DOCSLIB.ORG

The Activity of Trabectedin As a Single Agent Or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Activity of Trabectedin As a Single Agent Or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary Published OnlineFirst May 27, 2011; DOI: 10.1158/1078-0432.CCR-10-2987 Clinical Cancer Cancer Therapy: Preclinical Research The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary Seiji Mabuchi1, Takeshi Hisamatsu1, Chiaki Kawase1, Masami Hayashi1, Kenjiro Sawada1, Kazuya Mimura1, Kazuhiro Takahashi2, Toshifumi Takahashi2, Hirohisa Kurachi2, and Tadashi Kimura1 Abstract Purpose: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. Experimental Design: Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel- resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. Results: Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. Conclusion: Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC. Clin Cancer Res; 17(13); 4461–72. Ó2011 AACR. Introduction 2–5). The lack of effective chemotherapy for recurrent CCC after frontline treatment is another important problem in Ovarian carcinoma is the fourth most common cause of the clinical management of CCC. Therefore, to improve the cancer death among women in the United States, with survival of patients with CCC, the development of novel more than 21,880 new cases diagnosed and 13,850 deaths treatment strategies in the setting of both first-line treat- estimated to have occurred in 2010 (1). ment and salvage treatment of recurrent disease are needed. Clear cell carcinoma (CCC) of the ovary has been known Trabectedin, which was formerly known as ecteinasci- to show poorer sensitivity to platinum-based frontline din-743 (ET-743), is an antineoplastic agent that was chemotherapy and to be associated with a worse prognosis originally derived from the Caribbean marine tunicate than the more common serous adenocarcinoma (SAC; refs. Ecteinascidia turbinate. It binds covalently to the minor groove of DNA, bending DNA toward the major groove and disrupting transcription, leading to G2–M cell-cycle Authors' Affiliations: 1Department of Obstetrics and Gynecology, Osaka arrest and ultimately apoptosis (6). Although the exact University Graduate School of Medicine, Osaka; and 2Department of mechanism of its action is not clear, it is thought that Obstetrics and Gynecology, Yamagata University, School of Medicine, the cytotoxic activity of trabectedin is based on the inhibi- Yamagata, Japan tion of transcription-dependent nucleotide-excision repair Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). (NER) via the trapping of the proteins responsible for NER, which induces cells to undergo apoptosis (7). S. Mabuchi and T. Hisamatsu contributed equally to this work. In a preclinical study, trabectedin showed significant Corresponding Author: Seiji Mabuchi, Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yama- antitumor activity in vitro and in vivo against a range of daoka, Suita, Osaka 565-0871, Japan. Phone: 81-668-793-354; Fax: 81- solid tumor cells, including soft-tissue sarcoma (STS), 668-793-359; E-mail: [email protected] ovarian, breast, prostate, and renal cancers; melanoma; doi: 10.1158/1078-0432.CCR-10-2987 and non–small-cell lung cancer (8–11). On the basis Ó2011 American Association for Cancer Research. of the promising results of preclinical and clinical studies www.aacrjournals.org 4461 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst May 27, 2011; DOI: 10.1158/1078-0432.CCR-10-2987 Mabuchi et al. Translational Relevance everolimus has been approved for the treatment of renal cell carcinoma (19). In preclinical investigations, everoli- Clear cell carcinoma (CCC) of the ovary is a distinc- mus has been shown to inhibit the proliferation of ovarian tive subtype of epithelial ovarian cancer associated with cancer cells and enhance their sensitivity to cisplatin both a poorer sensitivity to platinum-based chemotherapy in vitro and in vivo (20–22), and its efficacy in ovarian and worse prognosis than the more common serous cancer patients is currently being evaluated in several phase adenocarcinoma. To improve survival, the identifica- I/II trials (23). However, no reports have addressed the role tion of a novel anticancer agent that more effectively of mTOR in the acquisition of resistance to trabectedin. targets CCC is necessary. Our results show that treat- In the current investigation, we evaluated the therapeutic ment with trabectedin significantly inhibited the growth efficacy of trabectedin as a single agent in vitro and in vivo. of CCC in vitro and in vivo. The growth-inhibitory effect We also examined the antitumor activity of trabectedin in of trabectedin on CCC cells was greater than those of both cisplatin-resistant and paclitaxel-resistant CCC cells. cisplatin, paclitaxel, and SN-38, which are clinically Finally, we investigated the role of AKT–mTOR signaling in employed as a part of the first-line chemotherapy for the mechanism of acquired resistance to trabectedin and this disease. This finding may be relevant for the plan- assessed the therapeutic potential of trabectedin in combi- ning of future clinical studies of first-line treatments of nation with everolimus in CCC cells. CCC of the ovary. Moreover, the significant antitumor activity of trabectedin against cisplatin- and paclitaxel- Materials and Methods resistant CCC shown in the current study may represent a novel treatment option for patients with recurrent Reagents/antibodies disease after first-line chemotherapy. Trabectedin was obtained from PharmaMar. Everolimus was obtained from Novartis Pharma AG. Cisplatin, pacli- taxel, and 7-ethyl-10-hydroxycamptothecin (SN-38) were purchased from Sigma. LY294002 was purchased from Cell (10, 12, 13), trabectedin is now approved in Europe for the Signal Technology. Enhanced chemiluminescence (ECL) treatment of STS after anthracycline and ifosfamide failure Western blotting detection reagents were from Perkin and for treating patients who cannot receive these agents Elmer. Antibodies recognizing p70S6K, phospho-p70S6K (14). (Thr389), mTOR, phospho-mTOR (Ser2448), AKT, phos- In ovarian cancer, trabectedin has been studied in several pho-AKT (Ser473), and b-actin were obtained from Cell phase I and II clinical trials, showing a favorable toxicity Signaling Technology. The Cell Titer 96-well proliferation profile and promising activity in recurrent ovarian cancer assay kit was obtained from Promega. patients (15, 16). Following the encouraging results of these studies, a phase III trial investigating the activity of Drug preparation trabectedin plus liposomal doxorubicin versus liposomal Trabectedin was prepared as a 1 mg/mL stock solution doxorubicin in patients with recurrent ovarian cancer has in ethanol. Everolimus was diluted to the appropriate recently been conducted. As this study showed a survival concentration in double-distilled water just before its benefit of trabectedin-based combination chemotherapy, administration by gavage in the animal studies. For the trabectedin has become the focus of attention for research- in vitro analyses, everolimus was prepared in dimethyl ers investigating the treatment of epithelial ovarian cancer sulfoxide (DMSO) before being added to the cell cultures (17). as described previously (20–22). Cisplatin was dissolved As most ovarian cancer cell lines investigated in pre- in sterilized double-distilled water to a final concentra- vious preclinical studies of trabectedin have been from tion of 1 mmol/L. SN-38 and paclitaxel were dissolved in ovarianSAC(6,8,9)andonlyasmallnumberof DMSO to final concentrations of 10 and 100 mmol/L, patients with CCC histology were included in the pre- respectively. vious clinical studies (15–17), the therapeutic potential of trabectedin in patients with CCC is unknown. Because Cell culture of its nature as a newly developed anticancer agent, the The human ovarian CCC cell lines RMG1, RMG2, and mechanism of resistance to trabectedin is largely HAC2 were kindly provided by Dr. H. Itamochi (Tottori unknown. To further improve the prognosis
Load more

Recommended publications
  • MASCC/ESMO ANTIEMETIC GUIDELINE 2016 with Updates in 2019
    1 ANTIEMETIC GUIDELINES: MASCC/ESMO MASCC/ESMO ANTIEMETIC GUIDELINE 2016 With Updates in 2019 Organizing and Overall Meeting Chairs: Matti Aapro, MD Richard J. Gralla, MD Jørn Herrstedt, MD, DMSci Alex Molassiotis, RN, PhD Fausto Roila, MD © Multinational Association of Supportive Care in CancerTM All rights reserved worldwide. 2 ANTIEMETIC GUIDELINES: MASCC/ESMO These slides are provided to all by the Multinational Association of Supportive Care in Cancer and can be used freely, provided no changes are made and the MASCC and ESMO logos, as well as date of the information are retained. For questions please contact: Matti Aapro at [email protected] Chair, MASCC Antiemetic Study Group or Alex Molassiotis at [email protected] Past Chair, MASCC Antiemetic Study Group 3 ANTIEMETIC GUIDELINES: MASCC/ESMO Consensus A few comments on this guideline set: • This set of guideline slides represents the latest edition of the guideline process. • This set of slides has been endorsed by the MASCC Antiemetic Guideline Committee and ESMO Guideline Committee. • The guidelines are based on the votes of the panel at the Copenhagen Consensus Conference on Antiemetic Therapy, June 2015. • Latest version: March 2016, with updates in 2019. 4 ANTIEMETIC GUIDELINES: MASCC/ESMO Changes: The Steering Committee has clarified some points: 2016: • A footnote clarified that aprepitant 165 mg is approved by regulatory authorities in some parts of the world ( although no randomised clinical trial has investigated this dose ). Thus use of aprepitant 80 mg in the delayed phase is only for those cases where aprepitant 125 mg is used on day 1. • A probable modification in pediatric guidelines based on the recent Cochrane meta-analysis is indicated.
    [Show full text]
  • Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights
    cancers Article Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights 1, 1, 1 Adrián Povo-Retana y, Marina Mojena y, Adrian B. Stremtan , Victoria B. Fernández-García 1, Ana Gómez-Sáez 1, Cristina Nuevo-Tapioles 2,3 , José M. Molina-Guijarro 4 , José Avendaño-Ortiz 5, José M. Cuezva 2,3 , Eduardo López-Collazo 5, Juan F. Martínez-Leal 4 and Lisardo Boscá 1,5,6,* 1 Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; [email protected] (A.P.-R.); [email protected] (M.M.); [email protected] (A.B.S.); [email protected] (V.B.F.-G.); [email protected] (A.G.-S.) 2 Centro de Biología Molecular (Centro Mixto CSIC-UAM), Nicolás Cabrera S/N, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain; [email protected] (C.N.-T.); [email protected] (J.M.C.) 3 Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain 4 Pharma Mar SA, 28770 Colmenar Viejo, Spain; [email protected] (J.M.M.-G.); [email protected] (J.F.M.-L.) 5 Instituto de Investigación Sanitaria La Paz (IdiPaz), Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (J.A.-O.); [email protected] (E.L.-C.) 6 Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-9149-72747 These authors have equal contribution. y Received: 28 August 2020; Accepted: 16 October 2020; Published: 20 October 2020 Simple Summary: Trabectedin and lurbinectedin are two potent onco-therapeutic drugs for the treatment of advanced soft tissue sarcomas.
    [Show full text]
  • To Induce Cytotoxicity of Ovarian Cancer Cells Through Increased Autophagy and Apoptosis
    Endocrine-Related Cancer (2012) 19 711–723 Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis Nan Liu1,2, Sheng Tai2,4, Boxiao Ding2, Ryan K Thor2, Sunita Bhuta2, Yin Sun2 and Jiaoti Huang2,3 1Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, Guangdong 510515, People’s Republic of China 2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles, 10833 Le Conte Avenue, 13-229 CHS, Los Angeles, California 90095-1732, USA 3Jonsson Comprehensive Cancer Center and Broad Center for Regenerative Medicine and Stem Cell Biology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, USA 4Department of Urology and Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China (Correspondence should be addressed to N Liu at Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University; Email: [email protected]; J Huang at Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles; Email: [email protected]) Abstract Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway plays a key role in the tumorigenesis of a variety of human cancers including ovarian cancer. However, inhibitors of this pathway such as Rad001 have not shown therapeutic efficacy as a single agent for this cancer. Arsenic trioxide (ATO) induces an autophagic pathway in ovarian carcinoma cells. We found that ATO can synergize with Rad001 to induce cytotoxicity of ovarian cancer cells.
    [Show full text]
  • Thames Valley Chemotherapy Regimens Sarcoma
    Thames Valley Thames Valley Chemotherapy Regimens Sarcoma Chemotherapy Regimens– Sarcoma 1 of 98 Thames Valley Notes from the editor All chemotherapy regimens, and associated guidelines eg antiemetics and dose bands are available on the Network website www.tvscn.nhs.uk/networks/cancer-topics/chemotherapy/ Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] Acknowledgements These regimens have been compiled by the Network Pharmacy Group in collaboration with key contribution from Prof Bass Hassan, Medical Oncologist, OUH Dr Sally Trent, Clinical Oncologist, OUH Dr James Gildersleve, Clinical Oncologist, RBFT Dr Sarah Pratap, Medical Oncologist, OUH Dr Shaun Wilson, TYA - Paediatric Oncologist, OUH Catherine Chaytor, Cancer Pharmacist, OUH Varsha Ormerod, Cancer Pharmacist, OUH Kristen Moorhouse, Cancer Pharmacist, OUH © Thames Valley Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner. Chemotherapy Regimens– Sarcoma 2 of 98 Thames Valley Thames Valley Chemotherapy Regimens Sarcoma Network Chemotherapy Regimens used in the management of Sarcoma Date published: January 2019 Date of review: June 2022 Chemotherapy Regimens Name of regimen Indication Page List of amendments to this version 5 Imatinib GIST 6 Sunitinib GIST 9 Regorafenib GIST 11 Paclitaxel weekly (Taxol) Angiosarcoma 13 AC Osteosarcoma 15 Cisplatin Imatinib – if local Trust funding agreed Chordoma 18 Doxorubicin Sarcoma 21
    [Show full text]
  • Topotecan, Pegylated Liposomal Doxorubicin Hydrochloride, Paclitaxel, Trabectedin and Gemcitabine for Treating Recurrent Ovarian Cancer
    Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer Information for the public Published: TBC nice.org.uk What has NICE said? For recurrent ovarian cancer, the following possible treatments are recommended: paclitaxel (also known as Taxol) on its own or with platinum pegylated liposomal doxorubicin hydrochloride (PLDH, also known as Caelyx) on its own or with platinum. For ovarian cancer that has recurred for the first time and is platinum-sensitive, Nice does not recommend gemcitabine (Gemzar) with carboplatin (Paraplatin), trabectedin (Yondelis) with PLDH, or topotecan (Hycamtin or Potactasol). Topotecan is also not recommended for treating recurrent ovarian cancer that is platinum-resistant or platinum-refractory. What does this mean for me? If you have recurrent ovarian cancer and your doctor thinks that paclitaxel on its own or with platinum, or pegylated liposomal doxorubicin hydrochloride (PLDH) on its own, is the right treatment, you should be able to have the treatment on the NHS. These treatments should be available on the NHS within 3 months of the guidance being issued. © NICE TBC. All rights reserved. Page 1 of 3 Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer You may be able to have PLDH with platinum treatment on the NHS as long as your doctor gets your written consent to have it and the NHS within your area agrees to provide it. If you are already taking gemcitabine with carboplatin, trabectedin with PLDH, or topotecan for recurrent ovarian cancer, you should be able to continue taking it until you and your doctor decide it is the right time to stop.
    [Show full text]
  • Pegylated Liposomal Doxorubicin Hydrochloride, Paclitaxel, Trabectedin and Gemcitabine for Treating Recurrent Ovarian Cancer
    Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer Technology appraisal guidance Published: 26 April 2016 nice.org.uk/guidance/ta389 © NICE 2016. All rights reserved. Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer (TA389) Contents 1 Recommendations ......................................................................................................................................................... 3 2 The technologies............................................................................................................................................................. 5 Gemcitabine....................................................................................................................................................................................... 5 Paclitaxel ............................................................................................................................................................................................. 5 Pegylated liposomal doxorubicin hydrochloride................................................................................................................. 6 Topotecan............................................................................................................................................................................................ 7 Trabectedin........................................................................................................................................................................................
    [Show full text]
  • YONDELIS (Trabectedin) for Injection, for Intravenous Use  Embryofetal Toxicity: Can Cause Fetal Harm
    Hepatotoxicity: Hepatotoxicity may occur. Monitor and delay and/or HIGHLIGHTS OF PRESCRIBING INFORMATION reduce dose if needed (5.3) These highlights do not include all the information needed to use Cardiomyopathy: Severe and fatal cardiomyopathy can occur. Withhold YONDELIS® safely and effectively. See full prescribing information for YONDELIS in patients with left ventricular dysfunction (5.4) YONDELIS. Capillary leak syndrome: Monitor and discontinue YONDELIS for capillary leak syndrome (5.5) YONDELIS (trabectedin) for injection, for intravenous use Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a Initial U.S. Approval: 2015 fetus and use effective contraception (5.7, 8.1, 8.3) ----------------------------INDICATIONS AND USAGE---------------------------- ------------------------------ADVERSE REACTIONS------------------------------- YONDELIS is an alkylating drug indicated for the treatment of patients with The most common (≥20%) adverse reactions are nausea, fatigue, vomiting, unresectable or metastatic liposarcoma or leiomyosarcoma who received a constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and prior anthracycline-containing regimen (1) headache. The most common (5%) grades 3-4 laboratory abnormalities are: -----------------------DOSAGE AND ADMINISTRATION----------------------- neutropenia, increased ALT, thrombocytopenia, anemia, increased AST, and Administer at 1.5 mg/m2 body surface area as a 24-hour intravenous increased creatine phosphokinase. (6.1) infusion, every 3 weeks through a central venous line (2.1, 2.5) Premedication: dexamethasone 20 mg intravenously, 30 min before each To report SUSPECTED ADVERSE REACTIONS, contact Janssen infusion (2.2) Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA- Hepatic Impairment: Administer at 0.9 mg/m2 body surface area as a 1088 or www.fda.gov/medwatch.
    [Show full text]
  • Cancer Drugs Used Today
    The American Society of Pharmacognosy Barry R. O’Keefe, Executive Committee American Society of Pharmacognosy Brandcenter, Virginia Commonwealth University, Richmond, VA, September 26, 2014 The American Society of Pharmacognosy Founded in 1959 in Chicago, IL to “promote the growth and development of pharmacognosy, to provide opportunity for association among workers in science, to provide opportunities for presentation of research achievements, and to promote the publication of meritorious research.” The American Society of Pharmacognosy The Premier Society in the United States Devoted to the Study of Natural Products • ASP members have been responsible for the discovery of several of the most important anti-cancer drugs used today. • Almost all of the currently used antibiotics have been derived from natural products. • Natural products are also the templates for antiviral, anti-cholesterol, anti-diabetic, anti-malaria and immunosuppressive agents as well as pain medications. • ASP members are also active in chemical ecology, biodiversity, responsible sourcing and sustainable development of plants, animals, microbes and marine organisms. Why Should You Care About Pharmacognosy? The World’s Forests and Oceans are Rapidly Being Depleted of Unique Species. Natural Products Research and the ASP in Particular Support Biodiversity Efforts Around the Globe. Why Should You Care About Natural Products? >50% of antimicrobial and anti-cancer drugs come from natural products. All Small Molecule Drugs Most large pharmaceutical companies have eliminated
    [Show full text]
  • Relevance of the Fanconi Anemia Pathway in the Response of Human Cells to Trabectedin
    1309 Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin Jose´A. Casado,1 Paula Rı´o,1 Esther Marco,2 human cells to trabectedin reported herein, together with Vero´nica Garcı´a-Herna´ndez,3 Alberto Domingo,3 observations showing the role of the FA pathway in cancer Laura Pe´rez,1,5 Juan Carlos Tercero,5 suppression, strongly suggest that screening for mutations Juan Jose´Vaquero,4 Beatriz Albella,1 in FA genes may facilitate the identification of tumors Federico Gago,2 and Juan A. Bueren1 displaying enhanced sensitivity to this novel anticancer drug. [Mol Cancer Ther 2008;7(5):1309–18] 1Division of Hematopoiesis and Gene Therapy Program, Centro de Investigaciones Energe´ticas, Medioambientales y Tecnolo´gicas and Centro de Investigacio´n Biome´dica en Red de Introduction Enfermedades Raras; Departments of 2Pharmacology, 3Biochemistry and Molecular Biology, and 4Organic Chemistry, Trabectedin (ET-743; Yondelis; Fig. 1A) is a potent Universidad de Alcala´, Alcala´de Henares; and 5PharmaMar S.A., antitumor drug currently undergoing phase II/III clinical Madrid, Spain trials that has recently received regulatory approval from the European Medicines Agency for the treatment of Abstract metastatic or advanced soft-tissue sarcoma after failure to anthracyclines and ifosfamide (1). Trabectedin binds in the Trabectedin (Yondelis; ET-743) is a potent anticancer drug DNA minor groove by establishing a covalent bond with that binds to DNA by forming a covalent bond with a the exocyclic 2-amino group of a guanine in one strand guanine in one strand and one or more hydrogen bonds and one or two hydrogen bonds with other DNA bases in with the opposite strand.
    [Show full text]
  • (Trabectedin) for the Treatment of Soft Tissue Sarcoma
    YONDELIS® (TRABECTEDIN) FOR THE TREATMENT OF SOFT TISSUE SARCOMA PHARMAMAR SINGLE TECHNOLOGY APPRAISAL SUBMISSION TO THE NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE 2ND MARCH 2009 CONTENTS Section A ...................................................................................................... 3 1 Description of technology under assessment .......................................... 3 2 Statement of the decision problem .......................................................... 6 Section B ...................................................................................................... 8 3 Executive summary ................................................................................. 8 4 Context .................................................................................................. 11 5 Equity and equality ................................................................................ 16 6 Clinical evidence .................................................................................... 17 6.1 Identification of studies ...................................................................... 17 6.2 Study selection .................................................................................. 18 6.3 Summary of methodology of relevant RCTs ...................................... 24 6.4 Results of the relevant comparative RCTs ........................................ 36 6.5 Meta-analysis .................................................................................... 43 6.6 Indirect/mixed treatment
    [Show full text]
  • The Antitumor Drugs Trabectedin and Lurbinectedin Induce
    1 The antitumor drugs trabectedin and lurbinectedin induce 2 transcription-dependent replication stress and genome 3 instability 4 5 Emanuela Tumini 1, Emilia Herrera-Moyano 1, Marta San Martín-Alonso 1, 6 Sonia Barroso 1, Carlos M. Galmarini 2 and Andrés Aguilera 1 * 7 8 1 Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, 9 CSIC-Universidad Pablo de Olavide-Universidad de Sevilla, Av. Américo 10 Vespucio 24, 41092 SEVILLE, Spain; 2 PharmaMar, Av. de los Reyes 1, 11 28770 Colmenar Viejo, Spain 12 13 *Corresponding author: Andrés Aguilera, Centro Andaluz de Biología 14 Molecular y Medicina Regenerativa-CABIMER; Av. Américo Vespucio 24, 15 41092 SEVILLE, Spain. Phone: +34 954468372. E-mail: [email protected] 16 17 Running title: ET743 and PM01183 and RNA-dependent DNA damage 18 19 Keywords 20 Trabectedin, lurbinectedin, R-loops, genome instability, cancer 21 22 Conflict of interests statement 23 Dr C.M. Galmarini is an employee and shareholder of PharmaMar. The 24 remaining authors declare no conflict of interest. 25 1 26 ABSTRACT 27 28 R-loops are a major source of replication stress, DNA damage and genome 29 instability, which are major hallmarks of cancer cells. Accordingly, growing 30 evidence suggests that R-loops may also be related to cancer. Here we 31 show that R-loops play an important role in the cellular response to 32 trabectedin (ET743), an anticancer drug from marine origin and its derivative 33 lurbinectedin (PM01183). Trabectedin and lurbinectedin induced RNA-DNA 34 hybrid-dependent DNA damage in HeLa cells, causing replication 35 impairment and genome instability.
    [Show full text]
  • Rucaparib for Advanced BRCA-Mutated Ovarian Cancer
    Horizon Scanning Research January 2016 & Intelligence Centre Rucaparib for advanced BRCA- mutated ovarian cancer LAY SUMMARY Ovarian cancer is the fifth most common cancer for women in the UK. Symptoms of ovarian cancer are often vague early on and many women are not diagnosed until after the cancer has grown and spread to other parts of the body. Less than half of women with ovarian This briefing is based on cancer survive five years from diagnosis with many not responding to information current treatments. available at the time of research and a Ovarian, fallopian tube, and primary peritoneal cancer all begin in the limited literature same part of the ovary or fallopian tube. Rucaparib is a new drug for search. It is not the treatment of ovarian, fallopian tube, or primary peritoneal cancer. It intended to be a is taken as a tablet, twice daily with water. definitive statement on the safety, If rucaparib is licensed for use in the UK, it could be a new treatment efficacy or option for patients with ovarian, fallopian tube, or primary peritoneal effectiveness of the cancer. This may improve survival when current treatments have health technology stopped working. covered and should not be used for commercial NIHR HSRIC ID: 4201 purposes or commissioning without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP Ovarian, fallopian tube and peritoneal cancer: advanced; deleterious or suspected deleterious BRCA-mutated tumour (inclusive of both germline BRCA and somatic BRCA mutations) – treated with three or more prior lines of chemotherapy.
    [Show full text]