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In Vivo Evaluation of Ixabepilone (BMS247550), a Novel Epothilone B Derivative, Against Pediatric Cancer Models Jennifer K
Cancer Therapy: Preclinical In vivo Evaluation of Ixabepilone (BMS247550), A Novel Epothilone B Derivative, against Pediatric Cancer Models Jennifer K. Peterson,1Chandra Tucker,1Edward Favours,1PamelaJ. Cheshire,1Jeremy Creech,1 Catherine A. Billups,2 Richard Smykla,3 Francis Y.F. Lee,3 and Peter J. Houghton1 Abstract Purpose:Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types.The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models. Experimental Design: Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four),Wilms’ tumors (six), osteosarcoma (four), or brain tumors (seven).Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg). Results: At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved z50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms’ tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (z50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. -
First Genomic Insights Into Members of a Candidate Bacterial Phylum Responsible for Wastewater Bulking
First genomic insights into members of a candidate bacterial phylum responsible for wastewater bulking Yuji Sekiguchi1, Akiko Ohashi1, Donovan H. Parks2, Toshihiro Yamauchi3, Gene W. Tyson2,4 and Philip Hugenholtz2,5 1 Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan 2 Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia 3 Administrative Management Department, Kubota Kasui Corporation, Minato-ku, Tokyo, Japan 4 Advanced Water Management Centre, The University of Queensland, St. Lucia, Queensland, Australia 5 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia ABSTRACT Filamentous cells belonging to the candidate bacterial phylum KSB3 were previously identified as the causative agent of fatal filament overgrowth (bulking) in a high-rate industrial anaerobic wastewater treatment bioreactor. Here, we obtained near complete genomes from two KSB3 populations in the bioreactor, including the dominant bulking filament, using diVerential coverage binning of metagenomic data. Fluorescence in situ hybridization with 16S rRNA-targeted probes specific for the two populations confirmed that both are filamentous organisms. Genome-based metabolic reconstruction and microscopic observation of the KSB3 filaments in the presence of sugar gradients indicate that both filament types are Gram-negative, strictly anaerobic fermenters capable of -
Management of Brain and Leptomeningeal Metastases from Breast Cancer
International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. -
Use of Vacuum Therapy in Access Port Catheter Extravasation of Vesicant Cytotoxic Agents
Journal of Lung, Pulmonary & Respiratory Research Case Report Open Access Use of vacuum therapy in access port catheter extravasation of vesicant cytotoxic agents Abstract Volume 5 Issue 4 - 2018 Extravasation of vesicant cytotoxic is a severe complication of chemotherapy. Alejandro Gabriel Da Lozzo,1 Alberto Daniel Although access port catheters are used to reduce extravasation, rates up to 4.7% have Giménez Conca,2 Sung Ho Hyon,3 María been reported. Complications can be severe with tissue necrosis or even organ failure 2 and death. The principal cause is needle malpositioning. Treatment mostly includes Paula Cardenas 1 immediate explantation of the port and subcutaneous lavage. We report two cases: Thoracic Surgery, Hospital Italiano de Buenos Aires, Argentina 2Hematology, Hospital Italiano de Buenos Aires, Argentina one with conservative treatment with port explant and local wound care and another 3Minimally Invasive Surgery, Hospital Italiano de Buenos Aires, patient with aggressive treatment that included port explant, lavage and use of vacuum Argentina therapy to complete suction of any remnant vesicant cytotoxic. Alejandro Gabriel Da Lozzo, Thoracic Keywords: cytotoxic, extravasation, vacuum therapy, breast edema, surgical lavage Correspondence: Surgery, General Surgery Service, Hospital Italiano de Buenos Aires, Argentina, Tel +54 911 34375357, Email [email protected] Received: July 19, 2018 | Published: August 06, 2018 Introduction so nursing care protocols based in patient safety with early warning are encouraged, especially with high risk drug administration. The Access port catheters have been successfully employed in cancer principal cause of extravasation is needle malpositioning or secondary 1 therapy since first described in the 1980s. They provide a way to disconnection between the needle and the port.4 Cytotoxic drugs are administer drugs when peripheral venous access is not available classified based upon their potential for local toxicity (Table 1). -
Ixabepilone and Eribulin Mesylate: Two Novel Agents Approved for the Chemotherapeutic Treatment of Metastatic Breast Cancer
Review: Clinical Trial Outcomes Ixabepilone and eribulin mesylate: two novel agents approved for the chemotherapeutic treatment of metastatic breast cancer Clin. Invest. (2013) 3(4), 385–394 While the majority of breast cancer patients present with early stage Yael S Zack & Linda T Vahdat* disease, 40% of these patients will eventually progress to metastatic Division of Hematology and Oncology, disease. Resistance to existing chemotherapeutic agents continues to Department of Medicine, Weill Cornell Medical pose a challenge in the management of these patients. This review College, 425 East 61St, NY, 10065, USA will analyze the two most recently approved chemotherapy drugs for *Author for correspondence: Tel.: +1 212 821 0644 the treatment of breast cancer; ixabepilone and eribulin mesylate. Fax: +1 212 821 0758 Ixabepilone is a semisynthetic analog of epothilone B, and is thought to E-mail: [email protected] overcome taxane resistance via disruption to microtubule homeostasis. Two Phase III studies, one by Rugo et al. and the other by Thomas et al., showed improvement in progression-free survival with the combination of ixabepilone and capecitabine to approximately 6 months compared with 4.2 months in the capecitabine-alone group in both trials. These resulted in ixabepilone being approved for use alone or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer after failure of an anthracycline and a taxane in either the adjuvant or the metastatic setting. The drug has been shown to have activity even in heavily pretreated patients who have received at least two prior chemotherapy regimens for the treatments of metastatic disease. -
Patient Benefit and Risk in Anticancer Drug Development: a Systematic Review of the Ixabepilone Trial Portfolio
medRxiv preprint doi: https://doi.org/10.1101/19003467; this version posted August 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio Benjamin Carlislea, James Mattinaa, Tiger Zhenga, Jonathan Kimmelmana* aStudies of Translation, Ethics and Medicine (STREAM) Biomedical Ethics Unit McGill University 3647 Peel Street Montreal QC H3A 1X1 1 Corresponding author, Email: [email protected], Telephone: 514-398- 6980, Fax: 514-398-8349 NOTE: This preprint reports new research that has not been certified1 by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/19003467; this version posted August 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Abstract OBJECTIVE: To describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone—a drug that was approved in the US but not in Europe. DATA SOURCES: Trials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTION: Inclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. -
22065S006 Ixempra
Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) CLINICAL REVIEW Application Type Pediatric Exclusivity Determination Application Number(s) sNDA 22-065/S-006 Priority or Standard Priority Submit Date(s) 1/14/2011 Received Date(s) 1/18/2011 PDUFA Goal Date 7/14/2011 extended to 10/18/2011 Division / Office DDOP/OODP Reviewer Name(s) Amir Shahlaee, MD CDTL Ke Liu, MD, PhD Review Completion Date 9/9/2011 Established Name Ixabepilone (Proposed) Trade Name Ixempra® Therapeutic Class Microtubule inhibitor Applicant Bristol-Myers Squibb Formulation(s) Intravenous Injection Dosing Regimen Not applicable Indication(s) None Intended Population(s) None 1 Reference ID: 3020673 Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6 1.1 Recommendation on Regulatory Action ............................................................. 6 1.2 Risk Benefit Assessment.................................................................................... 6 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7 1.4 Recommendations for Postmarket Requirements and Commitments ................ 7 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8 2.1 Product Information ............................................................................................ 8 2.2 Tables of Currently Available Treatments for Proposed Indications .................. -
Natural Products. a History of Success and Continuing Promise for Drug Discovery and Development
Natural Products. A History of Success and Continuing Promise for Drug Discovery and Development Gordon M. Cragg NIH Special Volunteer [email protected] David J. Newman Natural Products Branch Developmental Therapeutics Program National Cancer Institute EARLY DOCUMENTATION OF USE OF MEDICINAL PLANTS http://www.nlm.nih.gov/hmd/collections/archives/index.html • Mesopotamian ~2,600 B. C. E. • Egyptian ~ 1,800 B. C. E. • Chinese – ~1,100 B. C. E. and continuing • Indian ~ 1,000 B. C. E. and continuing • Greek ~ 500 B. C. E. Greco-Roman expertise preserved and coordinated with other traditions by Islamic cultures during the Dark Ages ~ 400-1,100 CE Avicenna. Persian pharmacist, physician, poet, philosopher author: canon medicinae – “final codification of Greco-Roman medicine” Great Moments in Pharmacy Collection APhA Traditional Medicine and Drug Discovery • 80% of the world population resides in developing countries • 80% of people in developing countries utilize plants to meet their primary health care needs • Global pop. ca. 7 billion ca. 4.5 billion people utilize plants to meet their primary health care needs Farnsworth NR, et al. Medicinal Plants in Therapy. Bull. W.H.O. 63:965-981 (1985) Fabricant and Farnsworth, EnViron. Health Perspect. 109, 69-75 (2001) Cordell and Clovard, J. Nat. Prod., 75, 514-525 (2012) Norman Farnsworth 1800s. Discovery of some active principles of major herbal preparations Newman and Cragg. Natural Product Chemistry for Drug Discovery, eds. Buss and Butler, M. S., Royal Soc. Chem., Cambridge, 2010, pp. 3-27 European chemists (apothecaries) revolutionized drug discovery and development. 1817. Sertϋrner reports isolation of morphine from Papaver somniferum. -
Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of Neurooncology Magazine 2012; 2 (1) 25-36
Volume 2 (2012) // Issue 1 // e-ISSN 2224-3453 Neurology · Neurosurgery · Medical Oncology · Radiotherapy · Paediatric Neuro- oncology · Neuropathology · Neuroradiology · Neuroimaging · Nursing · Patient Issues Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of NeuroOncology Magazine 2012; 2 (1) 25-36 Homepage: www.kup.at/ journals/eano/index.html OnlineOnline DatabaseDatabase FeaturingFeaturing Author,Author, KeyKey WordWord andand Full-TextFull-Text SearchSearch THE EUROPEAN ASSOCIATION OF NEUROONCOLOGY Member of the Chemotherapy and Polyneuropathies Chemotherapy and Polyneuropathies Wolfgang Grisold1, Stefan Oberndorfer2, Anthony J Windebank3 Abstract: Peripheral neuropathies induced by taxanes) immediate effects can appear, caused to be caused by chemotherapy or other mecha- chemotherapy (CIPN) are an increasingly frequent by different mechanisms. The substances that nisms, whether treatment needs to be modified problem. Contrary to haematologic side effects, most frequently cause CIPN are vinca alkaloids, or stopped due to CIPN, and what symptomatic which can be treated with haematopoetic taxanes, platin derivates, bortezomib, and tha- treatment should be recommended. growth factors, neither prophylaxis nor specific lidomide. Little is known about synergistic neu- Possible new approaches for the management treatment is available, and only symptomatic rotoxicity caused by previously given chemo- of CIPN could be genetic susceptibility, as there treatment can be offered. therapies, or concomitant chemotherapies. The are some promising advances with vinca alka- CIPN are predominantly sensory, duration-of- role of pre-existent neuropathies on the develop- loids and taxanes. Eur Assoc Neurooncol Mag treatment-dependent neuropathies, which de- ment of a CIPN is generally assumed, but not 2012; 2 (1): 25–36. velop after a typical cumulative dose. Rarely mo- clear. -
Studies Towards Secondary Metabolite Formation in Myxobacteria: Elucidation of Biosynthetic Pathways and Yield Optimization
Studies towards secondary metabolite formation in Myxobacteria: Elucidation of biosynthetic pathways and yield optimization Dissertation zur Erlangung des Grades des Doktors der Naturwissenschaften der Naturwissenschaftlich-Technischen Fakultät III Chemie, Pharmazie, Bio- und Werkstoffwissenschaften der Universität des Saarlandes von Stefan Müller Saarbrücken 2015 Tag des Kolloquiums: 31.07.2015 Dekan: Prof. Dr. Dirk Bähre Berichterstatter: Prof. Dr. Rolf Müller Prof. Dr. Rolf W. Hartmann Vorsitz: Prof. Dr. Uli Kazmaier Akad. Mitarbeiter: Dr. Judith Becker Diese Arbeit entstand unter der Anleitung von Prof. Dr. Rolf Müller in der Fachrichtung 8.2 Pharmazeutische Biotechnologie der Naturwissenschaftlich-Technischen Fakultät III der Universität des Saarlandes in der Zeit von Mai 2011 bis April 2015. Veröffentlichungen der Dissertation Veröffentlichungen der Dissertation Teile dieser Arbeit wurden vorab mit Genehmigung der Naturwissenschaftlich-Technischen Fakultät III, vertreten durch den Mentor der Arbeit, in folgenden Beiträgen veröffentlicht: Müller S, Rachid S, Hoffmann T, Surup F, Volz C, Zaburannyi N, & Müller R (2014) Biosynthesis of crocacin involves an unusual hydrolytic release domain showing similarity to condensation domains. Chemistry & Biology, 21 (7), 855-865. Hoffmann T, Müller S, Nadmid S, Garcia R, & Müller R (2013) Microsclerodermins from terrestrial myxobacteria: An intriguing biosynthesis likely connected to a sponge symbiont. Journal of the American Chemical Society, 135 (45), 16904-16911. Darüber hinaus konnte zu einer weiteren Publikation, welche nicht Teil dieser Arbeit ist, beigetragen werden: Jahns C, Hoffmann T, Müller S, Gerth K, Washausen P, Höfle G, Reichenbach H, Kalesse M, & Müller R (2012) Pellasoren: Structure elucidation, biosynthesis, and total synthesis of a cytotoxic secondary metabolite from Sorangium cellulosum. Angewandte Chemie International Edition, 51 (21), 5239-5243. -
Figure Chemotherapy Sequencing Chart
6-Manchini_Cover 6/23/143:25PMPage20 2 0 l *Foll F i J First Chemotherapy Agent g o Y u o Vi Trastuzumab Topotecan Temsiro Streptozocin Rituximab Doxor D Pentostatin Pemetrexed Panitumumab Pac D Da Pac Oxa Mitoxantrone Mitomycin Methotrexate Mesna Cyclo D Dacarbazine Cytarabine C Mel Mechlorethamine Leucovorin C Ixabep Irinotecan Ifosfamide C Carboplatin Bl Bevacizumab Idar Gemcitabine Vinorelbine Vincristine Fluorourac Fl Etoposide Epir Be Y - u w SITE I isplatin etuximab armustine oxor ocetaxel actinomycin - r SAME u n e SITE COM n u e published guide published r THERAPEUTIC THERAPEUTIC d b o D p l l l N u d n u n i i i mycin arabine lastine U platin h taxel (Abraxane) taxel taxel b O amustine or b p u u a PLICATION alan icin i C icin N T T h b b l u D one l C os icin (Liposomal) icin icin l h b i R OMPATIBLE mus E o icin e U p i S l P h f G (5-FU) TED m A amide LI H TIBLE o N e t E h m e l i nes a r a t o p l y o S g Benda mustine Benda mustine e y q O u n Bevacizumab Bevacizumab e n c c o i l n o Bleo mycin Bleo mycin g g T1 y C ND ND ND ND ND , T h P Carbop latin C2 Carbop latin a h r a t r m Carmustine Carmustine R a c E y Cetuximab Cetuximab V G1 T1 P1 C1 I PD/T l N PD E , T T . -
Correlation Between Sorangium Cellulosum Subgroups and Their Potential for Secondary Metabolite Production
J. Microbiol. Biotechnol. (2013), 23(3), 297–303 http://dx.doi.org/10.4014/jmb.1210.10054 First published online January 22, 2013 pISSN 1017-7825 eISSN 1738-8872 Correlation Between Sorangium cellulosum Subgroups and Their Potential for Secondary Metabolite Production Lee, Chayul, Dongju An, Hanbit Lee, and Kyungyun Cho* Myxobacteria Bank, Department of Biotechnology, Hoseo University, Asan 336-795, Korea Received: October 18, 2012 / Revised: November 15, 2012 / Accepted: November 16, 2012 Phylogenetic analysis of the groEL1 and xynB1 gene worldwide [4]; approximately 1,000 of these strains have sequences from Sorangium cellulosum strains isolated in been isolated in Korea [5]. Secondary metabolites produced Korea previously revealed the existence of at least 5 by S. cellulosum were initially isolated from different subgroups (A-E). In the present study, we used sequence strains. However, the number of strains known to produce analysis of polymerase chain reaction-amplified biosynthetic identical metabolites has increased, as the isolated strains genes of strains from the 5 subgroups to indicate correlations have been characterized [7, 14]. The relationships between between S. cellulosum subgroups and their secondary strains producing the same metabolites remain to be metabolic gene categories. We detected putative biosynthetic elucidated. We previously reported that S. cellulosum genes for disorazol, epothilone, ambruticin, and soraphen strains isolated in Korea could be classified into 5 in group A, group C, group D, and group E strains, subgroups based on the DNA sequences of their groEL1 respectively. With the exception of KYC3204, culture and xynB1 genes, which code for heat-shock protein and extracts from group A, group B, and group C strains cellulase, respectively [15].