DOCSLIB.ORG

Antiproliferating Activity of the Mitotic Inhibitor Pironetin Against Vindesine- and Paclitaxel-Resistant Human Small Cell Lung Cancer H69 Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antiproliferating Activity of the Mitotic Inhibitor Pironetin Against Vindesine- and Paclitaxel-Resistant Human Small Cell Lung Cancer H69 Cells ANTICANCER RESEARCH 27: 729-736 (2007) Antiproliferating Activity of the Mitotic Inhibitor Pironetin against Vindesine- and Paclitaxel-resistant Human Small Cell Lung Cancer H69 Cells MITSUZI YOSHIDA1, YUKI MATSUI1, YOSHINORI IKARASHI1, TAKEO USUI2, HIROYUKI OSADA2 and HIRO WAKASUGI1 1Pharmacology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045; 2Antibiotics Laboratory, RIKEN Discovery Research Institute, 2-1 Hirosawa Wako-shi, Saitama 351-0198, Japan Abstract. Pironetin, isolated from Streptomyces sp., is a for anticancer chemotherapy. Microtubules are composed potent inhibitor of microtubule assembly and the first of ·-tubulin and ‚-tubulin heterodimers. Microtubule- compound identified that covalently binds to ·-tubulin at targeted drugs previously reported have a characteristic Lys352. We examined whether pironetin is an effective agent ability to bind directly to different sites of ‚-tubulin in vitro. against human small cell lung cancer H69 cells, including Therefore, they are classified into vinca alkaloid, taxane and two cell lines resistant to the microtubule-targeted drugs colchicine types depending upon their binding site on vindesine (H69/VDS) and paclitaxel (H69/Txl) that interact microtubules. with ‚-tubulin. Pironetin was found to be effective against Pironetin (Figure 1), isolated from Streptomyces sp., is a these resistant cells as well as their parental cells. In addition, potent inhibitor of microtubule assembly (1) and the first pironetin inhibited the growth of human leukemic K562 compound identified that covalently binds to ·-tubulin at multidrug-resistant cells (K562/ADM), which have mdr1 gene Lys352 (2). In our study, we examined whether pironetin expression, as well as the parental K562 cells. In these cell shows antiproliferating activity against clinically employed lines, including the parental and resistant cells, pironetin microtubule-targeted drug-resistant H69 human small cell caused complete mitotic arrest; in addition, apoptosis lung cancer cells and the multidrug-resistant K562 human inductions by 30 and 100 nM pironetin were observed. In this leukemic cells. study, the new mitotic inhibitor, pironetin, was found to be effective not only against human tumor cell lines resistant to Materials and Methods microtubule-targeted drugs, but also multidrug-resistant cells with mdr1 gene expression. These results suggest that Chemicals. Pironetin was kindly supplied from Nippon Kayaku Co., pironetin is a useful agent for overcoming drug resistance in Ltd (Tokyo, Japan). Vindesine sulfate was purchased from Shionogi (Osaka, Japan). Paclitaxel (Taxol®), doxorubicin (Adriamycin®), cancer chemotherapy. propidium iodide, Nonidet® p 40, sperminetetrahydrochloride, trypsin, trypsin inhibitor, ribonuclease A, monoclonal anti-P- Microtubules are a cytoskeletal element essential in the glycoprotein antibody (Clone F4) and peroxidase-conjugated anti- segregation of chromosomes during cell division, as well as mouse IgG were purchased from Sigma (St. Louis, MO, USA). in axon transport, secretory processes and the maintenance Polyclonal anti-caspase-3 antibody was purchased from Cell of specific cell morphology. Thus, they are essential in all Signaling Technology (Danvers, MA, USA). Pironetin and paclitaxel eukaryotic cells and are among the most successful targets were dissolved in dimethyl sulfoxide (DMSO) and used at final concentrations of DMSO below 0.001% and 0.06%, respectively. Cell lines. The human small-cell lung cancer H69 cells and leukemic K562 and HL-60 cells were grown in RPMI-1640 medium Correspondence to: Dr. Mitsuzi Yoshida, Pharmacology Division, supplemented with 10% fetal bovine serum. Vindesine-resistant National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, (H69/VDS) and paclitaxel-resistant (H69/Txl) H69 cells were Tokyo 104-0045, Japan. Tel: +81 3 3542-2511, Fax: +81 3 3542- established in our laboratory as reported elsewhere (3, 4). H69/VDS 1886, e-mail: [email protected] and H69/Txl resistant cell lines were maintained in the presence of vindesine (10 nM) and paclitaxel (20 nM), respectively, in the Key Words: Pironetin, mitotic inhibitor, ·-tubulin, ‚-tubulin, culture medium. Doxorubicin-resistant K562 cells (K562/ADM) resistant cells, vindesine, paclitaxel, mdr1, apoptosis, caspase-3, were used as positive control for typical multidrug-resistant cells sub-G1. expressing the mdr1 gene (5). 0250-7005/2007 $2.00+.40 729 ANTICANCER RESEARCH 27: 729-736 (2007) Table I. Sensitivities of H69, H69/VDS and H69/Txl cells to vindesine, paclitaxel and pironetin in the MTT assay. IC50 (nM) Cell line Vindesine Paclitaxel Pironetin H69 5.5±0.3 57±1.0 17.5±0.9 Figure 1. Chemical structure of pironetin. H69/VDS 55±4.0 530±40 20.3±2.3 (10.0)* (9.3) (1.2) H69/Txl 53±5.0 2350±260 11.5±0.4 Antitumor activity in vitro (MTT assay). Sensitivities of tumor and (9.6) (41.2) (0.7) resistant cell lines to antitumor drugs were examined with a 3-(4,5- dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) *Values in parentheses show relative resistance compared to H69 cells. assay, as outlined elsewhere (6). Briefly, H69/VDS and H69/Txl cells were cultured in vindesine- and paclitaxel-free medium for 1 week before the assay; H69 (104 cells/ml), H69/VDS (104 cells/ml), H69/Txl (2x104 cells/ml), K562 (2x103 cells/ml), and K562/ADM (2x103 cells/ml) were then seeded into a 96-well microplate in a The DNA contents were analyzed with the FACSCalibur volume of 180 Ìl. A 20-Ìl aliquot of various concentrations of automated system (BD Biosciences, San Jose, CA, USA) using antitumor drugs was added to each well. Because H69 and its CellQuest software (BD Biosciences). resistant cell lines grow so slowly that their doubling times are over 50 h, differing from the circa 12-h doubling time of K562 cell lines, Immunoblot analysis. Apoptosis caused by pironetin was also H69 and the resistant cell lines were cultured for 7 days and K562 detected by immunoblot analysis using polyclonal anti-caspase-3 and its adriamycin-resistant cells were cultured for 4 days at 37ÆC antibody. Cells were cultured with pironetin and lysed in M-PER mammalian protein extraction reagent (Pierce, Rockford, IL, in an atmosphere of 5% CO2 in air. A 50-Ìl aliquot of MTT (2 mg/ml) dissolved in Ca2+, Mg2+-free Dulbecco's phosphate- USA) containing 1 mM dithiothreitol (DTT) and protease buffered saline was added to each well and the plates were inhibitors. Equal amounts of total protein were separated by 4% incubated for 4 h. The MTT-formazan crystals were dissolved in to 20% (W/V) SDS-PAGE and transferred electrophoretically to DMSO and the optical density of each solution was measured at polyvinylidene difluoride (PVDF) membranes. Expression of P- 570 nm and 630 nm using a Microplate Manager III (BIO-RAD glycoprotein in tumor cell lines was also examined by immunoblot Laboratories, Hercules, CA, USA) analysis program on a analysis using monoclonal anti-P-glycoprotein antibody. Macintosh computer interfaced with a Benchmark Microplate Immunoblot stainings were performed as described elsewhere (8). Reader (BIO-RAD Laboratories). The IC50 was defined as the drug concentration required to Results inhibit cell growth to 50% that of the control. The relative resistance was defined as the IC50 of the resistant subline/IC50 of Antiproliferating activity of pironetin against vindesine- and the parental cell line. paclitaxel-resistant H69 cells. Human small cell lung cancer H69 cells were sensitive to vindesine and paclitaxel; the Apoptosis assay (flow cytometry). Apoptosis induction by pironetin was determined with flow cytometry by the detergent-trypsin concentration-response curves of H69 to vindesine and method of Vindelov (7). The cells (5x105) were suspended in 200 paclitaxel obtained are shown in Figure 2. From these Ìl of citrate buffer including 5% dimethylsulfoxide. Samples were figures, the IC50s of H69 for vindesine and paclitaxel were frozen rapidly in polypropylene tubes immersed in a mixture of estimated as 5.5±0.3 nM and 57±1.0 nM, respectively dry ice and acetone and then stored in a freezer at –80ÆC. Stock (Table I). H69/VDS cells resistant to vindesine showed ® solution: Trisodium citrate (3.4 mM), 0.1% Nonidet p 40, 1.5 about tenfold resistance to vindesine compared to parental mM sperminetetrahydro-chloride and Tris(hydroxymethyl)- H69 cells. H69/Txl cells showed 41.2-fold resistance to aminomethane were dissolved in distilled water and the pH was adjusted to 7.6. The stock solution was used as the basis for paclitaxel compared to H69 cells. Moreover, at preparing solution A, B and C. Before analysis, the samples were concentrations up to 1 ÌM, paclitaxel promoted the growth thawed rapidly in a water bath at 37ÆC and then 1800 Ìl of of H69/Txl cells as shown in Figure 2B. H69/Txl and solution A (0.003% trypsin in the stock solution) was added to H69/VDS cells were also resistant to vindesine and the tube and mixed gently. After 10 min at room temperature, paclitaxel, with their relative resistances of 9.6 and 9.3, 1500 Ìl of solution B (0.05% trypsin inhibitor and 0.01% respectively. However, H69/Txl and H69/VDS cells as well ribonuclease A in the stock solution) were added. The solutions as the parental cells were sensitive to pironetin (Figure 3). were again mixed by inversion of the tube and after 10 min at room temperature, 1500 Ìl ice-cold solution C (0.042% Pironetin caused growth inhibition of the resistant H69/Txl propidium iodide and 0.12% spermine tetrahydrocloride in the cells to a higher degree than the parental H69 cells, with a stock solution) were added. The solutions were mixed for 15 min. relative resistance of 0.7 (Table I). 730 Yoshida et al: Antiproliferating Activity of Pironetin Figure 2. Concentration-response curves of H69, H69/VDS and H69/Txl cells to (A) vindesine and (B) paclitaxel. Values are average ±S.D. of three independent experiments performed in quintuplicate with H69 (●), H69/VDS (■), and H69/Txl (▲) cells.
Load more

Recommended publications
  • Human Cytogenetics Prenatal Diagnostics
    Cytogenetics Human Cytogenetics Prenatal Diagnostics Optimized Medium for Culture and Genetic Analysis of Human Amniotic Fluid Cells BIOAMF-1 and Chorionic Villi ( CV ) Samples Basal Medium and Supplement Chromosome Karyotyping was first developed in the BIOAMF-1 is designed for the primary culture of field of Cytogenetics. human amniotic fluid cells and chorionic villi (CV) The basic principle of the method is the preparation samples in both open (5% CO2) and closed systems. of chromosomes for microscopic observation by The medium allows rapid growth of amniocytes or arresting cell mitosis at metaphase with colchicine and treating the cells with a hypotonic solution. This chorionic villi for use in karyotyping. is followed by regular or fluorescent staining of the No supplementation with serum or serum- chromosomes, which are then tested with the aid of a substitutes is necessary. microscope and computer programs to arrange and The medium consists of two components: basal identify the chromosomes for the presence of genetic medium and frozen supplements. abnormalities. In principle, this method enables the identification Instructions for Use of any abnormality - excess chromosomes or For the preparation of 500ml complete medium, use chromosome deficiency, broken chromosomes, 01-190-1A with 01-192-1E. or excess genetic material (as a result of a For the preparation of 100ml complete medium, use recombination process). 01-190-1B with 01-192-1D. Clinical cytogenetics laboratories use this method Thaw the BIOAMF-1 Supplement by swirling in a with amniotic fluid, chorionic villi, blood cells, skin cells, and so on, which can be cell cultured to obtain 37ºC water bath, and transfer the contents to the mitotic cells.
    [Show full text]
  • Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer
    cancers Review Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer Lukas Gorecki 1 , Martin Andrs 1,2 and Jan Korabecny 1,* 1 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; [email protected] (L.G.); [email protected] (M.A.) 2 Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic * Correspondence: [email protected]; Tel.: +420-495-833-447 Simple Summary: Selective killing of cancer cells is privileged mainstream in cancer treatment and targeted therapy represents the new tool with a potential to pursue this aim. It can also aid to overcome resistance of conventional chemo- or radio-therapy. Common mutations of cancer cells (defective G1 control) favor inhibiting intra-S and G2/M-checkpoints, which are regulated by ATR–CHK1–WEE1 pathway. The ATR–CHK1–WEE1 axis has produced several clinical candidates currently undergoing clinical trials in phase II. Clinical results from randomized trials by ATR and WEE1 inhibitors warrant ongoing clinical trials in phase III. Abstract: Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra-S or G2/M checkpoints has also been extensively Citation: Gorecki, L.; Andrs, M.; pursued.
    [Show full text]
  • Metals and Metal Compounds in Cancer Treatment
    ANTICANCER RESEARCH 24: 1529-1544 (2004) Review Metals and Metal Compounds in Cancer Treatment BERNARD DESOIZE Laboratoire de Biochimie et de Biologie Moléculaire, EA 3306, IFR 53, Faculté de Pharmacie, 51 rue Cognacq-Jay, 51096 Reims cedex, France Abstract. Metals and metal compounds have been used in The importance of metal compounds in medicine is medicine for several thousands of years. In this review we undisputed, as can be judged by the use of compounds of summarized the anti-cancer activities of the ten most active antimony (anti-protozoal), bismuth (anti-ulcer), gold (anti- metals: arsenic, antimony, bismuth, gold, vanadium, iron, arthritic), iron (anti-malarial), silver (anti-microbial) and rhodium, titanium, gallium and platinum. The first reviewed platinum (anti-cancer) in the treatment of various diseases. metal, arsenic, presents the anomaly of displaying anti-cancer In terms of anti-tumour activity, a wide range of compounds and oncogenic properties simultaneously. Some antimony of both transition metals and main group elements have derivatives, such as Sb2O3, salt (tartrate) and organic been investigated for efficacy (1). The earliest reports on the compounds, show interesting results. Bismuth directly affects therapeutic use of metals or metal-containing compounds in Helicobacter pylori and gastric lymphoma; the effects of cancer and leukemia date from the sixteenth century. bismuth complexes of 6-mercaptopurine are promising. Superoxide dismutase inhibition leads to selective killing Gold(I) and (III) compounds show anti-tumour activities, of cancer cells in vitro and in vivo (2,3). As a consequence, although toxicity remains high. Research into the potential use reactive oxygen species (ROS) may not only be involved in of gold derivatives is still ongoing.
    [Show full text]
  • Actin Gesting That Cytoskeletal Laments May Be Exploited to Supplement Chemotherapeutic Approaches Currently Used Microfilaments in the Clinical Setting
    Biochimica et Biophysica Acta 1846 (2014) 599–616 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan Review Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach Matthew Trendowski ⁎ Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA article info abstract Article history: Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to Received 2 August 2014 readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and Received in revised form 19 September 2014 there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There Accepted 21 September 2014 are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an Available online 5 October 2014 ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate fi fi Keywords: lament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo ef cacy, sug- fi Actin gesting that cytoskeletal laments may be exploited to supplement chemotherapeutic approaches currently used Microfilaments in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous Intermediate filaments variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evalu- Drug synergy ation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage Chemotherapy malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.
    [Show full text]
  • Elevated MARCKS Phosphorylation Contributes to Unresponsiveness of Breast Cancer to Paclitaxel Treatment
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 17 Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment Ching-Hsien Chen1, Chun-Ting Cheng2,3, Yuan Yuan4, Jing Zhai5, Muhammad Arif1, Lon Wolf R. Fong1, Reen Wu1 and David K. Ann2,3 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, California, USA 2 Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, USA 3 Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA 4 Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California, USA 5 Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California, USA Correspondence to: David K. Ann, email: [email protected] Correspondence to: Reen Wu, email: [email protected] Keywords: phospho-MARCKS, MANS peptide, paclitaxel, mitotic inhibitor, breast cancer Received: December 23, 2014 Accepted: March 26, 2015 Published: April 14, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho-MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy.
    [Show full text]
  • Inhibition of Polo-Like Kinase 4 Induces Mitotic Defects and DNA Damage in Diffuse Large B-Cell Lymphoma
    www.nature.com/cddis ARTICLE OPEN Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma 1 1 1 1 1 1 1 1,2,3,4,5,6 ✉ Yi Zhao , Juan Yang✉ , Jiarui Liu , Yiqing Cai , Yang Han , Shunfeng Hu , Shuai Ren , Xiangxiang Zhou and Xin Wang 1,2,3,4,5,6 © The Author(s) 2021 Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.
    [Show full text]
  • Eldisine * (Vindesine Sulphate)
    PACKAGE LEAFLET: INFORMATION FOR THE USER 2. WHAT YOU NEED TO KNOW BEFORE YOU USE ELDISINE your bone marrow. These cells divide quickly to make new blood Do not use Eldisine if you: cells. Your doctor or nurse will take samples of your blood when Eldisine * • are allergic to vindesine sulphate or any of the other ingredients you are treated with Eldisine. The hospital’s laboratory will then (Vindesine Sulphate) in Eldisine (see section 6 – Contents of the pack and other count the numbers of different types of blood cells (platelets, white information) cells and red cells). Your doctor may decide to change the dose or Read all of this leaflet carefully before you start taking this • suffer from any disease affecting the nerves or muscles (such as put off treating you if your blood cell counts are too low. Your blood medicine. Charcot-Marie-Tooth syndrome) cell counts soon improve as the bone marrow makes new cells. - Keep this leaflet. You may need to read it again. • have a bacterial infection. A lot of injections (more than one a week) may cause more side- - If you have any further questions, ask your doctor or pharmacist. Warnings and precautions effects. - This medicine has been prescribed for you. Do not pass it on to Talk to your doctor or pharmacist before using Eldisine if you: Eldisine works by sticking to certain molecules in dividing cells to others. It may harm them, even if their signs of illness are the • are having radiotherapy in the liver area stop the cells dividing. It also sticks to the same sort of molecule in same as yours.
    [Show full text]
  • 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.
    [Show full text]
  • Human Karyotyping Open Small Res
    HUMAN CYTOGENETICS www.bioind.com Biological Industries With over 35 years of expertise in cell culture media development and manufacturing, Biological Industries’ (BI) products including BIO-AMF™, BIO-HEMATO™, and BIO-PB™ brands—are used in cytogenetic laboratories all around the world. Our cytogenetic product line gives you the option of selecting high quality tools that can help you make critical decisions in the lab. When your cytogenetics analysis is supported by the BI-team and BI media and supplements, you can be confident in the conclusions you reach. Today, our product and services portfolio benefits both life science and medical customers. Whether it is in developing culture media for cell therapy, media to assist IVF procedures, or supplying media and reagents for classical cell culture, we are committed to providing our customers with a Culture of Excellence. We do this through our advanced GMP manufacturing and quality control systems, superior regulatory expertise, in-depth market knowledge, and extensive technical customer support, training, and R&D capabilities. BOOST PERFORMANCE INCREASE CONSISTENCY Performance Quality Control Support • Consistent lot-to-lot performance • Manufactured in compliance with • Regional technical support • Optimized products for the analysis the FDA’s quality system regulation • Documentation and traceability of amniotic fluid, chorionic villus, (cGMP) and the current requirements of documentation including Certificate peripheral blood, bone marrow, ISO 9001 and ISO 13485 of Analysis, and Certificates
    [Show full text]
  • Vinorelbine Inj. USP
    VINORELBINE INJECTION USP survival between the 2 treatment groups. Survival (Figure 1) for patients receiving Vinorelbine Injection USP pIus cisplatin was Patients treated with Vinorelbine Injection USP should be frequently monitored for myelosuppression both during and after significantly better compared to the-patients who received single-agent cisplatin. The results of this trial are summarized in Table 1. therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count PRESCRIBING INFORMATION Vinorelbine Injection USP plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine Injection USP: In a recovery usually within the following 7 to 14 days. Complete blood counts with differentials should be performed and results large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, reviewed prior to administering each dose of Vinorelbine Injection USP. Vinorelbine Injection USP should not be administered to WARNING: Vinorelbine Injection USP should be administered under the supervision of a physician experienced in the use of or 2 were randomized to treatment with single-agent Vinorelbine Injection USP (30 mg/m2/week), Vinorelbine Injection USP (30 patients with granulocyte counts <1,000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2/week for 7 weeks, then every evidence of infection and/or fever. See DOSAGE AND ADMINISTRATION for recommended dose adjustments for granulocytopenia.
    [Show full text]
  • DRUG NAME: Vinorelbine
    Vinorelbine DRUG NAME: Vinorelbine SYNONYM(S): Vinorelbine tartrate, VRL, VNL, NVB COMMON TRADE NAME(S): NAVELBINE® CLASSIFICATION: Mitotic inhibitor Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Vinorelbine is a semisynthetic vinca alkaloid derived from vinblastine. Vinca alkaloids such as vincristine and vinblastine are originally derived from periwinkle leaves (vinca rosea).1 Vinorelbine inhibits cell growth by binding to the tubulin of the mitotic microtubules.2 Like other mitotic inhibitors, vinorelbine also promotes apoptosis in cancer cells.1 In vitro vinorelbine shows both multidrug and non-multidrug resistance.2 Microtubules are present in mitotic spindles, neuronal axons, and other cells. Inhibition of mitotic microtubules appears to correlate with antitumour activity, while inhibition of axonal microtubules seems to correlate with neurotoxicity. Compared to vincristine and vinblastine, vinorelbine is more selective against mitotic than axonal microtubules in vitro, which may account for its decreased neurotoxicity.3 Vinorelbine is a radiation-sensitizing agent.4 It is cell cycle phase-specific (M phase).2 PHARMACOKINETICS: Interpatient variability moderate to large interpatient variability5,6 Distribution Widely distributed in the body, mostly in spleen, liver, kidneys, lungs, thymus; moderately in heart, muscles; minimally in fat, brain, bone marrow.3 High levels found in both normal and malignant lung tissue, with slow diffusion out of tumour tissue.1 cross
    [Show full text]
  • Identification and Analysis of the Signalling Networks That Regulate Ciz1 Levels in Normal and Cancer Cell Lines
    Identification and analysis of the signalling networks that regulate Ciz1 levels in normal and cancer cell lines PhD Biomedical and Life Sciences By Teklė Paužaitė Lancaster University A Thesis submitted in fulfilment of requirement for the degree of Doctor of Philosophy March 2019 Declaration This dissertation is the result of my own work and includes nothing, which is the outcome of work done in collaboration except where specifically indicated in the text. It has not been previously submitted, in part or whole, to any university of institution for any degree, diploma, or other qualification. Signed: Teklė Paužaitė Date: 01 07 2019 II Dedication This thesis is dedicated to the strongest, most caring and extraordinary person I know, my mother Eglė Paužienė. III Abstract Ciz1 is a nuclear protein that associates with cyclin A – cyclin dependent kinase 2 (CDK2) and facilitates the initiation of DNA replication. Ciz1 overexpression has been linked to common cancer types, including breast, colon, prostate, lung, and liver cancers. This suggests that identification of mechanisms that regulate Ciz1 levels may represent potential drug targets in cancer. This work identifies that CDK2 and DDK activity are required to maintain Ciz1 levels. Chemical or genetic inhibition of CDK2 or DDK (Cdc7-Dbf4) activity in murine fibroblasts reduced Ciz1 levels. Further analysis demonstrated that CDK and DDK activity promotes Ciz1 accumulation in G1 phase by reducing ubiquitin proteasome system (UPS) mediated degradation. Furthermore, Ciz1 levels are actively controlled by the proteasome, as inhibition of protein translation rapidly reduced Ciz1 levels, and this is reversed by proteasomal inhibition. The data suggest a model where Ciz1 is regulated by opposing kinase and UPS activities, leading to Ciz1 accumulation in response to rising kinase activity in G1 phase, and its degradation later in the cell cycle.
    [Show full text]