skeleton development

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xin; Chen, Jian-long; Ma, Zheng-lai; Zhang, Zhao-long; Lv, Shun; Mai, Dong-mei; Liu, Jia-jia [Department of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Medicine, Jinan University, Guangzhou 510632 (China); Chuai, Manli [Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH (United Kingdom); Lee, Kenneth Ka Ho; Wan, Chao [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Yang, Xuesong, E-mail: yang_xuesong@126.com [Department of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Medicine, Jinan University, Guangzhou 510632 (China); Institute of Fetal-Preterm Labor Medicine, Jinan University, Guangzhou 510632 (China)

    2014-11-15

    Dexamethasone (Dex) has anti-inflammatory and immunomodulatory properties against many conditions. There is a potential teratogenic risk, however, for pregnant women receiving Dex treatment. It has been claimed that Dex exposure during pregnancy could affect osteogenesis in the developing embryo, which still remains highly controversial. In this study, we employed chick embryos to investigate the effects of Dex exposure on skeletal development using combined in vivo and in vitro approach. First, we demonstrated that Dex (10{sup −8}–10{sup −6} μmol/egg) exposure resulted in a shortening of the developing long bones of chick embryos, and it accelerated the deposition of calcium salts. Secondly, histological analysis of chick embryo phalanxes exhibited Dex exposure inhibited the proliferation of chondrocytes, increased apoptosis of chondrocytes and osteocytes, and led to atypical arranged hypertrophic chondrocytes. The expression of genes related to skeletogenesis was also analyzed by semi-quantitative RT-PCR. The expression of ALP, Col1a2 and Col2a1 was decreased in the Dex treated phalanxes. A detectable increase was observed in Runx-2 and Mmp-13 expression. We next examined how Dex affected the different stages of skeletogenesis in vitro. Utilizing limb bud mesenchyme micromass cultures, we determined that Dex exposure exerted no effect on apoptosis but impaired chondrogenic cell proliferation. Interestingly, low dose of Dex moderately prompted nodule formation as revealed by alcian blue staining, but higher doses of Dex significantly inhibited similar chondrogenic differentiation. Dex exposure did not induce apoptosis when the chondrogenic precursors were still at the mesenchymal stage, however, cell viability was suppressed when the mesenchyme differentiated into chondrocytes. Alizarin red staining revealed that the capacity to form mineralized bone nodules was correspondingly enhanced as Dex concentrations increased. The mRNA level of Sox-9 was slightly

  16. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.

    Science.gov (United States)

    Golden, Encouse B; Lam, Philip Y; Kardosh, Adel; Gaffney, Kevin J; Cadenas, Enrique; Louie, Stan G; Petasis, Nicos A; Chen, Thomas C; Schönthal, Axel H

    2009-06-04

    The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this "miracle herb" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.

  17. Therapeutic potential of the proteasome inhibitor Bortezomib on titanium particle-induced inflammation in a murine model.

    Science.gov (United States)

    Mao, Xin; Pan, Xiaoyun; Cheng, Tao; Zhang, Xianlong

    2012-06-01

    Wear particle-induced aseptic loosening has been recognized as a harmful inflammatory process that jeopardizes the longevity of total joint replacement. The proteasome controls the activation of NF-κB and subsequent inflammatory mediators, such as TNF-α and IL-1β; thus, we investigated whether proteasome inhibition can ameliorate wear particle-induced inflammation in a murine model. A total of 48 BALB/C mice were divided into four groups. Titanium (Ti) particles were injected into the established air pouches of all mice (except negative controls) to provoke inflammation, and then 0.1 or 0.5 mg/kg of Bortezomib (Bzb, a proteasome inhibitor) was administered to ameliorate the inflammation response, while air pouches without Bzb administration were used as loading controls. The air pouches were harvested 2 or 7 days after Bzb injection for molecular and histological analyses. Inflammation responses in the air pouch tissues of Bzb treatment groups are lower than those in the Ti-stimulated group, and this occurs in a dose-dependent manner. Bzb can significantly attenuate the severity of Ti-induced inflammation in air pouches.

  18. The role of bortezomib, thalidomide and lenalidomide in the management of multiple myeloma: an overview of clinical and economic information.

    Science.gov (United States)

    Messori, Andrea; Maratea, Dario; Nozzoli, Chiara; Bosi, Alberto

    2011-04-01

    Bortezomib, thalidomide and lenalidomide can be aimed at treating patients with newly diagnosed multiple myeloma (both eligible and ineligible for transplantation) as well as those with relapsed or refractory disease. This review analysed the available clinical and economic data on these three drugs. Irrespective of which of the three agents is considered, the magnitude of the benefit in newly diagnosed cases (transplanted or non-transplanted) tends to be between 10 and 20 months per patient in terms of progression-free survival or survival; the survival benefit is smaller in relapsed or refractory disease. In addition, a single-institution observational analysis evaluated the outcomes in nearly 3000 consecutive patients examined between 1971 and 2006. The survival in patients diagnosed between 2001 and 2006 was longer than that observed in patients diagnosed between 1994 and 2000. This finding supports the conclusion that novel agents provide a survival improvement compared with traditional therapy. Formal cost-effectiveness studies on these three agents are still lacking. A MEDLINE search retrieved only four short papers or letters and no full-length analysis. Hence, the cost effectiveness of these agents needs further investigation, with separate assessments of the different therapeutic settings. In a simplified analysis, we tried to contrast the average cost of treatment for each of the novel agents versus their respective benefit, expressed in quality-adjusted survival. Despite its preliminary nature, our assessment indicates that the cost effectiveness of these three agents is likely to be within commonly accepted pharmacoeconomic thresholds.

  19. Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved.

    Science.gov (United States)

    Lentacker, Ine; Geers, Bart; Demeester, Joseph; De Smedt, Stefaan C; Sanders, Niek N

    2010-01-01

    Drug delivery with microbubbles and ultrasound is gaining more and more attention in the drug delivery field due to its noninvasiveness, local applicability, and proven safety in ultrasonic imaging techniques. In this article, we tried to improve the cytotoxicity of doxorubicin (DOX)-containing liposomes by preparing DOX-liposome-containing microbubbles for drug delivery with therapeutic ultrasound. In this way, the DOX release and uptake can be restricted to ultrasound-treated areas. Compared to DOX-liposomes, DOX-loaded microbubbles killed at least two times more melanoma cells after exposure to ultrasound. After treatment of the melanoma cells with DOX-liposome-loaded microbubbles and ultrasound, DOX was mainly present in the nuclei of the cancer cells, whereas it was mainly detected in the cytoplasm of cells treated with DOX-liposomes. Exposure of cells to DOX-liposome-loaded microbubbles and ultrasound caused an almost instantaneous cellular entry of the DOX. At least two mechanisms were identified that explain the fast uptake of DOX and the superior cell killing of DOX-liposome-loaded microbubbles and ultrasound. First, exposure of DOX-liposome-loaded microbubbles to ultrasound results in the release of free DOX that is more cytotoxic than DOX-liposomes. Second, the cellular entry of the released DOX is facilitated due to sonoporation of the cell membranes. The in vitro results shown in this article indicate that DOX-liposome-loaded microbubbles could be a very interesting tool to obtain an efficient ultrasound-controlled DOX delivery in vivo.

  20. New approaches in the management of advanced breast cancer – role of combination treatment with liposomal doxorubicin

    Directory of Open Access Journals (Sweden)

    Iain RJ Macpherson

    2009-08-01

    Full Text Available Iain RJ Macpherson, TR Jeffry EvansBeatson West of Scotland Cancer Centre, Glasgow, United KingdomAbstract: Metastatic breast cancer (MBC remains a major cause of morbidity and mortality in women worldwide. For three decades doxorubicin, alone or in combination with other cytotoxic agents, has been a mainstay of systemic therapy for MBC. However, its use is limited by cumulative cardiotoxicity. More recently liposomal formulations of doxorubicin have been developed which exhibit equal efficacy but reduced cardiotoxicity in comparison to conventional doxorubicin. The novel toxicity profile of liposomal doxorubicins has prompted their evaluation with various cytotoxic agents in patients with MBC. In addition, their favorable cardiac safety profile has prompted re-evaluation of concomitant therapy with doxorubicin and trastuzumab, a regimen of proven efficacy in MBC but previously considered to be associated with significant cardiotoxicity. We review clinical trial data addressing combination therapy with both pegylated and non-pegylated liposomal doxorubicin in patients with MBC.Keywords: breast cancer, anthracycline, liposome-encapsulated doxorubicin, pegylated liposomal doxorubicin, cardiotoxicity

  1. Bortezomib for acute humoral rejection treatment at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City: an update.

    Science.gov (United States)

    Leyva, Sergio; Marino, Lluvia A; Alberú, Josefina; Morales-Buenrostro, Luis E

    2010-01-01

    The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response, or to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will be necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal. Until now, it is evident that many patients needed retreatment and they were well tolerated.

  2. Dexamethasone prolongs local analgesia after subcutaneous infiltration of bupivacaine microcapsules in human volunteers

    DEFF Research Database (Denmark)

    Holte, Kathrine; Werner, Mads U; Lacouture, Peter G;

    2002-01-01

    BACKGROUND: The addition of small amounts of dexamethasone to extended-release formulations of bupivacaine in microcapsules has been found to prolong local analgesia in experimental studies, but no clinical data are available. METHODS: In a double-blinded study, 12 healthy male volunteers were ra...

  3. The influence of betamethasone and dexamethasone on motor development in young rats

    NARCIS (Netherlands)

    Gramsbergen, A; Mulder, EJH

    1998-01-01

    Synthetic corticosteroids such as dexamethasone and betamethasone are widely used in clinical practice of the perinatal period to enhance lung maturation. However, indications emerged both on the basis of investigations in humans and in experimental animals that such treatment leads to abnormal brai

  4. Functional aspects of dexamethasone upregulated nicotinic acetylcholine receptors in C2C12 myotubes

    NARCIS (Netherlands)

    Maestrone, E; Lagostena, L; Henning, RH; DenHertog, A; Nobile, M

    1995-01-01

    Three days of treatment with the glucocorticoid dexamethasone (1 nM-mu M) induced a concentration-dependent up-regulation of muscle nicotinic acetylcholine receptor (nAChR) in C2C12 mouse myotubes (EC(50)=10+/-7.3 nM), as assessed by [H-3]alpha-BuTx binding. The maximum increase in binding amounted

  5. The Dexamethasone Suppression Test as an Indication of Depression in Patients with Mental Retardation.

    Science.gov (United States)

    Mattes, Jeffrey A.; Amsell, Loren

    1993-01-01

    Administration of the Dexamethasone Suppression Test (DST) for three groups of institutionalized patients with severe/profound mental retardation found that the 12 depressed patients more frequently (though not significantly) had positive DSTs and significantly higher cortisol levels compared with nondepressed patients with and without other…

  6. Changes in Maternal Glucose Metabolism after the Administration of Dexamethasone for Fetal Lung Development

    Directory of Open Access Journals (Sweden)

    Xu Jian Yun

    2012-01-01

    Methods. Singleton pregnancies, twin pregnancies, and pregnancies with IGT between 28 and 33 weeks of gestation whose mothers were treated with dexamethasone were enrolled in this study. Exclusion criteria included gestational hypertension, diabetes, renal disorders, and infectious diseases. The fasting plasma glucose and insulin levels were checked before administration and 24 h, 48 h, and 72 h after treatment was completed. Results. Mean glucose levels were significantly higher in the twin pregnancy and IGT groups at 24 h and 48 h after the administration of dexamethasone than those in the singleton pregnancy group (P<0.05. Although there was no significant difference in glucose levels before administration and 72 h after dexamethasone administration among the three groups, insulin levels in the IGT group were significantly higher (P<0.05. Insulin levels in the singleton pregnancy group at 24 h and 48 h after treatment were significantly lower than in the twin and IGT groups. Conclusion. The effects on maternal fasting blood glucose and insulin levels of dexamethasone administrated to promote fetal lung maturation correlated with embryo number and the presence of IGT.

  7. A novel brain trauma model in the mouse : effects of dexamethasone treatment

    NARCIS (Netherlands)

    Hortobágyi, Tibor; Hortobagyi, S; Gorlach, C; Harkany, T; Benbyo, Z; Gorogh, T; Nagel, W; Wahl, M

    2000-01-01

    We describe a novel methodological approach for inducing cold lesion in the mouse as a model of human cortical contusion trauma. To validate its reproducibility and reliability, dexamethasone (Dxm) was repeatedly applied to demonstrate possible antioedematous drug effects. Following tho induction of

  8. Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS.

    Directory of Open Access Journals (Sweden)

    Julie E Goodwin

    Full Text Available Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.

  9. Low-Dose Dexamethasone Therapy from Infancy of Virilizing Congenital Adrenal Hyperplasia

    Directory of Open Access Journals (Sweden)

    Stephenson Kerry

    2009-12-01

    Full Text Available Objective. To assess the growth and control of adrenal androgen secretion in children with virilizing congenital adrenal hyperplasia (CAH treated with dexamethasone. Method. We examined doses used, control of adrenal androgen secretion, and growth and skeletal maturation of 8 children with CAH treated with dexamethasone beginning in infancy. Results. 3 boys and 5 girls with classical CAH (17-hydroxyprogesterone at diagnosis >20,000 ng/dL were treated with dexamethasone beginning at diagnosis ( ; all doses were given in the morning using a dosing syringe to administer a 0.1 mg/mL elixir. The children were treated for years over which time the change in bone age to chronological age ratio (BA/CA was . Most recent height Z' scores were , and body mass index (BMI scores were . Late afternoon levels of 17-hydroxyprogesterone, androstenedione, and testosterone were  ng/dL ( nmol/L,  ng/dL ( nmol/L, and  ng/dL; ( nmol/L, respectively. Conclusions. These observations show that low doses of dexamethasone can be used to effectively treat CAH beginning in infancy.

  10. Intratympanic injection of dexamethasone for treatment of tinnitus in patients with sudden sensorineural hearing loss.

    Science.gov (United States)

    Yoshida, Tadao; Teranishi, Masaaki; Iwata, Tomoyuki; Otake, Hironao; Nakashima, Tsutomu

    2012-01-09

    The purpose of this study is to test the effectiveness of intratympanic dexamethasone injections as a treatment for severe tinnitus in idiopathic sudden sensorineural hearing loss (SNHL). We studied 37 patients who received intratympanic dexamethasone injections and 14 control patients who did not receive it, with severe tinnitus after onset of unilateral sudden SNHL. Hearing level did not change during this study in any patient. The relationship between the duration of tinnitus and effectiveness of treatment was investigated in sudden SNHL. We used a visual analogue scale to evaluate 51 patients with severe tinnitus at the stage of stable hearing level after idiopathic sudden sensorineural hearing loss. Forty-one per cent of patients showed significant improvement after treatment. The average period between onset of sudden sensorineural hearing loss and initiation of intratympanic dexamethasone injection was significantly shorter (207 days) in the improved group than in the unchanged group (482 days) (Psudden SNHL at the stage of stable hearing level, and the shorter the period from onset of sudden deafness to the start of intratympanic dexamethasone treatment, the greater the improvement in tinnitus that can be expected.

  11. Interactions with insulin and dexamethasone in net synthesis of albumin and acute-phase proteins

    Energy Technology Data Exchange (ETDEWEB)

    Miller, L.L.

    1976-01-01

    The isolated rat liver perfused for 12 hours at pH 7.10 with a suspension of bovine erythrocytes in Krebs--Ringer bicarbonate buffer containing 3% bovine serum albumin has been used as a test system to study effects of glucagon and of dexamethasone in the presence and absence of insulin on net biosynthesis of rat serum albumin, fibrinogen, ..cap alpha../sub 1/-acid glycoprotein, ..cap alpha../sub 2/-(acute phase) globulin, and haptoglobin. Quantitative measurement of perfusate glucose, amino acid nitrogen, and urea affords a basis for determining net glucose and nitrogen balance in the perfusion system. Although the dose of dexamethasone (total 1.0 ..mu..g) used was insufficient to induce synthesis of ..cap alpha../sub 2/-acute phase globulin, net syntheses of albumin, fibrinogen, ..cap alpha../sub 1/-acid glycoprotein, and haptoglobin were increased. Glucagon given with dexamethasone depressed albumin and haptoglobin synthesis markedly, but not that of fibrinogen and ..cap alpha../sub 1/-acid glycoprotein. Glucagon with dexamethasone markedly enhanced ureogenesis and glycogenolysis and elicited an exaggerated negative nitrogen balance. The unfavorable effects of glucagon on albumin and haptoglobin synthesis and on nitrogen balance were reversed by giving insulin simultaneously. It is emphasized that insulin is essential for positive nitrogen balance.

  12. Targeting dexamethasone to Kupffer cells : Effects on liver inflammation and fibrosis in rats

    NARCIS (Netherlands)

    Melgert, BN; Olinga, P; Van der Laan, JMS; Weert, B; Cho, J; Schuppan, D; Groothuis, GMM; Meijer, DKF; Poelstra, K

    2001-01-01

    Kupffer cells (KC) play an important role in the pathogenesis of inflammatory liver diseases leading to fibrosis. Anti-inflammatory drugs are only effective when administered at high doses that may cause side effects. Therefore, dexamethasone coupled to mannosylated albumin (Dexa(5)-Man(10)-HSA) was

  13. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

    NARCIS (Netherlands)

    Plesner, Torben; Arkenau, Hendrik-Tobias; Gimsing, Peter; Krejcik, Jakub; Lemech, Charlotte; Minnema, Monique C; Lassen, Ulrik; Laubach, Jacob P; Palumbo, Antonio; Lisby, Steen; Basse, Linda; Wang, Jianping; Sasser, A Kate; Guckert, Mary E; de Boer, Carla; Khokhar, Nushmia Z; Yeh, Howard; Clemens, Pamela L; Ahmadi, Tahamtan; Lokhorst, Henk M; Richardson, Paul G

    2016-01-01

    Daratumumab, a human CD38 IgG1κ monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose-escalation) evaluated 4 daratumumab doses plus lenalidomide

  14. Analgesic Effect of Dexamethasone after Arthroscopic Knee Surgery: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Jairo Moyano

    2016-01-01

    Full Text Available Background. Dexamethasone is sometimes used as a coanalgesic because of its anti-inflammatory properties. Objective. To evaluate opioid use, postoperative pain intensity, and side effects after a single dose of dexamethasone in patients undergoing arthroscopic knee surgery. Methods. In this randomized controlled study patients were randomized to receive either 10 mg of intravenous dexamethasone (DM group or 0.9% normal saline (NS group during the intraoperative period. Primary outcomes were pain intensity and total morphine and codeine use after surgery. Results. Seventy-eight patients were included in the study. The DM group showed statistically significant higher pain intensity at the fourth postoperative hour (DM: 3.96/10, standard deviation [SD] 0.54; NS: 2.46/10, SD 0.45; p=0.036. No statistically significant difference in total opioid use (morphine plus codeine was identified with 15.9 (SD 1.97 codeine tablets used in DM group and 20 (SD 2.14 in NS group (p=0.25. Discussion. Pain intensity tended to decrease in both groups suggesting morphine as the main source of analgesia. Conclusions. Intravenous dexamethasone during the intraoperative period has no clinical impact on postoperative pain intensity during the first 48 h after arthroscopic knee surgery. This trial is registered with R000020892.

  15. Intraoperative High-Dose Dexamethasone and Severe AKI after Cardiac Surgery

    NARCIS (Netherlands)

    Jacob, Kirolos A.; Leaf, David E.; Dieleman, Jan M.; van Dijk, Diederik; Nierich, Arno P.; Rosseel, Peter M.; Maaten, van der Joost M.; Hofland, Jan; Diephuis, Jan C.; de Lange, Fellery; Boer, Christine; Kluin, Jolanda; Waikar, Sushrut S.

    2015-01-01

    Administration of prophylactic glucocorticoids has been suggested as a strategy to reduce postoperative AKI and other adverse events after cardiac surgery requiring cardiopulmonary bypass. In this post hoc analysis of a large placebo-controlled randomized trial of dexamethasone in 4465 adult patient

  16. Release of PLGA–encapsulated dexamethasone from microsphere loaded porous surfaces

    NARCIS (Netherlands)

    Dawes, G.J.S.; Fratila-Apachitei, L.E.; Necula, B.S.; Apachitei, I.; Witkamp, G.J.; Duszczyk, J.

    2009-01-01

    The aim of the present study was to investigate the morphology and function of a drug eluting metallic porous surface produced by the immobilization of poly lactide-co-glycolide microspheres bearing dexamethasone onto plasma electrolytically oxidized Ti–6Al–7Nb medical alloy. Spheres of 20 µm diamet

  17. Comparative study of proton pump inhibitors on dexamethasone plus pylorus ligation induced ulcer model in rats

    Directory of Open Access Journals (Sweden)

    Thippeswamy A. H. M.

    2010-01-01

    Full Text Available The present study was designed to compare ulcer protective effect of proton pump inhibitors viz. omeprazole, rabeprazole and lansoprazole against dexamethasone plus pylorus ligation induced ulcer model. Dexamethasone (5 mg/kg was used as an ulcerogen. Dexamethasone suspended in 1% CMC in water was given orally to all the rats 15 min after the pylorus ligation. Omeprazole (20 mg/kg, rabeprazole (20 mg/kg, and lansoprazole (20 mg/kg were administered by oral route 30 min prior to ligation was used for ulcer protective studies, gastric secretion and mucosal studies. Effects of proton pump inhibitors were determined by the evaluation of various biochemical parameters such as ulcer index, free and total acidity, gastric pH, mucin, pepsin and total proteins. Oral administration of proton pump inhibitors showed significant reduction in gastric acid secretion and ulcer protective activity against dexamethasone plus pylorus ligation induced ulcer model. The % protection of omeprazole, rabeprazole and lansoprazole was 84.04, 89.36 and 79.78, respectively. Rabeprazole significantly inhibited the acid-pepsin secretion and increased the gastric mucin secretion. The observations made in the present study suggest that rabeprazole is the most effective gastric antisecretory and ulcer healing agent as compared to omeprazole and lansoprazole.

  18. Treatment of acute relapses in multiple sclerosis at home with oral dexamethasone : a pilot study

    NARCIS (Netherlands)

    De Keyser, J; Zwanikken, C; Zorgdrager, A; Oenema, D

    1999-01-01

    The objective of this study was to investigate the feasibility of treating relapses of multiple sclerosis (MS) at home with oral dexamethasone. Twenty-five out of 28 consecutive patients with MS who presented with a relapse of less than 2 weeks' duration were treated on an open basis with oral dexam

  19. Dexamethasone treatment and fluid balance in preterm infants at risk for chronic lung disease

    NARCIS (Netherlands)

    Bos, AF; van Asselt, WA; Okken, A

    2000-01-01

    The influence of dexamethasone on diuresis in preterm infants has not been well studied. We examined 15 preterm infants at risk for chronic lung disease with gestational ages ranging from 26 to 29 wk (median 27.6 wk) and birthweights ranging from 700 to 1485 g (median 965 g). Urine output, blood glu

  20. Comparative Study of Intrathecal Dexamethasone with Epinephrine as Adjuvants to Lidocaine in Cesarean Section

    Directory of Open Access Journals (Sweden)

    Fereshteh Naziri

    2013-09-01

    Full Text Available Background: Different additives have been used with local anesthetics to provide prolonged duration of sensory block in spinal anesthesia. The aim of present study was to evaluate the onset and duration of sensory block of intrathecal dexamethasone and epinephrine as adjuvants to lidocaine in patients who were candidate for cesarean section. Materials and Methods: This double-blind clinical trial research was conducted on 90 pregnant women candidate for cesarean section under spinal anesthesia. Patients were randomly allocated to receive intrathecally either 75 mg hyperbaric lidocaine plus 100 μg epinephrine or 75 mg hyperbaric lidocaine plus 4 mg dexamethasone or 75 mg hyperbaric lidocaine. The onset and duration of sensory block as well as postoperative analgesia were assessed. Results: The time to reach the peak sensory block in lidocaine group was shorter than that of other two groups (p<0.001. Duration of sensory block in the control group, dexamethasone group, and epinephrine group were 64.16±7.99 min, 74.79±12.78 min, and 99.30±10.93 min, respectively (p<0.001. Conclusion: The present research shows that intrathecal dexamethasone and intrathecal epinephrine as adjuvant to lidocaine increases sensory block duration in the women candidate for cesarean section.

  1. The Effect of Ondansetron and Dexamethasone on Nausea and Vomiting under Spinal Anesthesia

    Science.gov (United States)

    Kalani, Navid; Zabetian, Hasan; Sanie, Mohammad Sadegh; Deylami, Mansour; Radmehr, Mohammad; Sahraei, Reza; Kargar Jahromi, Hossein; Kooti, Wesam

    2017-01-01

    BACKGROUND During abdominal surgery under regional anesthesia, nausea may happen due to several contributing factors. This study compared the effects of ondansetron and dexamethasone on nausea and vomiting under spinal anesthesia. METHODS One hundred and twenty patients of 15 to 35 years old with ASA class I and II were enrolled. Before administering either ondansetron or dexamethasone, blood pressure and heart rate of the patients were recorded. The patients received 70 mg of 5% lidocaine for spinal anesthesia. Patients who received 6 mg of ondansetron were considered as group A, while group B received 8 mg of dexamethasone. The level of nausea and vomiting, blood pressure, heart rate and respiratory rate of each patient was measured at 1, 5, 10, 15 and 30 minutes after spinal anesthesia and during recovery (every 5 minutes). RESULTS There was a significant difference between nausea and vomiting between the two groups after spinal anesthesia within the first and fifth minutes. There was no significant difference between nausea and vomiting between the two groups within 10, 15 and 30 minutes and during recovery at 5, 10, 15 and 30 minutes. CONCLUSION Dexamethasone and ondansetron were shown to equally reduce the incidence of nausea and vomiting under spinal anesthesia and can be recommended as a good choice for prevention of nausea and vomiting during surgeries. PMID:28289619

  2. [Extraction, Purification and Identification of a Dexamethasone-degrading Enzymes Generated by Pseudomonas Alcaligenes].

    Science.gov (United States)

    Zhu, Lili; Yang, Zhibang; Yang, Qian; Shi, Zhongquan; Deng, Xichuan

    2015-10-01

    In this research a strain of isolated Pseudomonas alcaligenes which causes degradation of dexamethasone was acclimated further and its proteins of every position in the bacterium were separated by the osmotic shock method. The separated intracellular proteins which had the highest enzyme activity were extracted by the salting out with ammonium sulfate and were purified with the cation exchange chromatography and gel chromatography. The purified proteins which was active to cause degradation of dexamethasone had been detected were cut with enzyme and were analyzed with mass spectrometry. The results showed that the degradation rate to dexamethasone by acclimated Pseudomonas alcaligenes were increased from 23.63% to 52.84%. The degrading enzymes were located mainly in the intracellular of the bacteria and its molecular weight was about 41 kD. The specific activity of the purified degrading enzymes were achieved to 1.02 U x mg(-1). Its 5-peptide amino acid sequences were consistent with some sequences of the isovaleryl-CoA dehydrogenase. The protein enzyme may be a new kind degrading enzyme of steroidal compounds. Our experimental results provided new strategies for cleanup of dexamethasone in water environment with microbial bioremediation technique.

  3. Comparative analysis of preemptive analgesic effect of dexamethasone and diclofenac following third molar surgery

    Directory of Open Access Journals (Sweden)

    José Leonardo Simone

    2013-06-01

    Full Text Available The objective of the study was to compare the analgesic effectiveness of dexamethasone and diclofenac sodium administered preemptively after surgical removal of third molars. Forty-four ASA (American Society of Anesthesiologists I patients (19 men, 35 women; 16–28 years old randomly and double-blindly received diclofenac sodium (50 mg or dexamethasone (8 mg or placebo 1 h before surgery. Intensity of pain, measured with a visual analog scale (VAS, was the variable studied at different postoperative times (1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 48 h, 4 d and 7 d. The total amount of rescue medication (TARM ingested (paracetamol was another variable of the study. The Kruskal-Wallis statistical test was used. A p value of < .05 was adopted to reject the null hypothesis. The dexamethasone group showed lower pain intensity (p < .05 than the diclofenac sodium and placebo groups (p < .05. No difference in TARM was observed among the groups (p < .05. Preemptively administered, dexamethasone was effective in controlling postoperative pain.

  4. Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

    Energy Technology Data Exchange (ETDEWEB)

    Gharanei, M.; Hussain, A. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Janneh, O. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Pharmacology Research Laboratories, 70, Pembroke Place, The University of Liverpool, Liverpool. L69 3GF (United Kingdom); Maddock, H.L., E-mail: h.maddock@coventry.ac.uk [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom)

    2013-04-15

    Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening in laser

  5. A Telomerase-Specific Doxorubicin-Releasing Molecular Beacon for Cancer Theranostics.

    Science.gov (United States)

    Ma, Yi; Wang, Zhaohui; Zhang, Min; Han, Zhihao; Chen, Dan; Zhu, Qiuyun; Gao, Weidong; Qian, Zhiyu; Gu, Yueqing

    2016-03-01

    A molecular beacon-based drug delivery system was designed for both detection of telomerase activity in living cells and telomerase-triggered drug release for precise cancer treatment. This system is composed of a gold nanoparticle core densely packed with FITC-labeled hairpin DNA sequences hybridized with telomerase primers. Molecules of the anticancer drug doxorubicin were intercalated into the stem region of the DNA sequence. The presence of telomerase will elongate the primers, leading to inner chain substitution followed by the release of the FITC fluorescence and the trapped doxorubicin. This molecular beacon could specifically distinguish tumor cells and normal cells based on telomerase activity, precisely release doxorubicin in response to telomerase activity in the tumor cells, and prevent toxicity to normal organs.

  6. Doxorubicin-Induced Gut Toxicity in Piglets fed Bovine Milk and Colostrum

    DEFF Research Database (Denmark)

    Shen, René Liang; Rathe, Mathias; Jiang, Pingping

    2016-01-01

    a single dose of doxorubicin (1 × 75 mg/m) in piglets fed bovine milk enriched with whey protein (BM). In Study 2, responses to doxorubicin treatment were investigated in piglets receiving either seven BC feedings per day (Only-BC, n = 13), four BC feedings (High-BC, n = 13), two BC feedings (Low-BC, n...... milk-fed piglets suggesting that colostrum and a bovine milk diet enriched with whey protein provided similar......OBJECTIVE: Chemotherapy-induced intestinal toxicity is a common adverse effect of cancer treatment. We hypothesized that a milk diet containing bovine colostrum (BC) would reduce intestinal toxicity in doxorubicin-treated piglets. METHODS: Study 1 investigated intestinal parameters nine days after...

  7. Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy

    DEFF Research Database (Denmark)

    Aggerholm-Pedersen, Ninna; Demouth, Christina; Safwat, Akmal;

    2016-01-01

    growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8......) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI....... However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin....

  8. Magnetic controllable biorecognition process of doxorubicin detected by electrochemical contact angle measurement.

    Science.gov (United States)

    Zhou, Jian; Zhang, Renyun; Li, Xiaomao; Gutmann, Sebastian; Lv, Gang; Wang, Xuemei

    2007-08-01

    Fe3O4 nanoparticles are the most commonly used magnetic materials with promising applications in biomedical and biochemical engineering. In this study, a novel application of the tetraheptylammonium capped Fe3O4 nanoparticles in controllable biorecognition process of anticancer drug doxorubicin through combination with external static magnetic field has been demonstrated. Our AFM and electrochemical studies illustrate that the presence of the tetraheptylammonium capped Fe3O4 nanoparticles could promote the binding behavior of doxorubicin to DNA. And the results of the electrochemical contact angle measurements indicate that the controllable biomolecular recognition of doxorubicin could be readily achieved by combining these functionalized Fe3O4 nanoparticles with changing the positions of external magnetic field.

  9. Perineural Dexamethasone to Improve Postoperative Analgesia with Peripheral Nerve Blocks: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    Gildasio S. De Oliveira

    2014-01-01

    Full Text Available Background. The overall effect of perineural dexamethasone on postoperative analgesia outcomes has yet to be quantified. The main objective of this quantitative review was to evaluate the effect of perineural dexamethasone as a nerve block adjunct on postoperative analgesia outcomes. Methods. A systematic search was performed to identify randomized controlled trials that evaluated the effects of perineural dexamethasone as a block adjunct on postoperative pain outcomes in patients receiving regional anesthesia. Meta-analysis was performed using a random-effect model. Results. Nine randomized trials with 760 subjects were included. The weighted mean difference (99% CI of the combined effects favored perineural dexamethasone over control for analgesia duration, 473 (264 to 682 minutes, and motor block duration, 500 (154 to 846 minutes. Postoperative opioid consumption was also reduced in the perineural dexamethasone group compared to control, −8.5 (−12.3 to −4.6 mg of IV morphine equivalents. No significant neurological symptoms could have been attributed to the use of perineural dexamethasone. Conclusions. Perineural dexamethasone improves postoperative pain outcomes when given as an adjunct to brachial plexus blocks. There were no reports of persistent nerve injury attributed to perineural administration of the drug.

  10. Biodegradable hyaluronic acid hydrogels to control release of dexamethasone through aqueous Diels–Alder chemistry for adipose tissue engineering

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Ming; Ma, Ye; Zhang, Ziwei; Mao, Jiahui [School of Materials Science and Engineering, Nanjing University of Science and Technology, Nanjing (China); Tan, Huaping, E-mail: hptan@njust.edu.cn [School of Materials Science and Engineering, Nanjing University of Science and Technology, Nanjing (China); Hu, Xiaohong [School of Material Engineering, Jinling Institute of Technology, Nanjing (China)

    2015-11-01

    A robust synthetic strategy of biopolymer-based hydrogels has been developed where hyaluronic acid derivatives reacted through aqueous Diels–Alder chemistry without the involvement of chemical catalysts, allowing for control and sustain release of dexamethasone. To conjugate the hydrogel, furan and maleimide functionalized hyaluronic acid were synthesized, respectively, as well as furan functionalized dexamethasone, for the covalent immobilization. Chemical structure, gelation time, morphologies, swelling kinetics, weight loss, compressive modulus and dexamethasone release of the hydrogel system in PBS at 37 °C were studied. The results demonstrated that the aqueous Diels–Alder chemistry provides an extremely selective reaction and proceeds with high efficiency for hydrogel conjugation and covalent immobilization of dexamethasone. Cell culture results showed that the dexamethasone immobilized hydrogel was noncytotoxic and preserved proliferation of entrapped human adipose-derived stem cells. This synthetic approach uniquely allows for the direct fabrication of biologically functionalized gel scaffolds with ideal structures for adipose tissue engineering, which provides a competitive alternative to conventional conjugation techniques such as copper mediated click chemistry. - Highlights: • A biodegradable hyaluronic acid hydrogel was crosslinked via aqueous Diels–Alder chemistry. • Dexamethasone was covalently immobilized into the hyaluronic acid hydrogel via aqueous Diels–Alder chemistry. • Dexamethasone could be released from the Diels–Alder hyaluronic acid hydrogel in a controlled fashion.

  11. Interplay between depressive-like behavior and the immune system in an animal model of prenatal dexamethasone administration

    Directory of Open Access Journals (Sweden)

    Susana eRoque

    2011-02-01

    Full Text Available Glucocorticoids, namely dexamethasone, are prescribed during late gestation in pregnancies at risk of originating premature newborns, to promote fetal lung maturation. However, adverse early life events have been reported to induce long-lasting changes in the immune and central nervous systems. The accumulating evidence on bidirectional interactions between both systems in psychiatric disorders like depression, prompted us to further investigate the long term impact of prenatal dexamethasone in depressive-like behavior, the immune system and in the ability to mount an immune response to acute infection. The adult male offspring of pregnant dams treated with dexamethasone, present depressive-like behavior concomitant with a decrease in CD8+ T lymphocytes and an increase in B and CD4+ regulatory T cells. This is accompanied by lower levels of serum interleukine-6 (IL-6 and IL-10. Despite of these differences, when spleen cells are stimulated, in vitro, with lipopolysaccharide, those from adult rats prenatally treated with dexamethasone display a stronger pro-inflammatory cytokine response. However, this immune system profile does not hamper the ability of rats prenatally treated with dexamethasone to respond to acute infection by Listeria monocytogenes. Of notice, L. monocytogenes infection triggers depressive-like behavior in control animals but does not worsen that already present in dexamethasone-treated animals. In summary, prenatal administration of dexamethasone has long lasting effects on the immune system and on behavior, which is not further aggravated by acute infection with L. monocytogenes.

  12. Dexamethasone-induced radioresistance occurring independent of human papilloma virus gene expression in cervical carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Rutz, H.P.; Mariotta, M.; Mirimanoff, R.O. [Lab. de Radiobiologie, Service de Radio-Oncologie, CHUV, Lausanne (Switzerland); Knebel Doeberitz, M. von [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Inst. fuer Virusforschung

    1998-02-01

    The aim of this study was to investigate the role of HPV 18 E6 and E7 gene products with respect to radiosensitivity of two cervical carcinoma cell lines. The two cervical carcinoma lines C4-1 and SW 756 were used in which treatment with dexamethasone allows to modulate expression levels of HPV 18 E6 and E7 genes: Upregulation in C4-1, down-regulation in SW 756. Effects of treatment with dexamethasone on plating efficiency and radiosensitivity were assessed using a clonogenic assay. Treatment with dexamethasone increased plating efficiency of the C4-1 cells, but did not affect plating efficiency of SW 756 cells. Treatment with dexamethasone induced enhanced radioresistance in both cell lines. Thus, in C4-1 cells the observed changes in radioresistance correlate to the enhancement in expression of HPV 18 genes E6/E7, whereas in SW 756, a reduced expression correlates negatively with the enhanced radioresistance. (orig./MG) [Deutsch] Das Ziel dieser Studie lag darin, die Rolle der HPV-18-Gene E6 und E7 in bezug auf die Strahlenempfindlichkeit von menschlichen Zervixkarzinomzellen zu untersuchen. Wir verwendeten zwei menschliche Zervixkarzinomzellinien, C4-1 und SW 756, in welchen die Expression der viralen Gene HPV 18 E6 und E7 mit Dexamethason moduliert werden kann: In C4-1 bewirkt die Behandlung mit Dexamethason eine Erhoehung der Expression dieser Gene, in SW 756 eine Verminderung. Die Wirkung auf die Wachstumsfaehigkeit der Zellen und auf die Wachstumshemmung durch die Bestrahlung wurde unter Verwendung eines klonogenen Assays bestimmt. Dexamethason bewirkte eine erhoehte Wachstumsfaehigkeit der C4-1 Zellen, ohne die Wachstumsfaehigkeit der SW-756-Zellen zu beeinflussen, wie schon frueher beschrieben. Die Resistenz beider Zellinien gegenueber Bestrahlung wurde erhoeht. Somit besteht in den C4-1-Zellen eine Korrelation der Expression der viralen Gene mit der Zunahme der Strahlenresistenz, wogegen in den SW-756-Zellen die Abnahme der Expression im Gegensatz zu

  13. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    Energy Technology Data Exchange (ETDEWEB)

    Tewari-Singh, Neera, E-mail: Neera.Tewari-Singh@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Jain, Anil K., E-mail: Anil.Jain@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Inturi, Swetha, E-mail: Swetha.Inturi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Ammar, David A., E-mail: David.Ammar@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Chapla, E-mail: Chapla.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Tyagi, Puneet, E-mail: Puneet.Tyagi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Kompella, Uday B., E-mail: Uday.Kompella@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Enzenauer, Robert W., E-mail: Robert.Enzenauer@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Petrash, J. Mark, E-mail: Mark.Petrash@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States)

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  14. Doxorubicin inhibits E. coli division by interacting at a novel site in FtsZ.

    Science.gov (United States)

    Panda, Pragnya; Taviti, Ashoka Chary; Satpati, Suresh; Kar, Mitali Madhusmita; Dixit, Anshuman; Beuria, Tushar Kant

    2015-11-01

    The increase in antibiotic resistance has become a major health concern in recent times. It is therefore essential to identify novel antibacterial targets as well as discover and develop new antibacterial agents. FtsZ, a highly conserved bacterial protein, is responsible for the initiation of cell division in bacteria. The functions of FtsZ inside cells are tightly regulated and any perturbation in its functions leads to inhibition of bacterial division. Recent reports indicate that small molecules targeting the functions of FtsZ may be used as leads to develop new antibacterial agents. To identify small molecules targeting FtsZ and inhibiting bacterial division, we screened a U.S. FDA (Food and Drug Administration)-approved drug library of 800 molecules using an independent computational, biochemical and microbial approach. From this screen, we identified doxorubicin, an anthracycline molecule that inhibits Escherichia coli division and forms filamentous cells. A fluorescence-binding assay shows that doxorubicin interacts strongly with FtsZ. A detailed biochemical analysis demonstrated that doxorubicin inhibits FtsZ assembly and its GTPase activity through binding to a site other than the GTP-binding site. Furthermore, using molecular docking, we identified a probable doxorubicin-binding site in FtsZ. A number of single amino acid mutations at the identified binding site in FtsZ resulted in a severalfold decrease in the affinity of FtsZ for doxorubicin, indicating the importance of this site for doxorubicin interaction. The present study suggests the presence of a novel binding site in FtsZ that interacts with the small molecules and can be targeted for the screening and development of new antibacterial agents.

  15. Ozone-Oxidative Preconditioning Prevents Doxorubicin-induced Cardiotoxicity in Sprague-Dawley Rats

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    Livan Delgado-Roche

    2014-08-01

    Full Text Available Objectives: Induced dilated cardiomyopathy is the main limitation of the anti-cancer drug doxorubicin, which causes oxidative stress and cardiomyocyte death. As ozone therapy can activate the antioxidant systems, this study aimed to investigate the therapeutic efficacy of ozone-oxidative preconditioning against doxorubicin-induced cardiotoxicity. Methods: The study was carried out from September 2013 to January 2014. Sprague-Dawley rats were randomly distributed in the following treatment groups: Group 1 were treated with 2 mg/kg intraperitoneal (i.p. of doxorubicin twice a week for 50 days; Group 2 were treated with 0.3 mg of ozone/oxygen mixture at 50 μg/ mL of ozone per 6 mL of oxygen by rectal insufflation and then treated with doxorubicin; Group 3 were treated as Group 2 but only with the oxygen, and Group 4 were treated with oxygen first, and then with sodium chloride i.p. as the control group. Results: The results showed that ozone therapy preserved left ventricle morphology which was accompanied by a reduction of serum pro-brain natriuretic peptide levels. The cardioprotective effects of ozoneoxidative preconditioning were associated with a significant increase (P <0.05 of antioxidant enzymes activities and a reduction of lipid and protein oxidation (P <0.05. Conclusion: Ozone-oxidative preconditioning prevents doxorubicin-induced dilated cardiomyopathy through an increase of antioxidant enzymes and a reduction of oxidised macromolecules. This establishes the background for future studies to determine if ozone therapy can be used as a complementary treatment for attenuating doxorubicin-induced cardiotoxicity in cancer patients.

  16. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I--Formulation development and in-vitro characterization.

    Science.gov (United States)

    Tinkov, Steliyan; Winter, Gerhard; Coester, Conrad; Bekeredjian, Raffi

    2010-04-01

    Despite high antitumor efficacy and a broad application spectrum, clinical treatment with anthracycline chemotherapeutics is often limited by severe adverse effects such as cardiotoxicity and myelosupression. In recent years, tumor drug targeting has evolved as a promising strategy to increase local drug concentration and reduce systemic side effects. One recent approach for targeting solid tumors is the application of microbubbles, loaded with chemotherapeutic drugs. These advanced drug carriers can be safely administered to the patient by intravenous infusion, and will circulate through the entire vasculature. Their drug load can be locally released by ultrasound targeted microbubble destruction. In addition, tumors can be precisely localized by diagnostic ultrasound since microbubbles act as contrast agents. In the present work a novel microbubble carrier for doxorubicin has been developed and characterized in-vitro. In contrast to many recent tumor-targeting MB designs the newly developed doxorubicin-loaded microbubbles possess a soft but stable phospholipid monolayer shell. Importantly, the active drug is embedded in the microbubble shell and is complexed to the phospholipids by both electrostatic and hydrophobic interactions. Despite their drug load, these novel microbubbles retained all important physical characteristics for ultrasound targeted microbubble destruction, comparable with the commercially available ultrasound contrast agents. In cell culture studies doxorubicin-loaded microbubbles in combination with ultrasound demonstrated an about 3 fold increase of the anti-proliferative activity compared to free doxorubicin and doxorubicin-loaded liposomes. For the first time in the literature the intracellular partition of free doxorubicin and phospholipid-complexed doxorubicin were compared. In conclusion, new doxorubicin-loaded microbubbles with ideal physical characteristics were developed. In-vitro studies show enhanced cytotoxic activity compared to

  17. Effects of combination of thiazolidinediones with melatonin in dexamethasone-induced insulin resistance in mice

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    M M Ghaisas

    2011-01-01

    Full Text Available In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o. or rosiglitazone (5 mg/kg/day, p.o. with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05 in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05 in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia.

  18. ANTIDIABETIC AND HYPOLIPIDEMIC ACTIVITY OF GYMNEMA SYLVESTRE IN DEXAMETHASONE INDUCED INSULIN RESISTANCE IN ALBINO RATS

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    Hemanth Kumar V, Nagendra Nayak IM , Shobha V Huilgol, Saeed M Yendigeri , Narendar K

    2015-07-01

    Full Text Available Background: Gymnema sylvestre plant was widely used for medicinal purpose. The plant leaves were traditionally used to treat diabetes. Aim: To determine the antidiabetic and hypolipidemic activity of Gymnema sylvestre in dexamethasone induced insulin resistance in Albino rats. Objectives: The present study was undertaken to evaluate antidiabetic and hypolipidemic activity of Gymnema sylvestre leaf aqueous extract against dexamethasone induced insulin resistance in Albino rats. Materials and Methods: Animals were divided into five groups. Normal control and diabetic control group received gum acacia (2% orally for 12days, and normal saline (i.p., dexamethasone (8mg/kg/i.p. from day 7- day12 respectively. Two test groups (Gymnema sylvestre leaf aqueous extract 2 and 4gm/kg/p.o./12days and standard control received metformin (2gm/kg/p.o./12 days. The two test groups, standard control group received dexamethasone (8mg/kg/i.p from day 7- day 12 respectively. The antidiabetic and hypolipidemic activity was estimated by measuring serum glucose, insulin, lipid levels and histopathological evaluation of liver tissue. Results were analyzed by using one way ANOVA followed by Scheffe’s multiple comparison test. Results: Treatment with aqueous extract of Gymnema sylvestre (2 and 4gm/kg/p.o significantly (p<0.01 altered the elevated glucose, lipid, insulin levels and also improved the histopathology of liver in dexamethasone induced insulin resistance rats. Conclusion: Treatment with aqueous extract of Gymnema sylvestre improved the altered glucose, insulin and lipid profile in insulin resistance rats.

  19. Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy.

    Science.gov (United States)

    Jenkins, P J; Sohaib, S A; Trainer, P J; Lister, T A; Besser, G M; Reznek, R

    1999-08-01

    The aim of this study was to further elucidate the activity of the hypothalamo-pituitary-adrenal (HPA) axis in patients with malignancy and to correlate this with the size of the adrenal glands. Fourteen patients with a variety of malignancies were studied prior to receiving cytotoxic chemotherapy. During routine staging computerized tomographic (CT) scans, the size of the body, medial and lateral limbs of the adrenal glands were measured and compared with those of a normal group of patients studied previously. Measurements of 09:00 h serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were made before and after the administration of dexamethasone (0.5 mg 6-hourly for 48 h) in addition to the peak cortisol response to i.v corticotropin releasing hormone (CRH). Overall, patients with malignancy had significantly larger adrenal glands than patients without malignancy; those with non-haematological malignancies had larger glands than patients with haematological malignancies. Following dexamethasone to suppress circulating cortisol levels, nine patients (64%) demonstrated abnormal resistance with cortisol levels > 50 nmol l(-1): mean value 294 nmol l(-1) (range 67-1147). Those patients who failed to suppress after dexamethasone had significantly larger adrenal glands than those that did suppress and tended to have non-haematological malignancies. ACTH levels were undetectable or low in three patients in whom it was measured and who did not suppress with dexamethasone. Following CRH, the cortisol levels were highest (823 and 853 nmol l(-1)) in two of these patients. Malignancy is associated with diffuse enlargement of the adrenal glands and resistance to dexamethasone-induced suppression of the HPA axis, which is not due to ectopic ACTH secretion. This disturbance of the normal control of the HPA axis is unexplained and its functional significance remains uncertain.

  20. Removal of dexamethasone from aqueous solution and hospital wastewater by electrocoagulation

    Energy Technology Data Exchange (ETDEWEB)

    Arsand, Daniel R., E-mail: danielarsand@pelotas.ifsul.edu.br [Chemistry Department, Federal University of Santa Maria, RS (Brazil); Kümmerer, Klaus, E-mail: klaus.kuemmerer@leuphana.de [Institute for Environmental Chemistry, Leuphana University Lüneburg (Germany); Martins, Ayrton F., E-mail: martins@quimica.ufsm.br [Chemistry Department, Federal University of Santa Maria, RS (Brazil)

    2013-01-15

    This study is concerned with the removal of the anti-inflammatory dexamethasone from aqueous solution and hospital wastewater by electrocoagulation. The variation of the toxicity during the electrocoagulation was also studied through experiments that were designed and optimized by means of response surface methodology. The coagulation efficiency was evaluated by measuring the dexamethasone concentration by high performance liquid chromatography coupled to a diode array detector. In addition, variation was evaluated through a Vibrio fischeri test. The results showed an increase in the removal of dexamethasone (up to 38.1%) with a rise of the current applied and a decrease of the inter-electrode distance, in aqueous solutions. The application to hospital effluent showed similar results for the removal of dexamethasone. The main effect of the electrocoagulation was that it removed colloids and reduced the organic load of the hospital wastewater. Regarding the current applied, the calculated energy efficiency was 100%. Without pH adjustment of the aqueous solution or hospital wastewater, the residual aluminum concentration always remained lower than 10 mg L{sup −1}, and, with adjustment (to pH 6.5), lower than 0.30 mg L{sup −1}, at the final stage. No toxicity variation was observed during the electrocoagulation process in aqueous solution, either in the presence or absence of dexamethasone. - Highlights: ► Removal of DEX and organic load from aqueous solution and hospital wastewater by EC ► Evaluation of the toxicity during the removal of DEX by EC ► Suggestion of the EC process as a pretreatment for subsequent processes.

  1. Intracapsular dexamethasone implant in patients undergoing phacoemulsification and intraocular lens implantation

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    Lucas Monferrari Monteiro Vianna

    2013-08-01

    Full Text Available PURPOSE: To relate the outcomes of 7 eyes of 7 patients in which a dexamethasone 0.7 mg implant (Ozurdex® was placed inside the capsule bag after phacoemulsification and intraocular lens (IOL implantation and compare with the fellow eyes, that were operated by the same technique and received dexamethasone eyedrops in the post-operatory. METHODS: Report review of 7 eyes of 7 patients who received dexamethasone 0.7 mg implant after phacoemulsification and IOL, comparing them to the fellow eyes. All the patients underwent bilateral cataract surgery, with one month interval, by the same technique and by experienced surgeons, without complications. Post operatory medication consisted of moxifloxacin eye drops for all the 14 eyes and topic dexamethasone for the 7 eyes that did not received the implant. RESULTS: Nuclear cataract classification (according to LOCS III was 3.28 ± 0.69 in the implant eye group and 3.14 ± 0.83 in the fellow eye group. Postoperative best spectacle correct visual acuity (BSCVA was 0.85 ± 0.12 and 0.87 ± 0.13, respectively in the implant and fellow eye groups. The intraocular pressure remained stable and similar to the pre-operative measurements. Anterior chamber reaction and cornea edema were similar in both groups in the follow-up. Two of the four no sutured pellet migrated to the anterior chamber during the first post-operative week and had to be repositioned. Another no sutured pellet dislocated and remained partially inside the capsule bag. The 3 patients with IOL haptic-sutured pellet had no complications. CONCLUSIONS: In the present study, dexamethasone 0.7mg implant were effective in controlling the inflammation after phacoemulsification and IOL implantation, with no significant side effects.

  2. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

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    Yang FY

    2012-02-01

    Full Text Available Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug

  3. Melatonin and Doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To investigate whether Melatonin has synergistic effects with Doxorubicin in the growth-inhibition and apoptosis-induction of human hepatoma cell lines HepG2 and Bel-7402.METHODS:The synergism of Melatonin and Doxorubicin inhibited the cell growth and induced cell apoptosis in human hepatoma cell lines HepG2 and Bel-7402.Cell viability was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)assay.Cell apoptosis was evaluated using TUNEL method and flow cytometry.Apoptosis-r...

  4. Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1{alpha}

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    Qin, Weiping, E-mail: weiping.qin@mssm.edu [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY (United States); Department of Medicine, Mount Sinai School of Medicine, NY (United States); Pan, Jiangping; Wu, Yong [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY (United States); Bauman, William A. [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY (United States); Department of Medicine, Mount Sinai School of Medicine, NY (United States); Department of Rehabilitation Medicine, Mount Sinai School of Medicine, NY (United States); Cardozo, Christopher, E-mail: Chris.Cardozo@mssm.edu [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY (United States); Department of Medicine, Mount Sinai School of Medicine, NY (United States); Department of Rehabilitation Medicine, Mount Sinai School of Medicine, NY (United States)

    2010-12-17

    Research highlights: {yields} In rat gastrocnemius muscle, dexamethasone reduced PGC-1{alpha} cellular and nuclear levels without altering mRNA levels for this factor. {yields} Dexamethasone reduced phosphorylating of p38 MAPK, which stabilizes PGC-1{alpha} and promotes its nuclear entry. {yields} Co-administration of testosterone with dexamethasone increased cellular and nuclear levels of PGC-1{alpha} protein without changing its mRNA levels. {yields} Co-administration of testosterone restored p38 MAPK levels to those of controls. -- Abstract: Glucocorticoid-induced muscle atrophy results from muscle protein catabolism and reduced protein synthesis, associated with increased expression of two muscle-specific ubiquitin ligases (MAFbx and MuRF1), and of two inhibitors of protein synthesis, REDD1 and 4EBP1. MAFbx, MuRF1, REDD1 and 4EBP1 are up-regulated by the transcription factors FOXO1 and FOXO3A. The transcriptional co-activator PGC-1{alpha} has been shown to attenuate many forms of muscle atrophy and to repress FOXO3A-mediated transcription of atrophy-specific genes. Dexamethasone-induced muscle atrophy can be prevented by testosterone, which blocks up-regulation by dexamethasone of FOXO1. Here, an animal model of dexamethasone-induced muscle atrophy was used to further characterize effects of testosterone to abrogate adverse actions of dexamethasone on FOXO1 levels and nuclear localization, and to determine how these agents affect PGC-1{alpha}, and its upstream activators, p38 MAPK and AMPK. In rat gastrocnemius muscle, testosterone blunted the dexamethasone-mediated increase in levels of FOXO1 mRNA, and FOXO1 total and nuclear protein. Dexamethasone reduced total and nuclear PGC-1{alpha} protein levels in the gastrocnemius; co-administration of testosterone with dexamethasone increased total and nuclear PGC-1{alpha} levels above those present in untreated controls. Testosterone blocked dexamethasone-induced decreases in activity of p38 MAPK in the gastrocnemius

  5. Peri-operative dexamethasone therapy and post-operative psychosis in patients undergoing major oral and maxillofacial surgery

    Directory of Open Access Journals (Sweden)

    Chethan Manohara Koteswara

    2014-01-01

    Full Text Available A broad array of behavioral symptoms, including psychosis, can transpire post-operatively following a variety of surgeries. It is difficult to diagnose the exact cause of post-operative psychosis. We report three cases, which developed psychosis post-operatively after undergoing major oral and maxillofacial surgeries. All the three patients were administered dexamethasone peri-operatively. Dexamethasone is used to prevent or reduce post-operative edema. The exact dose of dexamethasone, which can cause psychosis, is unknown. It is important to raise awareness about this potential complication so that measures for management can be put in place in anticipation of such an event.

  6. Suppressive effect of dexamethasone on the neutrophil expression of CD18 in rats with radiation induced brain edema

    Institute of Scientific and Technical Information of China (English)

    Laixing Wang; Yibin Fang; Xiaoping Zhou; Xiaowu Hu; Jianmin Liu

    2006-01-01

    BACKGROUND: Stereo-tactic radiation therapy (SRT) is widely used to treat intracranial diseases, but some patients suffered from radiation induced brain edema after SRT. Once radiation induced brain edema occurs,the treatment is quite difficult, and it always leads to a poor outcome. Dexamethasone has certain therapeutic effect on traumatic brain edema, but the biological mechanism is still unclear.OBJECTIVE: To observe the effect of dexamethasone on the neutrophil expression of CD18.DESIGN: A randomized control observation.SETTING: Changhai Hospital of the Second Military Medical University of Chinese PLA.MATERIALS : The experiment was carried out in Changhai Hospital of the Second Military Medical University of Chinese PLA from January 1999 to December 1999. Twenty SD rats (male and female each in half) weighing (250±50) g were used.METHODS: Twenty SD rats were divided into four groups at random. ① Blank control group (n=5): The rats were not treated without dexamethasone or irradiation; ② Irradiation group (n=5): The rats were given irradiation but no dexamethasone treatment; ③ Irradiation+1 mg/kg dexamethasone group (n=5):The rats were treated with irradiation and dexamethasone of 1 mg/kg; ④ Irradiation+5 mg/kg dexamethasone group (n=5): The rats were treated with irradiation and dexamethasone of 5 mg/kg. The heads of the rats were irradiated with 10 MeV X-ray (30 Gy), and brain tissue was removed after 2weeks to observe the pathological changes. Blood samples were taken from the carotid artery, gradient centrifugation was used, and neutrophile layer was obtained, the level of neutrophile expression of CD18 mRNA and quantity of membrane proteins in blood were detected with Northern blot and flow cytometry respectively.MAIN OUTCOME MEASURES: ① Blood cell count; ② Pathological results; ③ level of neutrophile expression of CD18 mRNA and quantity of membrane proteins.RESULTS: All the 20 SD rats were involved in the analysis of results without

  7. Peri-operative dexamethasone therapy and post-operative psychosis in patients undergoing major oral and maxillofacial surgery.

    Science.gov (United States)

    Koteswara, Chethan Manohara; Patnaik, Pritish

    2014-01-01

    A broad array of behavioral symptoms, including psychosis, can transpire post-operatively following a variety of surgeries. It is difficult to diagnose the exact cause of post-operative psychosis. We report three cases, which developed psychosis post-operatively after undergoing major oral and maxillofacial surgeries. All the three patients were administered dexamethasone peri-operatively. Dexamethasone is used to prevent or reduce post-operative edema. The exact dose of dexamethasone, which can cause psychosis, is unknown. It is important to raise awareness about this potential complication so that measures for management can be put in place in anticipation of such an event.

  8. Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90.

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    Luiz Felipe M Prota

    Full Text Available BACKGROUND: Dexamethasone is widely used for pulmonary exacerbation in patients with cystic fibrosis, however, not much is known about the effects of glucocorticoids on the wild-type cystic fibrosis channel transmembrane regulator (CFTR. Our aim was to determine the effects of dexamethasone treatment on wild-type CFTR expression. METHODS AND RESULTS: Dose-response (1 nM to 10 µM and time course (3 to 48 h curves were generated for dexamethasone for mRNA expression in Calu-3 cells using a real-time PCR. Within 24 h, dexamethasone (10 nM showed a 0.3-fold decrease in CFTR mRNA expression, and a 3.2-fold increase in αENaC mRNA expression compared with control groups. Dexamethasone (10 nM induced a 1.97-fold increase in the total protein of wild-type CFTR, confirmed by inhibition by mifepristone. To access surface protein expression, biotinylation followed by Western blotting showed that dexamethasone treatment led to a 2.35-fold increase in the amount of CFTR in the cell surface compared with the untreated control groups. Once protein translation was inhibited with cycloheximide, dexamethasone could not increase the amount of CFTR protein. Protein stability was assessed by inhibition of protein synthesis with cycloheximide (50 µg/ml at different times in cells treated with dexamethasone and in untreated cells. Dexamethasone did not alter the degradation of wild-type CFTR. Assessment of the B band of CFTR within 15 min of metabolic pulse labeling showed a 1.5-fold increase in CFTR protein after treatment with dexamethasone for 24 h. Chaperone 90 (HSP90 binding to CFTR increased 1.55-fold after treatment with dexamethasone for 24 h, whereas chaperone 70 (HSP70 binding decreased 0.30 fold in an immunoprecipitation assay. CONCLUSION: Mature wild-type CFTR protein is regulated by dexamethasone post transcription, involving cotranslational mechanisms with HSP90 and HSP70, which enhances maturation and expression of wild-type CFTR.

  9. Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study

    Science.gov (United States)

    Campbell, Toby C.; Zhang, Chong; Kim, KyungMann; Kolesar, Jill M.; Oettel, Kurt R.; Blank, Jules H.; Robinson, Emily G.; Ahuja, Harish G.; Kirschling, Ron J.; Johnson, Peter H.; Huie, Michael S.; Wims, Mary E.; Larson, Martha M.; Hernan, Hilary R.; Traynor, Anne M.

    2014-01-01

    Summary Introduction The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0–2. Patients took vorinostat 400 mg PO daily days 1–14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. Results Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1–6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients. PMID:23728919

  10. Bendamustine, bortezomib and prednisone for the treatment of patients with newly diagnosed multiple myeloma: results of a prospective phase 2 Spanish/PETHEMA trial

    Science.gov (United States)

    Mateos, María-Victoria; Oriol, Albert; Rosiñol, Laura; de Arriba, Felipe; Puig, Noemí; Martín, Jesús; Martínez-López, Joaquín; Echeveste, María Asunción; Sarrá, Josep; Ocio, Enrique; Ramírez, Gemma; Martínez, Rafael; Palomera, Luis; Payer, Angel; Iglesias, Rebeca; de la Rubia, Javier; Alegre, Adrian; Chinea, Ana Isabel; Bladé, Joan; Lahuerta, Juan José; Miguel, Jesús-F. San

    2015-01-01

    Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diagnosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamustine (90 mg/m2 on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was performed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be better reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401. PMID:25911554

  11. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma.

    Science.gov (United States)

    Ambati, Srikanth R; Lopes, Eloisi Caldas; Kosugi, Kohji; Mony, Ullas; Zehir, Ahmet; Shah, Smit K; Taldone, Tony; Moreira, Andre L; Meyers, Paul A; Chiosis, Gabriela; Moore, Malcolm A S

    2014-03-01

    Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and in vivo experiments in NSG and nude mice using the A673 cell line. We noted a significant therapeutic window in the activity of PU-H71 against Ewing cell lines and benign cells. PU-H71 treatment resulted in G2/M phase arrest. Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines. Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice. We also investigated the effects of bortezomib, a proteasome inhibitor, alone and in combination with PU-H71 in Ewing sarcoma. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. Ewing sarcoma xenografts were significantly inhibited when mice were treated with the combination compared to vehicle or either drug alone. This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma.

  12. N-Acetylgalactosamine-Targeted Delivery of Dendrimer-Doxorubicin Conjugates Influences Doxorubicin Cytotoxicity and Metabolic Profile in Hepatic Cancer Cells.

    Science.gov (United States)

    Kuruvilla, Sibu P; Tiruchinapally, Gopinath; ElAzzouny, Mahmoud; ElSayed, Mohamed E H

    2017-03-01

    This study describes the development of targeted, doxorubicin (DOX)-loaded generation 5 (G5) polyamidoamine dendrimers able to achieve cell-specific DOX delivery and release into the cytoplasm of hepatic cancer cells. G5 is functionalized with poly(ethylene glycol) (PEG) brushes displaying N-acetylgalactosamine (NAcGal) ligands to target hepatic cancer cells. DOX is attached to G5 through one of two aromatic azo-linkages, L3 or L4, achieving either P1 ((NAcGalβ -PEGc)16.6 -G5-(L3-DOX)11.6 ) or P2 ((NAcGalβ -PEGc)16.6 -G5-(L4-DOX)13.4 ) conjugates. After confirming the conjugates' biocompatibility, flow cytometry studies show P1/P2 achieve 100% uptake into hepatic cancer cells at 30-60 × 10(-9) m particle concentration. This internalization correlates with cytotoxicity against HepG2 cells with 50% inhibitory concentration (IC50 ) values of 24.8, 1414.0, and 237.8 × 10(-9) m for free DOX, P1, and P2, respectively. Differences in cytotoxicity prompted metabolomics analysis to identify the intracellular release behavior of DOX. Results show that P1/P2 release alternative DOX metabolites than free DOX. Stable isotope tracer studies show that the different metabolites induce different effects on metabolic cycles. Namely, free DOX reduces glycolysis and increases fatty acid oxidation, while P1/P2 increase glycolysis, likely as a response to high oxidative stress. Overall, P1/P2 conjugates offer a platform drug delivery technology for improving hepatic cancer therapy.

  13. Treatment of multiple myeloma: 2009 update.

    Science.gov (United States)

    2009-12-01

    (1) New marketing authorizations continue to be granted for treatments of multiple myeloma, and new trials and meta-analyses continue to be published. This review re-examines our previous conclusions based on data published between 2003 and 2008. We again used the standard Prescrire methodology to review the latest data; (2) In patients who are symptomatic but who do not qualify for haematopoietic stem cell transplantation (especially people aged over 65), the results of five comparative trials suggest that adding thalidomide to the melphalan-prednisone combination delays myeloma progression by an additional 5 to 10 months. There is possibly also an increase in overall survival time. This triple combination is therefore a first-line treatment option. There is no firm evidence that replacing thalidomide with bortezomib in this combination provides an advantage; (3) In symptomatic patients aged under 65, two meta-analyses have compared high-dose chemotherapy followed by autologous stem cell transplantation with conventional chemotherapy. Unlike early trials, these meta-analyses showed no overall survival benefit but only a delay in myeloma progression. Initial treatment with two successive transplantation procedures has a negative risk-benefit balance. (4) The optimal chemotherapy regimen prior to autologous stem cell transplantation is controversial. It is unclear which combination (vincristine + doxorubicin + dexamethasone, cyclophosphamide + dexamethasone, cyclophosphamide + dexamethasone, or bortezomib + dexamethasone, etc.) has a better risk-benefit balance in terms of survival and quality of life; (5) According to a meta-analysis of three clinical trials, thalidomide maintenance therapy appears to improve overall survival after Autologous stem cell transplantation; (6) Despite their inadequate evaluation, lenalidomide and pegylated liposomal doxorubicin are licensed for use in patients who relapse or who are refractory to initial treatment. In view of their

  14. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Minghui; Qian, Junmin, E-mail: jmqian@mail.xjtu.edu.cn; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid “burst” release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)–doxorubicin (PEG–DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG–DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG–DOX prodrug were confirmed by {sup 1}H NMR analysis. The PEG–DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG–DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy. - Highlights: • A novel stimuli-responsive PEGylated prodrugs is synthesized. • PEGylated prodrugs can self-assemble into spherical nanoparticles (140 nm

  15. Low Intensity Ultrasound Mediated Liposomal Doxorubicin Delivery Using Polymer Microbubbles.

    Science.gov (United States)

    Yu, Francois T H; Chen, Xucai; Wang, Jianjun; Qin, Bin; Villanueva, Flordeliza S

    2016-01-01

    Cardiotoxicity is the major dose-limiting factor in the chemotherapeutic use of doxorubicin (Dox). A delivery vehicle that can be triggered to release its payload in the tumoral microvasculature but not in healthy tissue would help improve the therapeutic window of the drug. Delivery strategies combining liposomal encapsulated Dox (LDox), microbubbles (MBs), and ultrasound (US) have been shown to improve therapeutic efficacy of LDox, but much remains to be known about the mechanisms and the US conditions that maximize cytotoxicity using this approach. In this study, we compared different US pulses in terms of drug release and acute toxicity. Drug uptake and proliferation rates using low-intensity US were measured in squamous cell carcinoma cells exposed to LDox conjugated to or coinjected with polymer MBs. The aims of this study were: (1) to compare the effects of low- and high-pressure US on Dox release kinetics; (2) to evaluate whether conjugating the liposome to the MB surface (DoxLPX) is an important factor for drug release and cytotoxicity; and (3) to determine which US parameters most inhibit cell proliferation and whether this inhibition is mediated by drug release or the MB/US interaction with cells. Low-pressure US (170 kPa) at high duty cycle (stable cavitation) released up to ∼ 70% of the encapsulated Dox from the DoxLPX, thus improving Dox bioavailability and cellular uptake and leading to a significant reduction in cell proliferation at 48 h. Flow cytometry showed that US generating stable oscillations of DoxLPX significantly increased cellular Dox uptake at 4 h after US exposure compared to LDox. Drug uptake was correlated with cytotoxicity at 48 h. Our results demonstrate that Dox-containing liposomes conjugated to polymer MBs can be triggered to release ∼ 70% of their payload using noninertial US. Following release, Dox became bioavailable to the cells and induced significantly higher cytotoxicity compared to nonreleased encapsulated drug. Our

  16. Weekly doxorubicin increases coronary arteriolar wall and adventitial thickness.

    Directory of Open Access Journals (Sweden)

    Delrae M Eckman

    Full Text Available BACKGROUND: Doxorubicin (DOX is associated with premature cardiovascular events including myocardial infarction. This study was performed to determine if the weekly administration of DOX influenced coronary arteriolar medial and/or adventitial wall thickening. METHODS: Thirty-two male Sprague-Dawley rats aged 25.1± 2.4 weeks were randomly divided into three groups and received weekly intraperitoneal injections of normal saline (saline, n = 7, or low (1.5 mg/kg to 1.75 mg/kg, n = 14 or high (2.5 mg/kg, n = 11 doses of DOX. The animals were treated for 2-12 weeks, and euthanized at pre-specified intervals (2, 4, 7, or 10+ weeks to obtain histopathologic assessments of coronary arteriolar lumen diameter, medial wall thickness, adventitial wall thickness, and total wall thickness (medial thickness + adventitial thickness. RESULTS: Lumen diameter was similar across all groups (saline: 315±34 µm, low DOX: 286±24 µm, high DOX: 242±27 µm; p = 0.22. In comparison to animals receiving weekly saline, animals receiving weekly injections of 2.5 mg/kg of DOX experienced an increase in medial (23±2 µm vs. 13±3 µm; p = 0.005, and total wall thickness (51±4 µm vs. 36±5 µm; p = 0.022, respectively. These increases, as well as adventitial thickening became more prominent after normalizing for lumen diameter (p<0.05 to p<0.001 and after adjusting for age, weight, and total cumulative DOX dose (p = 0.02 to p = 0.01. Animals receiving low dose DOX trended toward increases in adventitial and total wall thickness after normalization to lumen diameter and accounting for age, weight, and total cumulative DOX dose (p = 0.06 and 0.09, respectively. CONCLUSION: In conclusion, these data demonstrate that weekly treatment of rats with higher doses of DOX increases coronary arteriolar medial, adventitial, and total wall thickness. Future studies are warranted to determine if DOX related coronary arteriolar effects are

  17. Ultralow-dose dexamethasone to preserve endogenous cortisol stress response in nonclassical congenital adrenal hyperplasia: A new promising treatment

    NARCIS (Netherlands)

    D.C.M. van der Kaay (Danielle); E.L.T. van den Akker (Erica)

    2014-01-01

    textabstractIntroduction: Nonclassical congenital adrenal hyperplasia (CAH) is characterized by sufficient cortisol and aldosterone production at the cost of androgen overproduction. Hydrocortisone or dexamethasone in supraphysiological doses are current treatment; however, their downside is suppres

  18. Clinical and biochemical characteristics of Cushing’s disease with different suppression rates by high-dose dexamethasone

    Institute of Scientific and Technical Information of China (English)

    唐志清

    2013-01-01

    Objective To analyze the clinical and biochemical characteristics of Cushing’s disease with different suppression rates by high-dose dexamethasone.Methods Two hundred and two consecutive patients with

  19. Dexamethasone effects on creatine kinase activity and insulin-like growth factor receptors in cultured muscle cells

    Science.gov (United States)

    Whitson, Peggy A.; Stuart, Charles A.; Huls, M. H.; Sams, Clarence F.; Cintron, Nitza M.

    1989-01-01

    The effect of dexamethasone on the activity of creatine kinase (CK) and the insulin-like growth factor I (IGF-I) binding were investigated using skeletal- and cardiac-muscle-derived cultured cell lines (mouse, C2C12; rat, L6 and H9c2). It was found that, in skeletal muscle cells, dexamethasone treatment during differentiation of skeletal-muscle cells caused dose-dependent increases in CK activity and increases in the degree of myotube formation, whereas cardiac cells (H9c2) exhibited very low CK activity during culture or dexamethasone treatment. Results for IGF-I binding were similar in all three cell lines. The IGF-I binding to dexamethasone-treated cells (50 nM for 24 hr on the day prior to confluence) resulted in an increased number of available binding sites, with no effect on the binding affinities.

  20. [Dexamethasone affect on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors].

    Science.gov (United States)

    Fatkhullina, A R; Abramov, S N; Skibo, Iu V; Abramova, Z I

    2014-01-01

    Synthetic glucocorticoids are able to activate apoptosis in the cells by regulating the transcription of the respective genes. Effect of dexamethasone on apoptosis is an established fact. However, its influence on another program of cell death autophagy, is currently unproven. Therefore, in this paper we have analyzed the influence of dexamethasone on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors. The results showed that dexamethasone reduced the expression of bcl-2 and mTOR genes. However, the nature of the effect of dexamethasone on mTOR and bcl-2 expression was different: the expression of bcl-2 gene in the long-term cultivation was maintained at the same reduced level, while the expression of mTOR was first reduced and then increased.

  1. Effect of venous dexamethasone, oral caffeine and acetaminophen on relative frequency and intensity of postdural puncture headache after spinal anesthesia

    Directory of Open Access Journals (Sweden)

    Mehrdad Masoudifar

    2016-01-01

    Conclusions: Though the taking of acetaminophen + caffeine + dexamethasone is associated with a decrease in headache intensity and duration and decrease in PDPH incidence, compared with placebo, however, no essentially and statistically significant effect was produced.

  2. Interactions between N-acetyl-L-cysteine protected CdTe quantum dots and doxorubicin through spectroscopic method

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiupei, E-mail: xiupeiyang@163.com [Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, Nanchong 637000 (China); College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000 (China); Lin, Jia; Liao, Xiulin; Zong, Yingying; Gao, Huanhuan [College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000 (China)

    2015-06-15

    Highlights: • CdTe quantum dots with the diameter of 3–5 nm were synthesized in aqueous solution. • The modified CdTe quantum dots showed well fluorescence properties. • The interaction between the CdTe quantum dots and doxorubicin (DR) was investigated. - Abstract: N-acetyl-L-cysteine protected cadmium telluride quantum dots with a diameter of 3–5 nm were synthesized in aqueous solution. The interaction between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin was investigated by ultraviolet–visible absorption and fluorescence spectroscopy at physiological conditions (pH 7.2, 37 °C). The results indicate that electron transfer has occurred between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin under light illumination. The quantum dots react readily with doxorubicin to form a N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex via electrostatic attraction between the −NH{sub 3}{sup +} moiety of doxorubicin and the −COO{sup −} moiety of N-acetyl-L-cysteine/cadmium telluride quantum dots. The interaction of N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex with bovine serum albumin was studied as well, showing that the complex might induce the conformation change of bovine serum due to changes in microenvironment of bovine serum.

  3. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer.

    Science.gov (United States)

    Granados-Principal, Sergio; El-Azem, Nuri; Pamplona, Reinald; Ramirez-Tortosa, Cesar; Pulido-Moran, Mario; Vera-Ramirez, Laura; Quiles, Jose L; Sanchez-Rovira, Pedro; Naudí, Alba; Portero-Otin, Manuel; Perez-Lopez, Patricia; Ramirez-Tortosa, Mcarmen

    2014-07-01

    Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.

  4. Effects of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Jing-min OU; Xi-ping ZHANG; Cheng-jun WU; Di-jiong WU; Ping YAN

    2012-01-01

    Objective:To investigate the protective effects and mechanisms of action of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis (SAP).Methods:The rats were divided into sham-operated,model control,dexamethasone treated,and Salvia mi/tiorrhiza treated groups.At 3,6,and 12 h after operation,the mortality rate of different groups,pathological changes,Bcl-2-associated X protein (Bax) and nuclear factor-κB (NF-κB) protein expression levels in multiple organs (the pancreas,liver,kidneys,and lungs),toll-like receptor 4 (TLR-4) protein levels (only in the liver),intercellular adhesion molecule 1 (ICAM-1) protein levels (only in the lung),and terminal deoxynucleotidy transferase mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)staining expression levels,as well as the serum contents of amylase,glutamate-pyruvate transaminase (GPT),glutamic-oxaloacetic transaminase (GOT),blood urea nitrogen (BUN),and creatinine (CREA) were observed.Results:The mortality rate of the dexamethasone treated group was significantly lower than that of the model control group (P<0.05).The pathological changes in multiple organs in the two treated groups were relieved to different degrees (P<0.05 and P<0.01,respectively),the expression levels of Bax and NF-κB proteins,and apoptotic indexes of multiple organs were reduced (P<0.05 and P<0.01,respectively).The contents of amylase,GPT,GOT,BUN,and CREA in the two treated groups were significantly lower than those in model control groups (P<0.05 and P<0.01,respectively).The expression level of ICAM-1 protein in the lungs (at 3 and 12 h) in the dexamethasone treated group was significantly lower than that in the Salvia miltiorrhiza treated group (P<0.05).The serum contents of CREA (at 12 h) and BUN (at 6 h)of the Salvia miltiorrhiza treated group were significantly lower than those in the dexamethasone treated group (P<0.05).Conclusions:Both dexamethasone and Salvia

  5. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000.

    Science.gov (United States)

    Möricke, Anja; Zimmermann, Martin; Valsecchi, Maria Grazia; Stanulla, Martin; Biondi, Andrea; Mann, Georg; Locatelli, Franco; Cazzaniga, Giovanni; Niggli, Felix; Aricò, Maurizio; Bartram, Claus R; Attarbaschi, Andishe; Silvestri, Daniela; Beier, Rita; Basso, Giuseppe; Ratei, Richard; Kulozik, Andreas E; Lo Nigro, Luca; Kremens, Bernhard; Greiner, Jeanette; Parasole, Rosanna; Harbott, Jochen; Caruso, Roberta; von Stackelberg, Arend; Barisone, Elena; Rössig, Claudia; Conter, Valentino; Schrappe, Martin

    2016-04-28

    Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered

  6. Tween 20 increases intestinal transport of doxorubicin in vitro but not in vivo

    DEFF Research Database (Denmark)

    Al-Saraf, Amal; Holm, René; Nielsen, Carsten Uhd

    2016-01-01

    The chemotherapeutic drug substance doxorubicin has been reported to be a substrate of P-gp, which induces a barrier for oral administration and leads to a bioavailability of 3% in male Sprague Dawley rats. Literature studies have reported increased transport of P-pg substrates, like digoxin, whe...

  7. The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Timothy B Lautz

    Full Text Available Histone deacetylase (HDAC inhibitors, especially vorinostat, are currently under investigation as potential adjuncts in the treatment of neuroblastoma. The effect of vorinostat co-treatment on the development of resistance to other chemotherapeutic agents is unknown. In the present study, we treated two human neuroblastoma cell lines [SK-N-SH and SK-N-Be(2C] with progressively increasing doses of doxorubicin under two conditions: with and without vorinsotat co-therapy. The resultant doxorubicin-resistant (DoxR and vorinostat-treated doxorubicin resistant (DoxR-v cells were equally resistant to doxorubicin despite significantly lower P-glycoprotein expression in the DoxR-v cells. Whole genome analysis was performed using the Ilumina Human HT-12 v4 Expression Beadchip to identify genes with differential expression unique to the DoxR-v cells. We uncovered a number of genes whose differential expression in the DoxR-v cells might contribute to their resistant phenotype, including hypoxia inducible factor-2. Finally, we used Gene Ontology to categorize the biological functions of the differentially expressed genes unique to the DoxR-v cells and found that genes involved in cellular metabolism were especially affected.

  8. Magnesium homeostasis in colon carcinoma LoVo cells sensitive or resistant to doxorubicin.

    Science.gov (United States)

    Castiglioni, Sara; Cazzaniga, Alessandra; Trapani, Valentina; Cappadone, Concettina; Farruggia, Giovanna; Merolle, Lucia; Wolf, Federica I; Iotti, Stefano; Maier, Jeanette A M

    2015-11-13

    Neoplastic cells accumulate magnesium, an event which provides selective advantages and is frequently associated with TRPM7 overexpression. Little is known about magnesium homeostasis in drug-resistant cancer cells. Therefore, we used the colon cancer LoVo cell model and compared doxorubicin-resistant to sensitive cells. In resistant cells the concentration of total magnesium is higher while its influx capacity is lower than in sensitive cells. Accordingly, resistant cells express lower amounts of the TRPM6 and 7, both involved in magnesium transport. While decreased TRPM6 levels are due to transcriptional regulation, post-transcriptional events are involved in reducing the amounts of TRPM7. Indeed, the calpain inhibitor calpeptin markedly increases the levels of TRPM7 in resistant cells. In doxorubicin-sensitive cells, silencing TRPM7 shifts the phenotype to one more similar to resistant cells, since in these cells silencing TRPM7 significantly decreases the influx of magnesium, increases its intracellular concentration and increases resistance to doxorubicin. On the other hand, calpain inhibition upregulates TRPM7, decreases intracellular magnesium and enhances the sensitivity to doxorubicin of resistant LoVo cells. We conclude that in LoVo cells drug resistance is associated with alteration of magnesium homeostasis through modulation of TRPM7. Our data suggest that TRPM7 expression may be an additional undisclosed player in chemoresistance.

  9. Mesenchymal Stem Cell-Induced Doxorubicin Resistance in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Dar-Ren Chen

    2014-01-01

    Full Text Available Triple negative breast cancer (TNBC is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs, tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM, noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

  10. Mesenchymal stem cell-induced doxorubicin resistance in triple negative breast cancer.

    Science.gov (United States)

    Chen, Dar-Ren; Lu, Dah-Yuu; Lin, Hui-Yi; Yeh, Wei-Lan

    2014-01-01

    Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

  11. Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient.

    Science.gov (United States)

    Fritze, Andreas; Hens, Felicitas; Kimpfler, Andrea; Schubert, Rolf; Peschka-Süss, Regine

    2006-10-01

    This study examines a new method for the remote loading of doxorubicin into liposomes. It was shown that doxorubicin can be loaded to a level of up to 98% into large unilamellar vesicles composed of egg phosphatidylcholine/cholesterol (7/3 mol/mol) with a transmembrane phosphate gradient. The different encapsulation efficiencies which were achieved with ammonium salts (citrate 100%, phosphate 98%, sulfate 95%, acetate 77%) were significantly higher as compared to the loading via sodium salts (citrate 54%, phosphate 52%, sulfate 44%, acetate 16%). Various factors, including pH-value, buffer capacity, solubility of doxorubicin in different salt solutions and base counter-flow, which likely has an influence on drug accumulation in the intraliposomal interior are taken into account. In contrast to other methods, the newly developed remote loading method exhibits a pH-dependent drug release property which may be effective in tumor tissues. At physiological pH-value doxorubicin is retained in the liposomes, whereas drug release is achieved by lowering the pH to 5.5 (approximately 25% release at 25 degrees C or 30% at 37 degrees C within two h). The DXR release of liposomes which were loaded via a sulfate gradient showed a maximum of 3% at pH 5.5.

  12. 3D collagen type I matrix inhibits the antimigratory effect of doxorubicin

    Directory of Open Access Journals (Sweden)

    Millerot-Serrurot Emilie

    2010-08-01

    Full Text Available Abstract Background The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs. The present study was designed to investigate whether this microenvironment can influence the antimigratory effect of an anthracycline drug, doxorubicin, when tumor cells are grown in a matrix of type I collagen, a three-dimensional (3D context which simulates a natural microenvironment. Methods To this purpose, we studied the migratory parameters, the integrin expression, and the activation state of focal adhesion kinase (FAK and GTPase RhoA involved in the formation of focal adhesions and cell movement. These parameters were evaluated at non toxic concentrations which did not affect HT1080 cell proliferation. Results We show that while doxorubicin decreased cell migration properties by 70% in conventional two-dimensional (2D culture, this effect was completely abolished in a 3D one. Regarding the impact of doxorubicin on the focal adhesion complexes, unlike in 2D systems, the data indicated that the drug neither affected β1 integrin expression nor the state of phosphorylation of FAK and RhoA. Conclusion This study suggests the lack of antiinvasive effect of doxorubicin in a 3D environment which is generally considered to better mimic the phenotypic behaviour of cells in vivo. Consistent with the previously shown resistance to the cytotoxic effect in a 3D context, our results highlight the importance of the matrix configuration on the tumor cell response to antiinvasive drugs.

  13. Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

    Directory of Open Access Journals (Sweden)

    Jorge Eduardo Toblli

    2014-01-01

    Full Text Available Since anthracycline-induced cardiotoxicity (AIC, a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM modulates the influence of iron deficiency anaemia (IDA and doxorubicin (3–5 mg per kg body weight [BW] on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW, either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase, nitrosative stress (inducible nitric oxide synthase and nitrotyrosine, inflammation (tumour necrosis factor-alpha and interleukin-6, and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC.

  14. Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

    NARCIS (Netherlands)

    Todorova, Valentina K.; Kaufmann, Yihong; Hennings, Leah; Klimberg, V. Suzanne

    2010-01-01

    Doxorubicin (DOX), a widely used anticancer drug, has a dose-dependent cardiotoxicity, attributed mainly to free radical formation. The cardiomyocyte oxidative stress occurs rapidly after DOX treatment, resulting in harmful modifications to proteins, lipids, and DNA. Previous data showed that oral L

  15. Chitosan-based nanoparticles as drug delivery systems for doxorubicin: Optimization and modelling.

    Science.gov (United States)

    Soares, Paula I P; Sousa, Ana Isabel; Silva, Jorge Carvalho; Ferreira, Isabel M M; Novo, Carlos M M; Borges, João Paulo

    2016-08-20

    In the present work, two drug delivery systems were produced by encapsulating doxorubicin into chitosan and O-HTCC (ammonium-quaternary derivative of chitosan) nanoparticles. The results show that doxorubicin release is independent of the molecular weight and is higher at acidic pH (4.5) than at physiological pH. NPs with an average hydrodynamic diameter bellow 200nm are able to encapsulate up to 70% and 50% of doxorubicin in the case of chitosan and O-HTCC nanoparticles, respectively. O-HTCC nanoparticles led to a higher amount of doxorubicin released than chitosan nanoparticles, for the same experimental conditions, although the release mechanism was not altered. A burst effect occurs within the first hours of release, reaching a plateau after 24h. Fitting mathematical models to the experimental data led to a concordant release mechanism between most samples, indicating an anomalous or mixed release, which is in agreement with the swelling behavior of chitosan described in the literature.

  16. Weekly low-dose mitoxantrone plus doxorubicin as second-line chemotherapy for advanced breast cancer

    NARCIS (Netherlands)

    M. Bontenbal (Marijke); A.S.Th. Planting (André); C.J. Rodenburg (C.); A. Dees; J. Verweij (Jaap); C.C.M. Bartels (Carina); J. Alexieva-Figusch (Jana); W.L.J. van Putten (Wim); J.G.M. Klijn (Jan)

    1992-01-01

    textabstractWeekly low dose mitoxantrone (3 mg/m2) plus doxorubicin (8 mg/m2) was administered as second-line chemotherapy to 33 patients with advanced breast cancer. Four out of 28 evaluable patients (14%) obtained a partial response with a median duration of 34 weeks (range 18-67+ weeks), while 8

  17. The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

    NARCIS (Netherlands)

    W. van de Vrie (Wim); A.M. Jonker (Ard Mieke); R.L. Marquet (Richard); A.M.M. Eggermont (Alexander)

    1994-01-01

    textabstractthe feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimenta