DOCSLIB.ORG

VCD) Versus Bortezomib, Doxorubicin and Dexamethasone (Pad) in Newly Diagnosed Myeloma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
VCD) Versus Bortezomib, Doxorubicin and Dexamethasone (Pad) in Newly Diagnosed Myeloma Leukemia (2015) 29, 1721–1729 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma EK Mai1, U Bertsch1, J Dürig2, C Kunz3, M Haenel4, IW Blau5, M Munder6, A Jauch7, B Schurich8, T Hielscher3, M Merz9, B Huegle-Doerr1, A Seckinger1, D Hose1, J Hillengass9, MS Raab9, K Neben9, H-W Lindemann10, M Zeis11, C Gerecke12, IGH Schmidt-Wolf13, K Weisel14, C Scheid15, H Salwender16 and H Goldschmidt1 We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/ doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾ VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾ VGPR rates (37.0 versus 34.3%, P = 0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P = 0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, Po0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P = 0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P = 0.04 and 2.8 versus 0.4%, P = 0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾ VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy. Leukemia (2015) 29, 1721–1729; doi:10.1038/leu.2015.80 INTRODUCTION (GMMG, EudraCT No. 2010-019173-16) was designed to assess Induction therapy (IT) followed by high-dose melphalan (HDM) two independent primary end points: and autologous stem cell transplantation (ASCT) is the standard of 1. Demonstration of non-inferiority of bortezomib/cyclopho- care for younger multiple myeloma (MM) patients.1–3 ITs provide a sphamide/dexamethasone (VCD) IT compared to bortezomib/ crucial foundation for modern multi-drug-based myeloma treat- doxorubicin/dexamethasone (PAd) IT with respect to response rates (very good partial response (VGPR) or better, ⩾ VGPR). ment approaches, progressively inducing high rates of deep 4–8 2. Determination of the best of four treatment strategies with responses, thereby leading to prolonged progression-free fi 3,9–12 respect to PFS. The treatment strategies are de ned by PAd or survival (PFS) and overall survival (OS). VCD IT followed by standard intensification therapy (HDM+ASCT), Bortezomib/dexamethasone-based IT regimens are commonly lenalidomide consolidation and maintenance treatment with combined with either cytotoxic agents, such as doxorubicin6,7 or 5,13–16 4,17 either lenalidomide for 2 years or lenalidomide until complete cyclophosphamide, or immunomodulatory drugs (IMiDs, response (CR) is achieved. thalidomide and lenalidomide). The superiority of bortezomib- Herein we report the results of the first primary end point of the containing regimens to ITs without novel agents has been MM5 trial. demonstrated in a number of phase III trials.4,7–9,13,17 Until now, however, there has been no reported randomized phase III trial comparing a bortezomib/dexamethasone-based IT, with either PATIENTS AND METHODS doxorubicin or cyclophosphamide. Eligibility criteria The open-label, randomized, multicenter phase III clinical trial The key inclusion criteria were patients 18–70 years of age with MM5 of the German-speaking Myeloma Multicenter Group newly diagnosed MM18 who require systemic chemotherapy based on 1Department of Internal Medicine V, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg on behalf of the German-Speaking Myeloma Multicenter Group (GMMG), Heidelberg, Germany; 2Department of Hematology, University Hospital Essen, Essen, Germany; 3Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany; 4Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany; 5Medical Clinic, Charité University Medicine Berlin, Berlin, Germany; 6Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany; 7Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; 8Coordination Centers for Clinical Trials (KKS), University Hospital Heidelberg, Heidelberg, Germany; 9Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany; 10Department of Hematology and Oncology, Katholisches Krankenhaus Hagen, Hagen, Germany; 11Department of Hematology, Asklepios Hospital St. Georg Hamburg, Hamburg, Germany; 12Department of Hematology and Oncology, Helios Hospital Berlin Buch, Berlin, Germany; 13Center for Integrated Oncology, University Hospital Bonn, Bonn, Germany; 14Department of Hematology, Oncology and Immunology, University Hospital Tübingen, Tübingen, Germany; 15Department of Internal Medicine I, University Hospital Köln, Köln, Germany and 16Department of Hematology and Oncology, Asklepios Hospital Hamburg Altona, Hamburg, Germany. Correspondence: Professor Dr H Goldschmidt, Department of Internal Medicine V, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: [email protected] Received 3 November 2014; revised 12 March 2015; accepted 16 March 2015; accepted article preview online 19 March 2015; advance online publication, 8 May 2015 VCD is favorable to PAd as induction therapy in myeloma EK Mai et al 1722 Newly diagnosed symptomatic MM 18-70 years of age A1 + B1 A2 + B2 3 x PAd 3 x VCD 1) 1) Stem cell mobilisation (CAD + G-CSF) + leukapheresis First ASCT (melphalan 200 mg/m2) Second ASCT (melphalan 200 mg/m2) (if no nCR/CR) 2 x Lenalidomide A1 B1 A2 B2 Lenalidomide Lenalidomide Lenalidomide Lenalidomide for 2 years if no CR for 2 years if no CR 1) High Risk Patients, optional in Phase II trial for auto-allo SCT Randomized (n = 504) ineligible: VCD n =1 PAd n = 1 ITT (n = 502) Patients not receiving PAd (n = 251) VCD (n = 251) Patients not receiving allocated intervention due allocated intervention due to: to: - myocardial infarction - non-compliance (n = 1) prior to therapy (n = 1) Received allocated Received allocated - withdrawal of consent - death (n = 1) intervention (n = 248) intervention (n = 249) (n = 2) randomized PAd and One patient was excluded treated VCD (n = 1) from ITT due to unconfirmed diagnosis of symptomatic MM (see above) but received VCD 3 cycles n = 234 3 cycles n = 244 and was therefore 2 cycles n = 10 2 cycles n = 4 included in safety 1 cycle n = 5 1 cycle n = 1 analysis (n = 1) Excluded from PP Excluded from PP analysis analysis - incomplete induction - incomplete induction therapy (n = 9) ITT n = 251 ITT n = 251 therapy (n = 5) - missing response Per-Protocol n = 233 Per-Protocol n = 240 - missing response assessment (n = 6) Safety n = 249 Safety n = 249 assessment (n = 3) - randomized PAd and - patient not ITT not PP treated VCD (n = 1) but Safety (n = 1, see above) CAD + G-CSF CAD + G-CSF Stem cell collection Stem cell collection Figure 1. Flow chart and consort diagram of the GMMG-MM5 trial. (a) Flow chart: randomization was performed prior to start of induction therapy. Maintenance therapy consisted of either lenalidomide for 2 years or lenalidomide if no complete remission (CR) was achieved. (b) Consort diagram: 502 patients were randomized and received the hence displayed treatment. Abbreviations: ASCT, autologous stem cell transplantation; CAD, cyclophosphamide/doxorubicin/dexamethasone; G-CSF, granulocyte-colony stimulating factor (lenograstim); ITT, intention-to-treat population; MM, multiple myeloma; nCR, near complete remission; PAd, bortezomib/doxorubicin/dexamethasone; PP, per-protocol population; safety, safety population; VCD, bortezomib/cyclophosphamide/dexamethasone. ‘CRAB’ criteria;18 World Health Organization (WHO) performance status Study design and treatment 19 0–2 or 3, if MM related; and measureable MM disease. Key exclusion The MM5 trial is a prospective, open-label, randomized multicenter phase criteria included: systemic light chain amyloidosis; peripheral neuro- III clinical trial (EudraCT No. 2010-019173-16). A total of 31 transplant pathy/neuropathic pain ⩾ 2° (National Cancer Institute Common centers and 75 associated sites throughout Germany are participating in Terminology Criteria for Adverse Events, NCI CTCAE, version 4.0). this trial. The study was initiated by the GMMG and approved by ethics Patients with renal impairment (RI) or renal failure were not excluded committees in the University of Heidelberg and at all participating sites. from the study. Detailed inclusion/exclusion criteria are provided in the The MM5 trial is conducted according to the European Clinical Trial study protocol (see online Supplementary Material 1). Directive (2005) and the Declaration of Helsinki. Leukemia (2015) 1721 – 1729 © 2015 Macmillan Publishers Limited VCD is favorable to PAd as induction therapy in myeloma EK Mai et al 1723 Figure 2. Induction treatments. Schematic view of induction therapy regimens within the GMMG-MM5 trial. Five hundred and four patients were included
Load more

Recommended publications
  • A Phase II Study of the Novel Proteasome Inhibitor Bortezomib In
    Memorial Sloan-Kettering Cance r Center IRB Protocol IRB#: 05-103 A(14) A Phase II Study of the Novel Proteas ome Inhibitor Bortezomib in Combination with Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory I Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL Principal Investigator: John Gerecitano, M.D., Ph.D. Co-Principal Carol Portlock, M.D. Investigator(s): IFormerly: A Phase I/II Study of the Nove l Proteasome Inhibitor Bortezomib in Combinati on with Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) Amended: 07/25/12 Memorial Sloan-Kettering Cance r Center IRB Protocol IRB#: 05-103 A(14) Investigator(s): Paul Hamlin, M.D. Commack, NY Steven B. Horwitz, M.D. Philip Schulman, M.D. Alison Moskowitz, M.D. Stuart Lichtman, M.D Craig H. Moskowitz, M.D. Stefan Berger, M.D. Ariela Noy, M.D. Julie Fasano, M.D. M. Lia Palomba, M.D., Ph.D. John Fiore, M.D. Jonathan Schatz, M.D. Steven Sugarman, M.D David Straus, M.D. Frank Y. Tsai, M.D. Andrew D. Zelenetz, M.D., Ph.D. Matthew Matasar, M.D Rockville Center, NY Mark L. Heaney, M.D., Ph.D. Pamela Drullinksy, M.D Nicole Lamanna, M.D. Arlyn Apollo, M.D. Zoe Goldberg, M.D. Radiology Kenneth Ng, M.D. Otilia Dumitrescu, M.D. Tiffany Troso-Sandoval, M.D. Andrei Holodny, M.D. Sleepy Hollow, NY Nuclear Medicine Philip Caron, M.D. Heiko Schoder, M.D. Michelle Boyar, M.D.
    [Show full text]
  • VELCADE® (Bortezomib) for Injection
    1 VELCADE® (bortezomib) for Injection 2 PRESCRIBING INFORMATION 3 DESCRIPTION 4 VELCADE® (bortezomib) for Injection is an antineoplastic agent available for intravenous 5 injection (IV) use only. Each single dose vial contains 3.5 mg of bortezomib as a sterile 6 lyophilized powder. Inactive ingredient: 35 mg mannitol, USP. 7 Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic 8 ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its 9 hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic 10 anhydride form as a trimeric boroxine. 11 The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1- 12 oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. 13 Bortezomib has the following chemical structure: O OH H N N B N OH H O N 14 15 The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of 16 bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 17 6.5. 18 CLINICAL PHARMACOLOGY 19 Mechanism of Action 20 Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in 21 mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated 22 proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular 23 concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of 24 the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling 25 cascades within the cell.
    [Show full text]
  • Combining Milatuzumab with Bortezomib, Doxorubicin, Or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R
    CancerTherapy: Preclinical Combining Milatuzumab with Bortezomib, Doxorubicin, or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R. Smith,2 Susan Chen,1Maria Zalath,1and David M. Goldenberg1 Abstract Purpose: The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2. Experimental Design: Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM. Results: Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded sig- nificant antiproliferative effects in CD74+ cells.The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC50 of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-nB pathwayinCAGMMcells. In CAG-or KMS11-SCIDxenograftmodels ofdisseminated MM, milatuzumab more than doubled median survival time, compared withup to a 33% increase in median survival withbortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumabandbortezomibincreasedsurvivalsignificantlycomparedwitheither treatmentalone. Conclusions:The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are en- hanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically.
    [Show full text]
  • Antitumor Effects of Bortezomib (PS-341) on Primary Effusion Lymphomas
    Leukemia (2004) 18, 1699–1704 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00 www.nature.com/leu Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas JAn1, Y Sun1, M Fisher1 and MB Rettig1,2 1VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; and 2Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Primary effusion lymphomas (PELs) are a rare type of non- treatment of refractory multiple myeloma, where it has an Hodgkin’s lymphoma that are resistant to cytotoxic chemother- acceptable toxicity profile.4–6 By inhibiting the proteasome, apy. PELs manifest constitutive activation of nuclear factor kappa B (NF-jB), and inhibition of NF-jB induces apoptosis of which degrades proteins that are marked by ubiquitination, PELs and sensitizes to tumor necrosis factor-related apoptosis- bortezomib modulates the cellular concentrations of hundreds inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a of proteins that are involved in a wide variety of functions, peptidyl boronic acid inhibitor of the proteasome, is a potent including cell cycle progression, signal transduction, and agent against a wide range of hematologic malignancies and apoptosis.7,8 For example, the proteasome regulates the activity has been shown to inhibit NF-jB. Thus, we examined the of the NF-kB pathway, in that the degradation of I kappa B (IkB), cytotoxic effects of bortezomib alone and in combination with the NF-kB inhibitory protein, is dependent upon the ubiquitin– various drugs. Bortezomib potently inhibited NF-jB in PEL cells 9 in a dose-dependent manner.
    [Show full text]
  • Bortezomib Plus Docetaxel in Advanced Non-Small Cell Lung Cancer and Other Solid Tumors: a Phase I California Cancer Consortium Trial
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector ORIGINAL ARTICLE Bortezomib Plus Docetaxel in Advanced Non-small Cell Lung Cancer and Other Solid Tumors: A Phase I California Cancer Consortium Trial Primo N. Lara, Jr., MD,*† Mariana Koczywas, MD,‡ David I. Quinn, MD, PhD,§ Heinz Josef Lenz, MD,§ Angela M. Davies, MD,* Derick H.M. Lau, MD, PhD,*† Paul H. Gumerlock, PhD,* Jeff Longmate, PhD,‡ James H. Doroshow, MD,‡ David Schenkein, MD,͉͉ Oscar Kashala, MD,͉͉ and David R. Gandara, MD*† n recent years, the inhibition of the 26S proteasome has Background: This phase I study was performed to determine the emerged as a rational anti-neoplastic strategy. The 26S dose-limiting toxicity and maximum tolerated dose (MTD) of do- I proteasome is a very large proteolytic complex involved in a cetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. significant catabolic pathway, the ubiquitin–proteasome path- way, for many intracellular regulatory proteins, including I␬B Methods: Patients were enrolled in cohorts of three over six dose ␬ ␬ ␬ levels. Each treatment cycle was 3 weeks long and consisted of one kinase/nuclear factor- B(I B/NF- B), p53, and the cyclin- docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, dependent kinase inhibitors p21 and p27, which contribute to 8, and 11). Dose escalation and MTD determination were based on the regulation of the cell cycle, apoptosis, and angiogene- 1–3 the occurrence of dose-limiting toxicities in cycle 1 only.
    [Show full text]
  • Thesis Biochemistry By
    Ain shams Universirty Faculty Of Science Evaluation of anticancer effects of a novel proteasome inhibitor (Velcade), interferon (alpha-interferon) and antimyeloma antibodies on the growth of myeloma cells. Thesis Submitted for the Requirement of the Ph.D degree in Biochemistry By Hanan Mohammed Mohammed El shershaby. (M.Sc in Biochemistry) Under Supervision of Prof.Dr / Ibrahim Hassan Borai Prof.Dr/ Mohamed Taha Hussein El- Kolaly Prof. of Biochemistry Professor of Radiopharmaceutics Faculty Of Science Atomic Energy Authority Ain shams Universirty Prof.Dr/Naser Mohammed El-lahloby Prof. Dr/ Kamel Abd El.hameed Moustafa Prof. of Medical Oncology Professor of Biochemistry Cancer Institute Center Atomic Energy Authority Cairo University Dr / Ahmed Abd El.aziz sayed Assistant professor of Biochemistry Faculty Of Science Ain shams Universirty (2013) CONTENTS Introduction and Aim of the work 1 Review Of Literature 4 ◙ Multiple Myeloma 4 ◙ Cell cycle 16 ◙ Apoptosis 19 ◙ Caspases 23 ◙ Chemotherapy 25 ◙ Proteasomes 36 Bortezomib (Velcade) 38 ◙ Interferons 43 ◙ Immunity and Immune system 46 Antibodies 49 Production of Antibodies 51 ◙ Immunotherapy 57 ◙ Radioimmunotherapy ( RIT ) 61 ◙ Gene therapy 62 Materials and Methods 64 Results 92 Discussion 133 Summary 144 References 148 Arabic Summary LIST OF FIGURES Figure (1): Overview of the cell cycle. 16 Figure (2): Apoptosis – the programmed death of a cell. 20 Figure (3): The intrinsic and extrinsic pathways leading to apoptosis. 22 Figure (4): Structure of the 26S proteasome. 37 Figure (5): Chemical Structure of Bortezomib 38 Figure (6): Mechanism of action of Bortezomib 40 Figure (7): The different ways that Bortezomib can affect multiple myeloma 41 Figure (8): Antitumor actions of interferons.
    [Show full text]
  • Velcade, INN-Bortezomib
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Velcade. This scientific discussion has been updated until 1 May 2004. For information on changes after this date please refer to module 8. 1. Introduction Multiple myeloma Multiple myeloma is a B-cell malignancy of the plasma cell and represents the second most common hematological malignancy, with non-Hodgkin’s lymphoma being the most common. The incidence and prevalence of multiple myeloma are similar in the US and Europe. In 2000, there were approximately 19,000 cases diagnosed in the European Economic Area (Globocan, 2000), with a 5- year prevalence of approximately 47,000 cases. The course of multiple myeloma is characterized by an asymptomatic or subclinical phase before diagnosis (possibly for several years), a chronic phase lasting several years, and an aggressive terminal phase. Multiple myeloma leads to progressive morbidity and eventual mortality by lowering resistance to infection and causing significant skeletal destruction (with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, and, less commonly, neurological complications and hyperviscosity. From the time of diagnosis, the survival without treatment is between 6 to 12 months and extends to 3 years with chemotherapy. Approximately 25% of patients survive 5 years or longer, with fewer than 5% surviving longer than 10 years. Approved anticancer agents for the treatment of myeloma in the US include melphalan (1992), carmustine (BCNU, 1977) and cyclophosphamide (1959) and in addition, in Europe, epirubicin is also approved for treatment of this disease. At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that varies on the basis of both disease- and host-related factors (e.g., age, renal function, stage, alpha2- microglobulin, chromosomal abnormalities).
    [Show full text]
  • Generated by Bortezomib Immune Mechanism of the Antitumor Effects
    The Journal of Immunology Immune Mechanism of the Antitumor Effects Generated by Bortezomib Chih-Long Chang,*,†,‡ Yun-Ting Hsu,† Chao-Chih Wu,† Yuh-Cheng Yang,* Connie Wang,x T.-C. Wu,x,{,‖,# and Chien-Fu Hungx,{ Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation.
    [Show full text]
  • Prescribing Information | VELCADE® (Bortezomib)
    HIGHLIGHTS OF PRESCRIBING INFORMATION Hypotension: Use caution when treating patients taking These highlights do not include all the information needed to antihypertensives, with a history of syncope, or with dehydration. use VELCADE safely and effectively. See full prescribing (5.2) information for VELCADE. Cardiac Toxicity: Worsening of and development of cardiac VELCADE® (bortezomib) for injection, for subcutaneous or failure has occurred. Closely monitor patients with existing heart intravenous use disease or risk factors for heart disease. (5.3) Initial U.S. Approval: 2003 Pulmonary Toxicity: Acute respiratory syndromes have ------------------------RECENT MAJOR CHANGES-------------------------- occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. (5.4) Warnings and Precautions, Posterior Reversible Encephalopathy Syndrome: Consider MRI Thrombotic Microangiopathy (5.10) 04/2019 imaging for onset of visual or neurological symptoms; ------------------------INDICATIONS AND USAGE-------------------------- discontinue VELCADE if suspected. (5.5) VELCADE is a proteasome inhibitor indicated for: Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and treatment of adult patients with multiple myeloma (1.1) vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (5.6) treatment of adult patients with mantle cell lymphoma (1.2) Thrombocytopenia and Neutropenia: Monitor complete blood ----------------------DOSAGE AND ADMINISTRATION---------------------
    [Show full text]
  • Recent Advances in the Management of Hormone Refractory Prostate Cancer
    Korean J Uro-Oncol 2004;2(3):147-153 Recent Advances in the Management of Hormone Refractory Prostate Cancer Mari Nakabayashi, William K. Oh Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA A typical treatment strategy after AAWD is to use secondary INTRODUCTION hormonal manipulations, although studies have not yet demonstrated a survival benefit with this class of treatment. Prostate cancer is the most common cancer in men in the Options in this category include (1) the secondary use of anti- United States and accounted for 29,900 deaths in 2003.1 androgens (e.g., high-dose bicalutamide, nilutamide), (2) thera- Although most men with advanced prostate cancer respond pies targeted against adrenal steroid synthesis (e.g., ketocona- initially to androgen deprivation therapies (ADT) by either zole, corticosteroids), and (3) estrogenic therapies (e.g. diethy- bilateral orchiectomy or leuteinizing hormone releasing hor- lstilbestrol). Symptomatic improvement and PSA responses mone (LHRH) analogues, patients eventually progress to an (defined as PSA decline ＞50% after treatment) have been androgen-independent state in which the initial ADT no longer reported in approximately 20% to 80% of patients with is adequate to control disease.2 Progression of the disease hormone-refractory prostate cancer (HRPC) with a typical manifests as an increase in serum prostate-specific antigen duration of response of 2 to 6 months. Toxicity is generally (PSA) or may be accompanied by radiographic evidence of mild for these oral therapies, although serious side effects, tumor growth. Here we report a brief summary of recent including adrenal insufficiency, liver toxicity, and thrombosis, advances in the management of hormone refractory prostate may occur (Table 1).
    [Show full text]
  • ORIGINAL ARTICLE Sequence-Dependent Synergy Of
    Leukemia (2007) 21, 524–528 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu ORIGINAL ARTICLE Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma O Weigert1,2,3, A Pastore1,2,3, M Rieken2, N Lang1, W Hiddemann1 and M Dreyling1,2 1Department of Internal Medicine III, University of Munich, University Hospital Grosshadern, Munich, Germany and 2GSF-National Research Center for Environment and Health, Haematologicum, Munich, Germany Single-agent bortezomib, a potent, selective and reversible consisted of CHOP (cyclophosphamide, vincristine, doxorubi- inhibitor of the 26S proteasome, has demonstrated clinical cin and prednisone),12 R-FCM (rituximab, fludarabine, cyclo- efficacy in relapsed and refractory mantle cell lymphoma (MCL). 13 Objective response is achieved in up to 45% of the patients; phosphamide, and mitoxantrone) and gemcitabine/oxaliplatin however, complete remission rates are low and duration of with all relapses occurring within 1 year. No response was seen 90 response proved to be short. These limitations may be after radioimmunotherapy with rituximab/ Y-ibritumomab– overcome by combining proteasome inhibition with conven- tiuxetan 5 months earlier. Salvage therapy was started with tional chemotherapy. Here we present two case reports and in single-agent bortezomib 1.3 mg/m2 given intravenously twice vitro data suggesting synergistic efficacy of bortezomib weekly for 2 consecutive weeks, followed by a 1-week rest combined with cytarabine in MCL. Interestingly, efficacy in vitro correlated with sequence of treatment, indicating that period. Because of progressive lymphadenopathy at week 5, pretreatment with cytarabine, followed by proteasome inhibi- treatment was changed to a combination regimen consisting 2 tion, may be the preferred approach.
    [Show full text]
  • Cancer Nanobiotechnolgy
    Acta Pharmacologica Sinica (2017) 38: 735–737 © 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps Editorial Cancer nanobiotechnolgy Yong-zhuo HUANG*, Ya-ping LI Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Acta Pharmacologica Sinica (2017) 38: 735–737; doi: 10.1038/aps.2017.48 Advanced drug delivery techniques have been applied in uptake. Zhang and Wu et al[4] developed a dual-targeting cancer therapy to improve treatment outcomes and reduce hybrid nanoparticles for codelivery of doxorubicin (DOX) and adverse effects, and already achieved promising progress. In mitomycin C (MMC). The polymer-lipid hybrid nanoparticles particular, nanobiotechnology plays an increased important were modified by the vα β3 integrin-binding RGD peptide, thus role in combating cancer. Nano drug delivery systems can achieving a from-tissue-to-cell dual targeting, because both the improve the pharmacokinetics profiles and tumor biodistribu- angiogenic tumor vascular endothelium and invasive breast [5] tion of the antitumor drugs and their intracellular delivery; in cancer cells overexpress αvβ3 integrin. Sun and Huang et al addition, the drug instability and water insolubility problems designed a from-cell-to-mitochondria dual-targeting delivery can be solved by encapsulation into the nano systems. system by using the G13-C12 peptide targeting galectin-3 that Ideal delivery of antitumor drugs should maximize drug is highly expressed on the PC-3 human prostate cancer cells accumulation at tumors while minimize the unwanted drug and then redistributes to the mitochondria. Kang and Huang exposure to normal tissues, thus executing cytotoxicity specifi- et al[6] used the mannose-mediated tumor targeting liposomes cally in cancer cells and sparing normal cells[1].
    [Show full text]