DOCSLIB.ORG

University of Cincinnati

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
University of Cincinnati UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF DOCETAXEL A thesis submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in the Division of Pharmaceutical Sciences of the College of Pharmacy 2005 by Purvi B. Shroff MBBS, University of Mumbai, India, 2000. Committee Chair: Dr. Pankaj B. Desai, Ph.D i ABSTRACT Background: Bexarotene, a novel RXR agonist, is used in the treatment of cutaneous T cell lymphoma and is under investigation for the treatment of solid tumors in combination with other chemotherapeutic agents including docetaxel. Both docetaxel and bexarotene are metabolized by CYP3A4 and in animal studies bexarotene has been shown to enhance the activity of CYP3A enzymes and increase its content. Thus, there exists a potential for interactions between these two agents, which was evaluated in this study. Method: Bexarotene from commercial capsules was dissolved in DMSO. Employing pooled human liver microsomes, we assessed the influence of bexarotene on the metabolism of docetaxel. Microsomal fractions (1mg protein) were incubated with bexarotene (0.1 – 10µM) and docetaxel (0.5 – 5µM) in the presence of NADPH (1 mM). Using liquid-liquid extraction, unreacted docetaxel was extracted and levels were measured using a validated HPLC method. Next, we employed primary human hepatocytes to assess the inductive effects of bexarotene. Hepatocytes were treated with bexarotene (1 – 50µM) for 72 hours. Docetaxel metabolism by microsomal fractions was then evaluated. Testosterone 6β-hydroxylation and CYP3A4- specific protein and mRNA levels were also measured to evaluate whether bexarotene acts as an inducer of CYP3A4. Results: Bexarotene, at clinically relevant concentrations (1-10µM) did not inhibit docetaxel metabolism. Also, incubation of primary human hepatocytes with bexarotene did not enhance docetaxel metabolism, which was consistent with the observation that the ii testosterone 6β-hydroxylation and CYP3A4 expression in bexarotene – treated cells were not statistically different than those from untreated cells. Conclusions: Our findings suggest that bexarotene is unlikely to alter hepatic metabolism of docetaxel. Bexarotene appears to exhibit species – specific differences in the induction of CYP3A and further studies are required to understand the mechanistic basis of these differences. iii iv ACKNOWLEDGEMENTS I take this opportunity to deeply thank my advisor, Dr. Pankaj B. Desai, who not only initiated this project but also gave me valuable guidance till its completion. I remain indebted to him for his support, encouragement, advice, affection and critique of my work. On a personal note, he has been a source of inspiration to me. His wife, Sangita and his two daughters, Shivani and Kiran, are an extended family to me! I would also like to thank Dr. Jane Pruemer and Dr. Sadanand Patil for serving on my Masters Thesis Committee and giving me valuable inputs on this project. I appreciate them for reviewing my thesis and for their support and critique of my work. None of this work would have been possible without my parents and my in-laws who were supportive throughout my stay here in Cincinnati. I express my sincere gratitude to my parents once again for giving me the strength to believe in myself and get through life with pride. I cannot thank my husband, Manoj, enough for being so cooperative and patient with me. I hope to make up for all the sacrifices that he made for me to be here and pursue graduate studies at the University of Cincinnati, USA. He has made me the person that I am today with his love and support. I would like to appreciate Rucha, my senior in the laboratory, for not only teaching me laboratory skills but also being a great friend. I wish to thank her for all the wonderful moments that we shared while working together. I also thank Murad for his help in guiding me with HPLC techniques. I have enjoyed working with Niresh and Fang in the laboratory and I thank all of them for the healthy working environment that we have in the laboratory. v I wish to thank the faculty at UC for being such wonderful teachers and for all the guidance, encouragement and challenges they provided us during the classes. I appreciate that they participated in so many extracurricular activities and gave us a chance to interact with them outside the academic settings. I thank the Department of Pharmaceutical Sciences at the College of Pharmacy for their academic, fiscal and administrative support and for making our stay here in Cincinnati so comfortable. I deeply appreciate my friend, Hitesh Deshmukh, for all his patience, help, affection and encouragement. I cannot thank him enough for being such a kind human being that he is. I would also like to acknowledge all my friends and family here in the US and back in India for their love and support. Lastly, I would like to acknowledge my darling son, Taaraksh, who makes everything worthwhile in my life! With this I seek Lord Ganesha’s blessings and thank Him for all that He has showered upon me! vi TABLE OF CONTENTS ABSTRACT……………………………………………………………………………....ii ACKNOWLEDGEMENTS……………………………………………………………....iv TABLE OF CONTENTS…………………………………………………………………vi LIST OF FIGURES……………………………………………………………………….x LIST OF TABLES……………………………………………………………………...xiii 1. INTRODUCTION……………………………………………………………….....1 1.1. ADVERSE DRUG REACTIONS (ADRs)………………………………………1 1.2. DRUG – DRUG INTERACTIONS……………………………………………...2 1.3. DRUG INTERACTIONS IN ONCOLOGY…………………………………….2 1.4. TYPES OF DRUG-DRUG INTERACTIONS………………………………......3 1.5. NON-SMALL CELL LUNG CARCINOMA (NSCLC)………………………...5 1.6. BEXAROTENE………………………………………………………………….8 1.6.1. Chemistry 1.6.2. Mechanism of action of retinoids 1.6.3. Clinical Indications 1.6.4. Pharmacokinetics of bexarotene 1.6.5. Metabolism of bexarotene: role of CYP3A4 1.7. DOCETAXEL…………………………………………………………………..14 1.7.1. Chemistry 1.7.2. Mechanism of action of docetaxel 1.7.2.1. Background on microtubule structure vii 1.7.2.2. Mechanism of action of docetaxel 1.7.3. Clinical Indications 1.7.4. Pharmacokinetics of docetaxel 1.7.5. Metabolism of docetaxel: role of CYP3A4 1.8. CYTOCHROME P450 FAMILY…………………………………………….21 1.8.1. The CYP3A subfamily 1.8.2. CYP3A4 Inhibition 1.8.3. CYP3A4 Induction 1.8.4. Regulation of CYP3A4 2. RATIONAL AND HYPOTHESIS ………………………………………………28 2.1 SPECIFIC AIMS 2.1.1. Aim I 2.1.2. Aim II 3. MATERIALS AND METHODS…………………………………………………30 3.1. Experimental Strategy …………………………………………….............30 3.2. Human liver microsomal metabolism of docetaxel in the presence and in the absence of bexarotene…………………………………………………33 3.2.1. Chemicals 3.2.2. Reaction optimization 3.2.3. Assessment of the potential influence of bexarotene on docetaxel metabolism in human liver microsomal reactions 3.2.4. HPLC analysis of docetaxel viii 3.3. Assessment of the potential induction of docetaxel metabolism by bexarotene in primary human hepatocytes………………………….......38 3.3.1. Hepatocyte culture 3.3.2. Drug treatments 3.3.3. Assay of CYP3A4 in human hepatocytes 3.3.4. Docetaxel metabolism by human hepatocytes 3.3.5. Western blot analysis of immunoreactive CYP3A4 protein levels in human hepatocytes 3.3.6. Real-time PCR to assess the levels of CYP3A4 mRNA in human hepatocytes 3.4. Statistical Analysis………………………………………………………..42 4. RESULTS……………………………………………………………………......43 4.1. Human liver microsomal metabolism of docetaxel in the presence / absence of bexarotene………..…………………………………………..43 4.1.1. Michaelis-Menten plot of docetaxel metabolism kinetics 4.1.2. – 4.1.5. Human liver microsomal metabolism of docetaxel (0.5 – 5 µM) in the presence and the absence of bexarotene (0.1 – 10 µM). 4.2. Assessment of the potential induction of docetaxel metabolism by bexarotene in primary human hepatocytes……………………………….53 4.2.1. Typical chromatogram showing effect of rifampicin and bexarotene treatment of hepatocytes on CYP3A4 activity measured by testosterone 6β-hydroxylation as compared to untreated controls. 4.2.2. Effect of rifampicin and bexarotene treatment on the CYP3A4 activity as compared to untreated controls. 4.2.3. Effect of rifampicin and bexarotene treatment on docetaxel metabolism by human hepatocytes as compared to untreated controls. ix 4.2.4. Western blot analysis of rifampicin and bexarotene treatment on immunoreactive CYP3A4 protein levels as compared to untreated controls. 4.2.5. RT – PCR analysis of the effect of rifampicin and bexarotene treatment on the CYP3A4 specific mRNA levels as compared to untreated controls. 5 DISCUSSION……………………………………………………………………63 6 REFERENCES…………………………………………………………………..70 x LIST OF FIGURES 1.6.1. Chemical structure of bexarotene ……………………………………………….9 1.6.2. Mechanism of action of retinoids ..………………………………………………11 1.7.1. Chemical structure of docetaxel…..………………………………………………15 1.7.2. Biotransformation of docetaxel. The structural modifications of docetaxel are highlighted……………………………………………………………………….20 3.1.1. Diagrammatic representation of the experimental strategy to assess the inductive effects of
Load more

Recommended publications
  • Promising Findings for SCC in Organ Transplant Recipients Repeated PDT Treatments May Reduce the Incidence of Sccs in This High-Risk Population
    Oncology Watch Cyclic Photodynamic Therapy: Promising Findings for SCC in Organ Transplant Recipients Repeated PDT treatments may reduce the incidence of SCCs in this high-risk population. By Jonathan Wolfe, MD hotodynamic therapy with 5-aminolevulinic acid SOTRs typically undergo chemoprophylaxis with sys- (ALA, Levulan, DUSA Pharmaceuticals) has temic retinoids, although there have been few ran- become established as a safe and effective option domized controlled trials to quantify their benefit. Pfor the management of AKs (see the January edi- Acitretin is probably the most frequently used agent,3 tion, available at PracticalDermatology.com). The drug but isotretinoin and etretinate are also used, and there is indicated, along with blue light application, for the is anecdotal evidence to support the use of treatment of minimally to moderately thick actinic bexarotene.4 Of note, rebound flares have been associ- keratoses of the face or scalp. However, there has ated with discontinuation of retinoids, leading some to been increasing interest in the role of PDT to manage advocate chemoprevention as a lifelong therapy.3 other types of skin cancers. A recent study shows that the procedure may be effective for reducing the inci- An Emerging Option dence of squamous cell carcinoma (SCC) in solid Given the concerns about high rates of NMSCs in organ transplant recipients (SOTR). transplant recipients, there is interest in identifying optimal treatment and prevention strategies. While Skin Cancer and SOTRs retinoid chemoprophylaxis is an important and effec- Compared to the general population, solid organ trans- tive option, additional interventions are welcome. plant recipients are at higher risk of skin cancer, with Recent findings suggest a role for cyclic 5-ALA PDT up to a 100-fold estimated increase in the relative risk therapy.5 Twelve high-risk SOTRs received cyclic PDT of squamous cell carcinoma (SCC) compared to the treatments at four- to eight-week intervals for two non-transplanted population.
    [Show full text]
  • Incidence of Differentiation Syndrome Associated with Treatment
    Journal of Clinical Medicine Review Incidence of Differentiation Syndrome Associated with Treatment Regimens in Acute Myeloid Leukemia: A Systematic Review of the Literature Lucia Gasparovic 1, Stefan Weiler 1,2, Lukas Higi 1 and Andrea M. Burden 1,* 1 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland; [email protected] (L.G.); [email protected] (S.W.); [email protected] (L.H.) 2 National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, 8032 Zurich, Switzerland * Correspondence: [email protected]; Tel.: +41-76-685-22-56 Received: 30 August 2020; Accepted: 14 October 2020; Published: 18 October 2020 Abstract: Differentiation syndrome (DS) is a potentially fatal adverse drug reaction caused by the so-called differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), used for remission induction in the treatment of the M3 subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL). However, recent DS reports in trials of isocitrate dehydrogenase (IDH)-inhibitor drugs in patients with IDH-mutated AML have raised concerns. Given the limited knowledge of the incidence of DS with differentiating agents, we conducted a systematic literature review of clinical trials with reports of DS to provide a comprehensive overview of the medications associated with DS. In particular, we focused on the incidence of DS reported among the IDH-inhibitors, compared to existing ATRA and ATO therapies. We identified 44 published articles, encompassing 39 clinical trials, including 6949 patients. Overall, the cumulative incidence of DS across all treatment regimens was 17.7%.
    [Show full text]
  • BC Cancer Benefit Drug List September 2021
    Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal
    [Show full text]
  • Resimmune, an Anti-Cd3ε Recombinant Immunotoxin, Induces
    Non-Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Resimmune, an anti-CD3 recombinant immunotoxin, induces durable remissions in patients wiεth cutaneous T-cell lymphoma Arthur E. Frankel, 1 Jung H. Woo, 2 Chul Ahn, 1 Francine M. Foss, 3 Madeleine Duvic, 4 Paul H. Neville, 5 and David M. Neville 5 1University of Texas Southwestern Medical Center, Dallas, TX; 2Baylor Scott & White Health, Temple, TX; 3Yale University School of Medi - cine, New Haven, CT; 4The University of Texas MD Anderson Cancer Center, Houston, TX; and 5Angimmune, LLC, Bethesda, MD, USA ©2015 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.123711 Manuscript received on January 20, 2015. Manuscript accepted on March 18, 2015. Correspondence: [email protected] Supplemental Material Administration-- The study was performed under the sponsorship of Angimmune, LLC, registered in clinical trials.gov as NCT00611208, and approved by Institutional Review Boards at the participating institutions. In the dose escalation phase of the study, cohorts of new patients were treated with a single course of Resimmune as 15-minute infusions at doses ranging from 2.5 to 11.25µg/kg intravenously twice daily for 4 days. There was an expansion cohort at the maximal tolerated dose (MTD) in patients with stage IB-IIB CTCL and modified skin weighted assessment tool (mSWAT) scores of <50. In the expansion phase of the study, 13 patients received a single course at the 7.5µg/kg dose level. Patient eligibility-- Patients with CD3+ T cell malignancies diagnosed by morphologic, histochemical, and cell surface criteria and having failed a systemic therapy were eligible for the dose-escalation portion of the study.
    [Show full text]
  • Acitretin; Adapalene; Alitretinoin; Bexarotene; Isotretinoin
    8 February 2018 EMA/254364/2018 Pharmacovigilance Risk Assessment Committee (PRAC) Assessment report Referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data Retinoids containing medicinal products INN: Acitretin, Adapalene, Alitretinoin, Bexarotene, Isotretinoin, Tretinoin, Tazarotene Procedure number: EMEA/H/A-31/1446 Panretin EMEA/H/A-31/1446/C/000279/0037 Targretin EMEA/H/A-31/1446/C/000326/0043 Note: Assessment report as adopted by the PRAC and considered by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ......................................................................................... 2 1. Information on the procedure ................................................................. 3 2. Scientific discussion ................................................................................ 3 2.1. Introduction......................................................................................................... 3 2.2. Clinical aspects .................................................................................................... 5 2.3. Data on efficacy ..................................................................................................
    [Show full text]
  • Acitretin; Adapalene; Alitretinoin; Bexarotene; Isotretinoin
    21 June 2018 EMA/261767/2018 Updated measures for pregnancy prevention during retinoid use Warning on possible risk of neuropsychiatric disorders also to be included for oral retinoids On 22 March 2018, the European Medicines Agency (EMA) completed its review of retinoid medicines, and confirmed that an update of measures for pregnancy prevention is needed. In addition, a warning on the possibility that neuropsychiatric disorders (such as depression, anxiety and mood changes) may occur will be included in the prescribing information for oral retinoids (those taken by mouth). Retinoids include the active substances acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tazarotene and tretinoin. They are taken by mouth or applied as creams or gels to treat several conditions mainly affecting the skin, including severe acne and psoriasis. Some retinoids are also used to treat certain forms of cancer. The review confirmed that oral retinoids can harm the unborn child and must not be used during pregnancy. In addition, the oral retinoids acitretin, alitretinoin and isotretinoin, which are used to treat conditions mainly affecting the skin, must be used in accordance with the conditions of a new pregnancy prevention programme by women able to have children. Topical retinoids (those applied to the skin) must also not be used during pregnancy, and by women planning to have a baby. More information is available below. Regarding the risk of neuropsychiatric disorders, the limitations of the available data did not allow to clearly establish whether this risk was due to the use of retinoids. However, considering that patients with severe skin conditions may be more vulnerable to neuropsychiatric disorders due to the nature of the disease, the prescribing information for oral retinoids will be updated to include a warning about this possible risk.
    [Show full text]
  • Editorial Retinoids Induced Cancer Stem Cell Differentiation And
    Editorial Retinoids Induced Cancer Stem Cell Differentiation and Apoptosis for Cancer Therapies Xin Cao Project Leader of Targeted Drug Design and Validation, Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai, 200032, China E-mail: [email protected] Received 31 January 2019; Accepted 03 April 2019; Publication 19 April 2019 Abstract Retinoids show great potential in various kinds of cancer chemotherapy due to its ability to induce signals for cell differentiation or death, as well as inhibit cancer stem cell proliferation. This paper summarized the recent progress of retinoids induced cancer stem cell differentiation and apoptosis in cancer therapy field, with the highlighted novel retinoid named WYC-209 in our lab, which could inhibit the tumor stem cell and malignant melanoma tumors with high efficacy and little toxicity. Keywords: Retinoids, cancer stem cell, differentiation, apoptosis. The discovery of retinoic acid receptors (RARs) from early research elucidates how vitamin A (Figure 1(A)) regulates mammalian physiology including spermatogenesis, fertilization, pregnancy maintenance, morphogenesis and organogenesis. Then studies indicate the main metabolized active form of VitaminA, all-trans retinoic acid (ATRA, Figure 1(B)), played important roles in certain DNAactivation and protein expression regulations [1].Accordingly, Molecular and Cellular Therapies, Vol. 7 1, 1–8. doi: 10.13052/mct2052-8426.711 This is an Open Access publication. c 2019 the Author(s). All rights reserved. 2 Xin Cao Figure 1 Structures of several retinoids. retinoids firstly occurred as naturally low-molecular weight, fat-soluble unsaturated isoprenoids, including retinaldehyde, 9-cis retinoic acid and 13-cis retinoic acid et al., which also played essential roles as all-trans retinoic acid (ATRA) in various aspects of human vision, immunity, as well as fetal cell proliferations [2].
    [Show full text]
  • Standard Oncology Criteria C16154-A
    Prior Authorization Criteria Standard Oncology Criteria Policy Number: C16154-A CRITERIA EFFECTIVE DATES: ORIGINAL EFFECTIVE DATE LAST REVIEWED DATE NEXT REVIEW DATE DUE BEFORE 03/2016 12/2/2020 1/26/2022 HCPCS CODING TYPE OF CRITERIA LAST P&T APPROVAL/VERSION N/A RxPA Q1 2021 20210127C16154-A PRODUCTS AFFECTED: See dosage forms DRUG CLASS: Antineoplastic ROUTE OF ADMINISTRATION: Variable per drug PLACE OF SERVICE: Retail Pharmacy, Specialty Pharmacy, Buy and Bill- please refer to specialty pharmacy list by drug AVAILABLE DOSAGE FORMS: Abraxane (paclitaxel protein-bound) Cabometyx (cabozantinib) Erwinaze (asparaginase) Actimmune (interferon gamma-1b) Calquence (acalbrutinib) Erwinia (chrysantemi) Adriamycin (doxorubicin) Campath (alemtuzumab) Ethyol (amifostine) Adrucil (fluorouracil) Camptosar (irinotecan) Etopophos (etoposide phosphate) Afinitor (everolimus) Caprelsa (vandetanib) Evomela (melphalan) Alecensa (alectinib) Casodex (bicalutamide) Fareston (toremifene) Alimta (pemetrexed disodium) Cerubidine (danorubicin) Farydak (panbinostat) Aliqopa (copanlisib) Clolar (clofarabine) Faslodex (fulvestrant) Alkeran (melphalan) Cometriq (cabozantinib) Femara (letrozole) Alunbrig (brigatinib) Copiktra (duvelisib) Firmagon (degarelix) Arimidex (anastrozole) Cosmegen (dactinomycin) Floxuridine Aromasin (exemestane) Cotellic (cobimetinib) Fludara (fludarbine) Arranon (nelarabine) Cyramza (ramucirumab) Folotyn (pralatrexate) Arzerra (ofatumumab) Cytosar-U (cytarabine) Fusilev (levoleucovorin) Asparlas (calaspargase pegol-mknl Cytoxan (cyclophosphamide)
    [Show full text]
  • The Selective Retinoid X Receptor Agonist Bexarotene (LGD1069, Targretin) Prevents and Overcomes Multidrug Resistance in Advanced Breast Carcinoma
    824 The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma Wan-Ching Yen and William W. Lamph women (1). The American Cancer Society estimates that f215,990 women in the United States will be found to have Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., San Diego, California breast cancer and 40,110 women will die from the disease in 2004. Although chemotherapy provides the major therapeutic modality for treatment of advanced breast cancer, the 5-year survival for disseminated breast carci- Abstract noma is <20% due to relapse with drug-resistant disease. Acquired drug resistance represents a major challenge in Several mechanisms of drug resistance have been charac- the therapeutic management of breast cancer patients. We terized in breast cancer cell lines. The best understood reported previously that the retinoid X receptor–selective mechanism is P-glycoprotein (Pgp)–mediated drug resis- agonist bexarotene (LGD1069, Targretin) was efficacious tance (2). Pgp has been shown to contribute to resistance to in treating animal models of tamoxifen-resistant breast natural product–based chemotherapeutic agents, including cancer. The goal of this study was to evaluate the effect of taxanes, anthracyclines, Vinca alkaloids, podophyllotoxins, bexarotene on development of acquired drug resistance and and camptothecins (3). The relationship among Pgp its role in overcoming acquired drug resistance in advanced expression, Pgp function, and drug resistance in clinical breast cancer. Paclitaxel, doxorubicin, and cisplatin were samples of breast carcinoma was best illustrated by chosen as model compounds to determine the effect of Mechetner et al. (4). These investigators showed that the bexarotene on the development of acquired drug resis- level of Pgp expression in freshly resected breast tumors tance.
    [Show full text]
  • Cancer Drug Costs for a Month of Treatment at Initial Food
    Cancer drug costs for a month of treatment at initial Food and Drug Administration approval Year of FDA Monthly Cost Monthly cost (2013 Generic name Brand name(s) approval (actual $'s) $'s) Vinblastine Velban 1965 $78 $575 Thioguanine, 6-TG Thioguanine Tabloid 1966 $17 $122 Hydroxyurea Hydrea 1967 $14 $97 Cytarabine Cytosar-U, Tarabine PFS 1969 $13 $82 Procarbazine Matulane 1969 $2 $13 Testolactone Teslac 1969 $179 $1,136 Mitotane Lysodren 1970 $134 $801 Plicamycin Mithracin 1970 $50 $299 Mitomycin C Mutamycin 1974 $5 $22 Dacarbazine DTIC-Dome 1975 $29 $125 Lomustine CeeNU 1976 $10 $41 Carmustine BiCNU, BCNU 1977 $33 $127 Tamoxifen citrate Nolvadex 1977 $44 $167 Cisplatin Platinol 1978 $125 $445 Estramustine Emcyt 1981 $420 $1,074 Streptozocin Zanosar 1982 $61 $147 Etoposide, VP-16 Vepesid 1983 $181 $422 Interferon alfa 2a Roferon A 1986 $742 $1,573 Daunorubicin, Daunomycin Cerubidine 1987 $533 $1,090 Doxorubicin Adriamycin 1987 $521 $1,066 Mitoxantrone Novantrone 1987 $477 $976 Ifosfamide IFEX 1988 $1,667 $3,274 Flutamide Eulexin 1989 $213 $399 Altretamine Hexalen 1990 $341 $606 Idarubicin Idamycin 1990 $227 $404 Levamisole Ergamisol 1990 $105 $187 Carboplatin Paraplatin 1991 $860 $1,467 Fludarabine phosphate Fludara 1991 $662 $1,129 Pamidronate Aredia 1991 $507 $865 Pentostatin Nipent 1991 $1,767 $3,015 Aldesleukin Proleukin 1992 $13,503 $22,364 Melphalan Alkeran 1992 $35 $58 Cladribine Leustatin, 2-CdA 1993 $764 $1,229 Asparaginase Elspar 1994 $694 $1,088 Paclitaxel Taxol 1994 $2,614 $4,099 Pegaspargase Oncaspar 1994 $3,006 $4,713
    [Show full text]
  • Retinoid Treatment of Skin Diseases
    Review Eur J Dermatol 2015; 25(5): 384-91 Lisa BECKENBACH1 Retinoid treatment of skin diseases Jens M. BARON2 Hans F. MERK2 Harald LOFFLER¨ 1 , Retinoids (vitamin A and its metabolites) are potent natural regula- Philipp M. AMANN1 2 tors of cellular activities, including cell growth and differentiation, and they mediate many essential regulatory functions, especially in the skin. 1 Department of Dermatology, SLK Hospital Heilbronn, Am Gesundbrunnen Biologically active retinoids exert their effects by binding to nuclear 20 -26, 74078 Heilbronn, Germany retinoic acid receptors and retinoid-X-receptors. The group of pharma- 2 Department of Dermatology and cologically used retinoids include naturally occurring and chemically Allergology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, synthesised vitamin A derivatives. Due to their influence on keratinocyte Germany proliferation, epidermal differentiation and keratinisation, retinoids are commonly used in the field of dermatopharmacology. For safe admin- Reprints: P. M. Amann istration of retinoids, in-depth information about adverse effects and <[email protected]> comprehensive information of the patient are important. This article gives an overview on the effects, use, and side-effects of topical and systemic retinoids in dermatology. Key words: dermatopharmacology, retinoid therapy, retinoids, vitamin Article accepted on 05/2/2015 A derivatives itamin A (all-trans retinol) and its naturally occurring and synthetic derivatives, collectively Nonaromatic endogenous retinoids (1st generation) V referred to as retinoids, exert a wide variety of O profound effects during embryogenesis, reproduction, reg- OH OH ulation of inflammation, cell growth and cell differentiation. Their decisive role as critical gene regulators is primarily Vitamin A (all-trans retinol) Tretinoin (all-trans retinoic acid) mediated by their interaction with the nuclear retinoic acid receptors (RAR) and retinoid-X-receptors (RXR) [1].
    [Show full text]
  • NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010
    NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health This document is in the public domain and may be freely copied or reprinted. DISCLAIMER Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organizations or their programs or products. Furthermore, NIOSH is not responsible for the content of these Web sites. ORDERING INFORMATION To receive documents or other information about occupational safety and health topics, contact NIOSH at Telephone: 1–800–CDC–INFO (1–800–232–4636) TTY:1–888–232–6348 E-mail: [email protected] or visit the NIOSH Web site at www.cdc.gov/niosh For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.gov/niosh/eNews. DHHS (NIOSH) Publication Number 2010−167 September 2010 Preamble: The National Institute for Occupational Safety and Health (NIOSH) Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings was published in September 2004 (http://www.cdc.gov/niosh/docs/2004-165/). In Appendix A of the Alert, NIOSH identified a sample list of major hazardous drugs. The list was compiled from infor- mation provided by four institutions that have generated lists of hazardous drugs for their respec- tive facilities and by the Pharmaceutical Research and Manufacturers of America (PhRMA) from the American Hospital Formulary Service Drug Information (AHFS DI) monographs [ASHP/ AHFS DI 2003].
    [Show full text]