DOCSLIB.ORG

Topoisomerase II Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Topoisomerase II Inhibitors update on cancer therapeutics 3 (2008) 13–26 available at www.sciencedirect.com journal homepage: www.updateoncancer.com Topoisomerase II inhibitors Kenneth R. Hande ∗ 777 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232, United States article info abstract Keywords: Topoisomerase II is an enzyme essential for DNA replication, chromosome condensation Topoisomerase II and chromosome segregation. Inhibitors of topoisomerase II are important drugs used Chemotherapy in the therapy of many neoplasms including breast cancer, lung cancer, testicular can- Etoposide cer, lymphomas and sarcomas. This paper reviews the mechanism of action, toxicities, Anthracyclines pharmacology and clinical use of topoisomerase II inhibitors including etoposide, tenipo- Pharmacology side, doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone. New information Chemotherapy regarding these agents and on topoisomerase II inhibitors under development is highlighted. Published by Elsevier Ltd. 1. Introduction in DNA to modulate DNA topology [4]. After strand passage, the DNA backbone is religated and DNA structure restored. DNA topoisomerases are nuclear enzymes that make tran- Etoposide prevents topoisomerase II from religating cleaved sient strand breaks in DNA to allow a cell to manipulate its DNA [5]. Etoposide thus converts topoisomerase II into a poi- topology [1,2]. Topoisomerase I makes single-strand breaks. son that introduces high levels of transient protein-associated Topoisomerase II makes double-strand breaks and passes breaks in the genome of treated cells. double-stranded DNA through the nick to allow relaxation Topoisomerase II exists as two highly homologous iso- of over-coiled DNA [3]. Topoisomerases are highly conserved forms, alpha and beta, which differ in their production during enzymes essential for the survival of all eukaryotic organisms. the cell cycle. The alpha isoform concentration increases 2–3- There is little sequence homology between topoisomerase I fold during G2/M, and orders of magnitude is higher in rapidly and II (Table 1). Topoisomerases function in DNA replication, proliferating cells than in quiescent cell populations. The chromosome condensation, and chromosome segregation. alpha isoform appears to be the target of etoposide [6]. The Several currently approved chemotherapeutic drugs interfere beta enzyme does not change significantly during the cell with the action of topoisomerases. Currently available topoi- cycle and could potentially be a target in slow growing can- somerase I inhibitors are irinotecan (CPT-11) and topotecan. cers. Two scissile bonds are formed per every topoisomerase FDA-approved topoisomerase II inhibitors are etoposide, teni- II-mediated double-stranded DNA break. Results of DNA cleav- poside, doxorubicin, idarubicin, epirubicin, and mitoxantrone. age and ligation assay studies indicate a two-site model for This chapter will review critical concepts and update new the action of etoposide against human topoisomerase II alpha. information regarding topoisomerase II inhibitors. This model suggests that drug interactions at both scissile bonds are required in order to increase enzyme-mediated 2. Epipodophyllotoxins double-stranded DNA breaks [7]. There does not appear to be a single DNA binding site 2.1. Etoposide for etoposide-topoisomerase II targeted breaks. However, selected hot spots may be present for DNA binding (see 2.1.1. Mechanism of action sections on drug toxicity). The cell-signaling pathways that Topoisomerase II is a multi-subunit enzyme which uses ATP to lead to apoptosis following topoisomerase-induced DNA pass an intact helix through a transient double-stranded break damage are not completely understood. Current research ∗ Tel.: +1 615 322 4967; fax: +1 615 343 7602. E-mail address: [email protected]. 1872-115X/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.uct.2008.02.001 14 update on cancer therapeutics 3 (2008) 13–26 the anal canal have been associated with etoposide use Table1–DNAtopoisomerases [22]. Topoisomerase I Topoisomerase II Hypersensitivity reactions, including vasomotor changes 100 kDa 170 kDa; 180 kDa in the pulmonary and gastrointestinal systems, may also Makes single-strand Makes double-strand DNA occur following etoposide (or teniposide) use. These reactions DNA breaks breaks may result from the Tween 80 needed to solubilize etopo- ATP independent ATP dependent side. These reactions can usually be ameliorated with steroids, Genes located on Gene located on chromosomes histamine blockade, and/or using a slower infusion rate [23]. chromosome 20q12 17q21 and 3p24 Two types, alpha and beta Etoposide phosphate, a water-soluble pro-drug that is rapidly converted to etoposide by endogenous phosphatases [24],may reduce the risk of a hypersensitivity reaction since no solubi- is attempting to elucidate the mechanisms involved [8]. lizer is required. Etoposide phosphate has been safely used in Caspases are a group of cysteine proteases that orchestrate patients who have had a hypersensitivity reaction to etoposide apoptosis. Robertson et al. have identified caspase 2 as an [25]. Etoposide phosphate appears to have kinetics similar to important link between etoposide-induced DNA damage and etoposide, even in the transplant setting [26]. the engagement of the mitochondrial apoptotic pathway The most serious adverse event associated with etopo- [9]. Caspase 2 activates caspase 8 resulting in mitochondrial side is the development of acute myelogenous leukemia damage and subsequent downstream caspase 9 and 3 activa- [27,28]. On the basis of current clinical evidence, the World tion [10]. Caspase 3 appears critical for apoptosis-associated Health Organization has identified etoposide as carcinogenic chromatin margination, DNA fragmentation, and nuclear to humans [29]. Therapy-related acute myelogenous leukemia collapse. Cells lacking caspase 3 are resistant to etoposide also occurs with other topoisomerase II inhibitors [30,31]. Vari- [11]. Caspase 10 appears to trigger a feedback amplification ous studies have shown that topoisomerase II inhibitors target loop that amplifies caspases 9 and 3 [12]. Tumor necrosis selected binding sites at translocation breakpoints leading factor-related apoptosis inducing ligand (TRAIL) augments to MLL, AML1-ETO, PML-RARA and NUP98 rearrangements the expression of caspases induced by etoposide [13,14]. [32,33]. Etoposide-related leukemia develops relatively early Other cell-cycle control proteins are also important medi- after therapy (2–3 years). Most often (70% of cases), etoposide- ators in etoposide-induced apoptosis. P53, c-Myc and BAFF related leukemia is distinguished by a balanced translocation have been identified as pathways utilized to arrest cell cycle involving the mixed-lineage leukemia (MLL) gene on chromo- progression and induce apoptosis in certain cell lines exposed some 11. In vitro exposure of mouse embryonic stem cells to to etoposide [15]. Etoposide activates two pathways which etoposide results in MLL fusions [34]. The MLL gene is more lead to G2M arrest, one which depends on the presence of sensitive to topoisomerase II induced cleavage than other P53 while the other is P53 independent [16]. The presence genes such as RUNX1 and MLLT3 [35,36]. Lovett et al. has found of bcr-abl, which prolongs G2M arrest and allows for DNA that not only etoposide, but also its metabolites (etoposide repair mechanisms, decreases the cytotoxicity of etoposide. quinone and etoposide catechol) enhance DNA topoisomerase Cells with dysfunctional early G2/M checkpoint control (such II cleavage near the MLL translocation breakpoints [37]. MLL as ataxia-telangiectasia mutated deficient fibroblasts) have rearrangements occur through cleavage events in MLL and the increased chromosomal abnormalities following etoposide translocated gene in which both breaks become stable, DNA exposure [17]. ends are processed and then undergo ligation [38]. The double- Resistance to etoposide arises through multiple mecha- stranded DNA breaks in the MLL gene may not be directly nisms. Mutations at ser-1106 in the topoisomerase II molecule linked to topoisomerase II exposure. Hars et al. [39] suggest abrogate phosphorylation of the enzyme and reduce sensi- that the DNA breaks generated in the MLL locus are the result tivity to etoposide [18]. Rapid repair of DNA breaks caused of caspase activation of DNase by etoposide. MLL breakpoints by etoposide can also lead to drug resistance. Repair occurs can occur in stem cells found in cord blood and in fetal hepatic through the single-strand invasion pathway of homologous hematopoietic stem cells, potentially explaining the develop- recombination or by non-homologous DNA end-joining [19]. ment of infant leukemia resulting from in utero exposure to The repair of potentially lethal DNA damage by etoposide topoisomerase II inhibitors [40]. appears to be dependent on functioning FLT3 [20]. Resis- The incidence of secondary leukemia from etoposide use tance to etoposide is noted in cells that have the multidrug and the factors increasing the risk of leukemia have varied resistance (MDR) phenotype. By modifying the structure of from study to study. With rare exceptions, the risk for devel- etoposide to make it a prodrug, etoposide analogs have been opment of acute myeloid leukemia (AML) does not exceed 5% developed which are active, in vitro, against MDR resistant in patients treated for solid tumors, even with high cumula- tumors [21]. tive doses of topoisomerase
Load more

Recommended publications
  • Cyclophosphamide-Etoposide PO Ver
    Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE-ETOPOSIDE ORAL Regimen Lymphoma – Cyclophosphamide-Etoposide PO Indication Palliative treatment of malignant lymphoma Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrragic cystitis (rare), taste disturbances Etoposide Alopecia, hyperbilirubinaemia The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Patients diagnosed with Hodgkin’s Lymphoma carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as a diagnosis is made and the patient must be issued with an alert card to carry with them at all times. Monitoring Drugs FBC, LFTs and U&Es prior to day one of treatment Albumin prior to each cycle Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Version 1.1 (Jan 2015) Page 1 of 6 Lymphoma- Cyclophosphamide-Etoposide PO Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent.
    [Show full text]
  • CCNU-Dependent Potentiation of TRAIL/Apo2l-Induced Apoptosis in Human Glioma Cells Is P53-Independent but May Involve Enhanced Cytochrome C Release
    Oncogene (2001) 20, 4128 ± 4137 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release Till A RoÈ hn1, Bettina Wagenknecht1, Wilfried Roth1, Ulrike Naumann1, Erich Gulbins2, Peter H Krammer3, Henning Walczak4 and Michael Weller*,1 1Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of TuÈbingen, Medical School, TuÈbingen, Germany; 2Institute of Physiology, University of TuÈbingen, Medical School, TuÈbingen, Germany; 3Department of Immunogenetics, German Cancer Research Center, Heidelberg, Germany; 4Department of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany Death ligands such as CD95 ligand (CD95L) or tumor apy may be an eective therapeutic strategy for these necrosis factor-related apoptosis-inducing ligand/Apo2 lethal neoplasms. Oncogene (2001) 20, 4128 ± 4137. ligand (TRAIL/Apo2L) induce apoptosis in radio- chemotherapy-resistant human malignant glioma cell Keywords: brain; apoptosis; neuroimmunology; cyto- lines. The death-signaling TRAIL receptors 2 kines; immunotherapy (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/ DR4 were expressed more abundantly than the non- death-inducing (decoy) receptors TRAIL-R3/DcR1 and Introduction TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the Death receptor targeting is an attractive approach of absence of a protein synthesis inhibitor, cycloheximide experimental treatment for solid tumors that are (CHX). Three of the 12 cell lines were still TRAIL/ resistant to radiotherapy and chemotherapy, including Apo2L-resistant in the presence of CHX.
    [Show full text]
  • And Cisplatin-Resistant Ovarian Cancer
    Vol. 2, 607–610, July 2003 Molecular Cancer Therapeutics 607 Alchemix: A Novel Alkylating Anthraquinone with Potent Activity against Anthracycline- and Cisplatin-resistant Ovarian Cancer Klaus Pors, Zennia Paniwnyk, mediated stabilization of the topo II-DNA-cleavable complex Paul Teesdale-Spittle,1 Jane A. Plumb, and resulting in inhibition of poststrand passage DNA religa- Elaine Willmore, Caroline A. Austin, and tion (1). This event is not lethal per se but initiates a cascade 2 Laurence H. Patterson of events leading to cell death (2). Anthraquinones, as ex- Department of Pharmaceutical and Biological Chemistry, The School of emplified by mitoxantrone, are topo II inhibitors with proven Pharmacy, University of London, London WC1N 1AX, United Kingdom [K. P., L. H. P.]; Department of Pharmacy, De Montfort University, success for the treatment of advanced breast cancer, non- Leicester LE1 9BH, United Kingdom [Z. P., P. T. S.]; Cancer Research Hodgkin’s lymphoma, and acute leukemia (3). Intercalation is UK Department of Medical Oncology, University of Glasgow, Glasgow a crucial part of topo II inhibition by cytotoxic anthraquinones G61 1BD, United Kingdom [J. A. P.]; and School of Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, with high affinity for DNA (4). It is likely that the potent Newcastle upon Tyne NE2 4HH, United Kingdom [E. W., C. A. A.] cytotoxicity of anthraquinones is related to their slow rate of dissociation from DNA, the kinetics of which favors long- term trapping of the topo-DNA complexes (5). However, Abstract currently available DNA intercalators at best promote a tran- Chloroethylaminoanthraquinones are described with sient inhibition of topo II, because the topo-drug-DNA ter- intercalating and alkylating capacity that potentially nary complex is reversed by removal of the intracellular drug covalently cross-link topoisomerase II (topo II) to DNA.
    [Show full text]
  • ACNU-Based Chemotherapy for Recurrent Glioma in the Temozolomide Era
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2009 ACNU-based chemotherapy for recurrent glioma in the temozolomide era Happold, C Abstract: No standard of care for patients with recurrent glioblastoma has been defined since temo- zolomide has become the treatment of choice for patients with newly diagnosed glioblastoma. This has renewed interest in the use of nitrosourea-based regimens for patients with progressive or recurrent dis- ease. The most commonly used regimens are carmustine (BCNU) monotherapy or lomustine (CCNU) combined with procarbazine and vincristine (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n = 14) or in combination with other agents (n = 18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide. DOI: https://doi.org/10.1007/s11060-008-9728-9 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-10588 Journal Article Originally published at: Happold, C (2009).
    [Show full text]
  • BC Cancer Protocol Summary for Treatment of Lymphoma with Dose- Adjusted Etoposide, Doxorubicin, Vincristine, Cyclophosphamide
    BC Cancer Protocol Summary for Treatment of Lymphoma with Dose- Adjusted Etoposide, DOXOrubicin, vinCRIStine, Cyclophosphamide, predniSONE and riTUXimab with Intrathecal Methotrexate Protocol Code LYEPOCHR Tumour Group Lymphoma Contact Physician Dr. Laurie Sehn Dr. Kerry Savage ELIGIBILITY: One of the following lymphomas: . Patients with an aggressive B-cell lymphoma and the presence of a dual translocation of MYC and BCL2 (i.e., double-hit lymphoma). Histologies may include DLBCL, transformed lymphoma, unclassifiable lymphoma, and intermediate grade lymphoma, not otherwise specified (NOS). Patients with Burkitt lymphoma, who are not candidates for CODOXM/IVACR (such as those over the age of 65 years, or with significant co-morbidities) . Primary mediastinal B-cell lymphoma Ensure patient has central line EXCLUSIONS: . Cardiac dysfunction that would preclude the use of an anthracycline. TESTS: . Baseline (required before first treatment): CBC and diff, platelets, BUN, creatinine, bilirubin. ALT, LDH, uric acid . Baseline (required, but results do not have to be available to proceed with first treatment): results must be checked before proceeding with cycle 2): HBsAg, HBcoreAb, . Baseline (optional, results do not have to be available to proceed with first treatment): HCAb, HIV . Day 1 of each cycle: CBC and diff, platelets, (and serum bilirubin if elevated at baseline; serum bilirubin does not need to be requested before each treatment, after it has returned to normal), urinalysis for microscopic hematuria (optional) . Days 2 and 5 of each cycle (or days of intrathecal treatment): CBC and diff, platelets, PTT, INR . For patients on cyclophosphamide doses greater than 2000 mg: Daily urine dipstick for blood starting on day cyclophosphamide is given.
    [Show full text]
  • Arsenic Trioxide Is Highly Cytotoxic to Small Cell Lung Carcinoma Cells
    160 Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells 1 1 Helen M. Pettersson, Alexander Pietras, effect of As2O3 on SCLC growth, as suggested by an Matilda Munksgaard Persson,1 Jenny Karlsson,1 increase in neuroendocrine markers in cultured cells. [Mol Leif Johansson,2 Maria C. Shoshan,3 Cancer Ther 2009;8(1):160–70] and Sven Pa˚hlman1 1Center for Molecular Pathology, CREATE Health and 2Division of Introduction Pathology, Department of Laboratory Medicine, Lund University, 3 Lung cancer is the most frequent cause of cancer deaths University Hospital MAS, Malmo¨, Sweden; and Department of f Oncology-Pathology, Cancer Center Karolinska, Karolinska worldwide and results in 1 million deaths each year (1). Institute and Hospital, Stockholm, Sweden Despite novel treatment strategies, the 5-year survival rate of lung cancer patients is only f15%. Small cell lung carcinoma (SCLC) accounts for 15% to 20% of all lung Abstract cancers diagnosed and is a very aggressive malignancy Small cell lung carcinoma (SCLC) is an extremely with early metastatic spread (2). Despite an initially high aggressive form of cancer and current treatment protocols rate of response to chemotherapy, which currently com- are insufficient. SCLC have neuroendocrine characteristics bines a platinum-based drug with another cytotoxic drug and show phenotypical similarities to the childhood tumor (3, 4), relapses occur in the absolute majority of SCLC neuroblastoma. As multidrug-resistant neuroblastoma patients. At relapse, the efficacy of further chemotherapy is cells are highly sensitive to arsenic trioxide (As2O3) poor and the need for alternative treatments is obvious. in vitro and in vivo, we here studied the cytotoxic effects Arsenic-containing compounds have been used in tradi- of As2O3 on SCLC cells.
    [Show full text]
  • Arsenic Trioxide Potentiates the Effectiveness of Etoposide in Ewing Sarcomas
    INTERNATIONAL JOURNAL OF ONCOLOGY 49: 2135-2146, 2016 Arsenic trioxide potentiates the effectiveness of etoposide in Ewing sarcomas KAREN A. BOEHME1*, JULIANE NITSCH1*, ROSA RIESTER1, RUPert HANDGRETINGER2, SABINE B. SCHLEICHER2, TORSTEN KLUBA3,4 and FRANK TRAUB1,3 1Laboratory of Cell Biology, Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen; 2Department of Haematology and Oncology, Children's Hospital, Eberhard Karls University Tuebingen; 3Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, Tuebingen; 4Department for Orthopaedic Surgery, Hospital Dresden-Friedrichstadt, Dresden, Germany Received June 12, 2016; Accepted July 28, 2016 DOI: 10.3892/ijo.2016.3700 Abstract. Ewing sarcomas (ES) are rare mesenchymal tumours, the drug concentrations used. With the exception of ATO in most commonly diagnosed in children and adolescents. Arsenic RD-ES cells, all drugs induced apoptosis in the ES cell lines, trioxide (ATO) has been shown to efficiently and selectively indicated by caspase-3 and PARP cleavage. Combination of target leukaemic blasts as well as solid tumour cells. Since the agents potentiated the reduction of viability as well as the multidrug resistance often occurs in recurrent and metastatic inhibitory effect on clonal growth. In addition, cell death induc- ES, we tested potential additive effects of ATO in combina- tion was obviously enhanced in RD-ES and SK-N-MC cells tion with the cytostatic drugs etoposide and doxorubicin. The by a combination of ATO and etoposide compared to single Ewing sarcoma cell lines A673, RD-ES and SK-N-MC as well application. Summarised, the combination of low dose, physi- as mesenchymal stem cells (MSC) for control were treated ologically easily tolerable ATO with commonly used etoposide with ATO, etoposide and doxorubicin in single and combined and doxorubicin concentrations efficiently and selectively application.
    [Show full text]
  • 5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells
    Article Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells Maria Pereira-Oliveira, Ana Reis-Mendes, Félix Carvalho, Fernando Remião, Maria de Lourdes Bastos and Vera Marisa Costa * UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; [email protected] (M.P.-O.); [email protected] (A.R.-M.); [email protected] (F.C.); [email protected] (F.R.); [email protected] (M.L.B.) * Correspondence: [email protected] Received: 4 October 2018; Accepted: 3 January 2019; Published: 10 January 2019 Abstract: Currently, a common therapeutic approach in cancer treatment encompasses a drug combination to attain an overall better efficacy. Unfortunately, it leads to a higher incidence of severe side effects, namely cardiotoxicity. This work aimed to assess the cytotoxicity of doxorubicin (DOX, also known as Adriamycin), 5-fluorouracil (5-FU), cyclophosphamide (CYA), and their combination (5-Fluorouracil + Adriamycin + Cyclophosphamide, FAC) in H9c2 cardiac cells, for a better understanding of the contribution of each drug to FAC-induced cardiotoxicity. Differentiated H9c2 cells were exposed to pharmacological relevant concentrations of DOX (0.13–5 μM), 5-FU (0.13–5 μM), CYA (0.13–5 μM) for 24 or 48 h. Cells were also exposed to FAC mixtures (0.2, 1 or 5 μM of each drug and 50 μM 5-FU + 1 μM DOX + 50 μM CYA). DOX was the most cytotoxic drug, followed by 5-FU and lastly CYA in both cytotoxicity assays (reduction of 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide (MTT) and neutral red (NR) uptake).
    [Show full text]
  • Repositioning Fda-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome
    Author Manuscript Published OnlineFirst on December 15, 2016; DOI: 10.1158/1535-7163.MCT-16-0588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. REPOSITIONING FDA-APPROVED DRUGS IN COMBINATION WITH EPIGENETIC DRUGS TO REPROGRAM COLON CANCER EPIGENOME Noël J.-M. Raynal1,2, Elodie M. Da Costa2, Justin T. Lee1, Vazganush Gharibyan3, Saira Ahmed3, Hanghang Zhang1,Takahiro Sato1, Gabriel G. Malouf4, and Jean-Pierre J. Issa1 1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA, 19140, USA. 2Département de pharmacologie, Université de Montréal and Sainte-Justine University Hospital Research Center, 3175, Chemin de la Côte-Sainte- Catherine, Montréal (Québec) H3T 1C5, Canada. 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. 4Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de cancérologie, AP-HP, Paris, France. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Corresponding Author: Noël J.-M. Raynal, Département de Pharmacologie, Université de Montréal , Centre de recherche de l’Hôpital Sainte-Justine, 3175, Chemin de la Côte-Sainte-Catherine, Montréal (Québec), H3T 1C5, Canada. Phone : (514) 345-4931 ext. 6763. Email : [email protected] Running title: High-throughput screening for epigenetic drug combinations Key words: Drug repurposing, Drug combination, High-throughput drug screening, Epigenetic therapy The authors declare no potential conflicts of interest. 1 Downloaded from mct.aacrjournals.org on September 23, 2021.
    [Show full text]
  • Cardioprotective Effects of Exercise Training on Doxorubicin-Induced
    www.nature.com/scientificreports OPEN Cardioprotective efects of exercise training on doxorubicin‑induced cardiomyopathy: a systematic review with meta‑analysis of preclinical studies Paola Victória da Costa Ghignatti, Laura Jesuíno Nogueira, Alexandre Machado Lehnen & Natalia Motta Leguisamo* Doxorubicin (DOX)‑induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective efects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta‑analysis of preclinical studies for to assess the efcacy of exercise training on DOX‑induced cardiomyopathy. We included studies with animal models of DOX‑induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean diference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX‑treated animals. Trained DOX‑treated animals improved 7.40% (95% CI 5.75–9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior efect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27–10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior efect size in FS (MD = 7.89, 95% CI 6.11–9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX‑induced cardiomyopathy. Exercise prior to DOX exposure exerts greater efect sizes on FS preservation.
    [Show full text]
  • Fotemustine, Teniposide and Dexamethasone Versus High-Dose Methotrexate Plus Cytarabine in Newly Diagnosed Primary CNS Lymphoma: a Randomised Phase 2 Trial
    Journal of Neuro-Oncology https://doi.org/10.1007/s11060-018-2970-x CLINICAL STUDY Fotemustine, teniposide and dexamethasone versus high-dose methotrexate plus cytarabine in newly diagnosed primary CNS lymphoma: a randomised phase 2 trial Jingjing Wu1 · Lingling Duan1 · Lei Zhang1 · Zhenchang Sun1 · Xiaorui Fu1 · Xin Li1 · Ling Li1 · Xinhua Wang1 · Xudong Zhang1 · Zhaoming Li1 · Hui Yu1 · Yu Chang1 · Feifei Nan1 · Jiaqin Yan1 · Li Tian1 · Xiaoli Wang1 · Mingzhi Zhang1 Received: 25 March 2018 / Accepted: 5 August 2018 © The Author(s) 2018 Abstract Objective This prospective, randomized, controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen (fotemustine, teniposide and dexamethasone) compared to HD-MA therapy (high-dose metho- trexate plus cytarabine) and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma. Methods Participants were stratified by IELSG risk score (low versus intermediate versus high) and randomly assigned (1:1) to receive four cycles of FTD or HD-MA regimen. Both regimens were administered every 3 weeks and were followed by whole-brain radiotherapy. The primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Between June 2012, and June 2015, 52 patients were enrolled, of whom 49 patients were randomly assigned and analyzed. Of the 49 eligible patients, no significant difference was observed in terms of ORR between FTD (n = 24) and HD-MA (n = 25) groups (88% versus 84%, respectively, P = 0.628). Neither the 2-year PFS nor the 3-year OS rate differed significantly between FTD and HD-MA groups (37% versus 39% for 2-year PFS, P = 0.984; 51% versus 46% for 3-year OS, P = 0.509; respectively).
    [Show full text]
  • The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin As a Biomimetic Carrier for the Drug
    biomolecules Article The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug Marta Rubio-Camacho, José A. Encinar , María José Martínez-Tomé, Rocío Esquembre * and C. Reyes Mateo * Instituto e investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (UMH), E-03202 Elche, Spain; [email protected] (M.R.-C.); [email protected] (J.A.E.); [email protected] (M.J.M.-T.) * Correspondence: [email protected] (R.E.); [email protected] (C.R.M.); Tel.: +34-966-652-475 (R.E.); +34-966-658-469 (C.R.M.) Received: 18 June 2020; Accepted: 8 July 2020; Published: 9 July 2020 Abstract: The interaction of temozolomide (TMZ) (the main chemotherapeutic agent for brain tumors) with blood components has not been studied at the molecular level to date, even though such information is essential in the design of dosage forms for optimal therapy. This work explores the binding of TMZ to human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), as well as to blood cell-mimicking membrane systems. Absorption and fluorescence experiments with model membranes indicate that TMZ does not penetrate into the lipid bilayer, but binds to the membrane surface with very low affinity. Fluorescence experiments performed with the plasma proteins suggest that in human plasma, most of the bound TMZ is attached to HSA rather than to AGP. This interaction is moderate and likely mediated by hydrogen-bonding and hydrophobic forces, which increase the hydrolytic stability of the drug.
    [Show full text]