A Phase II Study of Docetaxel in Patients with Metastatic Squamous
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Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
International Journal of Molecular Sciences Review Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications Daniel Fernández-Villa 1, Maria Rosa Aguilar 1,2 and Luis Rojo 1,2,* 1 Instituto de Ciencia y Tecnología de Polímeros, Consejo Superior de Investigaciones Científicas, CSIC, 28006 Madrid, Spain; [email protected] (D.F.-V.); [email protected] (M.R.A.) 2 Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-915-622-900 Received: 18 September 2019; Accepted: 7 October 2019; Published: 9 October 2019 Abstract: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Keywords: folic acid antagonists; antifolates; antibiotics; antibacterials; immunomodulation; sulfonamides; antimalarial 1. -
Testicular Cancer Treatment Regimens
Testicular Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The National Comprehensive Cancer Network Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. Note: All recommendations are category 2A unless otherwise indicated. uPrimary Chemotherapy for Germ Cell Tumors1 REGIMEN DOSING Preferred Regimens BEP (Bleomycin + Etoposide + Days 1-5: Cisplatin 20mg/m2 IV over 60 minutes dailya Cisplatin)2,a,b Days 1-5: Etoposide 100mg/m2 IV over 60 minutes daily Days 1,8,15 OR Days 2,9,16: Bleomycin 30 units IV over 10 minutes daily. -
Prednisolone-Rituximab-Vincristine (Rpacebom)
Chemotherapy Protocol LYMPHOMA BLEOMYCIN-CYCLOPHOSPHAMIDE-DOXORUBICIN-ETOPOSIDE-METHOTREXATE- PREDNISOLONE-RITUXIMAB-VINCRISTINE (RPACEBOM) Regimen Lymphoma – RPACEBOM-Bleomycin-Cyclophosphamide-Doxorubicin-Etoposide- Methotrexate-Prednisolone-Rituximab-Vincristine Indication CD20 Positive Non Hodgkin’s Lymphoma Toxicity Drug Adverse Effect Bleomycin Pulmonary toxicity, rigors, skin pigmentation, nail changes Cyclophosphamide Dysuria, haemorrragic cystitis (rare), taste disturbances Doxorubicin Cardiotoxicity, urinary discolouration (red) Etoposide Hypotension on rapid infusion, alopecia, hyperbilirubinaemia Methotrexate Stomatitis, conjunctivitis, renal toxicity Weight gain, GI disturbances, hyperglycaemia, CNS disturbances, Prednisolone cushingoid changes, glucose intolerance Severe cytokine release syndrome, increased incidence of Rituxumab infective complications, progressive multifocal leukoencephalopathy Vincristine Peripheral neuropathy, constipation, jaw pain The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1.2 (Jan 2015) Page 1 of 16 Lymphoma- RPACEBOM-Bleomycin-Cyclophospham-Doxorubicin-Etoposide-Methotrexate-Prednisolone-Rituximab-Vincristine Monitoring Drugs FBC, LFTs and U&Es prior to day one and fifteen Albumin prior to each cycle Regular blood glucose monitoring Check hepatitis B status before starting treatment with rituximab The presence of a third fluid compartment e.g. ascites or renal failure may delay the clearance of methotrexate -
Resistance to Antifolates
Oncogene (2003) 22, 7431–7457 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Resistance to antifolates Rongbao Zhao1 and I David Goldman*,1 1Departments of Medicine and Molecular, Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA The antifolates were the first class of antimetabolites to the kinetics of the interaction between MTX and DHFR enter the clinics more than 50 years ago. Over the was fully understood, and not until the late 1970s and following decades, a full understanding of their mechan- early 1980s when polyglutamate derivatives of MTX were isms of action and chemotherapeutic potential evolved detected and their pharmacologic importance clarified. along with the mechanisms by which cells develop Likewise, an understanding of tumor cell resistance to resistance to these drugs. These principals served as a antifolates evolved slowly, often paralleling the emergence basis for the subsequent exploration and understanding of of new molecular concepts. As the mechanisms of the mechanisms of resistance to a variety of diverse resistance to antifolates were characterized, this provided antineoplastics with different cellular targets. This section insights and principles that were broadly applicable to describes the bases for intrinsic and acquired antifolate other antineoplastics. Ultimately, this knowledge led to the resistance within the context of the current understanding development of a new generation of antifolates, in the late of the mechanisms of actions and cytotoxic determinants 1980s and 1990s, which are potent direct inhibitors of of these agents. This encompasses impaired drug transport tetrahydrofolate (THF)-cofactor-dependent enzymes. Sev- into cells, augmented drug export, impaired activation of eral of these drugs are now in clinical trials, and the antifolates through polyglutamylation, augmented hydro- activity of one, pemetrexed, has been confirmed in a large lysis of antifolate polyglutamates, increased expression Phase III trial (Vogelzang et al., 2003). -
DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents
molecules Review DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents Maria Valeria Raimondi 1,*,† , Ornella Randazzo 1,†, Mery La Franca 1 , Giampaolo Barone 1 , Elisa Vignoni 2, Daniela Rossi 2 and Simona Collina 2,* 1 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy; [email protected] (O.R.); [email protected] (M.L.F.); [email protected] (G.B.) 2 Drug Sciences Department, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] (E.V.); [email protected] (D.R.) * Correspondence: [email protected] (M.V.R.); [email protected] (S.C.); Tel.: +390-912-389-1915 (M.V.R.); +390-382-987-379 (S.C.) † These Authors contributed equally to this work. Academic Editors: Simona Collina and Mariarosaria Miloso Received: 25 February 2019; Accepted: 20 March 2019; Published: 22 March 2019 Abstract: Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field. -
Protein Kinase C As a Therapeutic Target in Non-Small Cell Lung Cancer
International Journal of Molecular Sciences Review Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer Mohammad Mojtaba Sadeghi 1,2, Mohamed F. Salama 2,3,4 and Yusuf A. Hannun 1,2,3,* 1 Department of Biochemistry, Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA; [email protected] 2 Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; [email protected] 3 Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA 4 Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Dakahlia Governorate, Egypt * Correspondence: [email protected] Abstract: Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. Citation: Sadeghi, M.M.; Salama, PKC isoforms α, ", η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates M.F.; Hannun, Y.A. Protein Kinase C with worse prognosis in NSCLC patients. -
Toward a Better Understanding of Methotrexate
ARTHRITIS & RHEUMATISM Vol. 50, No. 5, May 2004, pp 1370–1382 DOI 10.1002/art.20278 © 2004, American College of Rheumatology REVIEW Toward a Better Understanding of Methotrexate Joel M. Kremer More is known about the metabolism, toxicity, literature. It is the goal of this contribution to review the pharmacokinetics, and clinical profile of methotrexate major and significant concepts regarding MTX metabo- (MTX) than any other drug currently in use in either lism which may be relevant to the treatment of rheu- rheumatology or oncology. In the 56 years since Farber matic disease, not to summarize publications about its et al first described clinical remissions in children with clinical effects. It will become apparent in the course of acute leukemia after treatment with the folate antago- the discussion that most of what we know about the nist aminopterin (1), antifolate drugs, dominated by metabolism of MTX is derived from the oncology liter- MTX, have been used to treat millions of patients with ature. Clinicians who have become familiar with the malignant and autoimmune diseases. It is estimated that concepts presented should be better equipped to pre- MTX is now prescribed to at least 500,000 patients with scribe the drug in a more effective and rational manner. rheumatoid arthritis (RA) worldwide, making it by far In addition, emerging insights into the role of naturally the most commonly used disease-modifying antirheu- occurring genetic variations in cellular pathways of MTX matic drug (DMARD). Indeed, MTX is prescribed for metabolism hold promise for predicting both efficacy more patients with RA than are all of the biologic drugs and toxicity of the drug. -
Malarial Dihydrofolate Reductase As a Paradigm for Drug Development Against a Resistance-Compromised Target
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target Yongyuth Yuthavonga,1, Bongkoch Tarnchompooa, Tirayut Vilaivanb, Penchit Chitnumsuba, Sumalee Kamchonwongpaisana, Susan A. Charmanc, Danielle N. McLennanc, Karen L. Whitec, Livia Vivasd, Emily Bongardd, Chawanee Thongphanchanga, Supannee Taweechaia, Jarunee Vanichtanankula, Roonglawan Rattanajaka, Uthai Arwona, Pascal Fantauzzie, Jirundon Yuvaniyamaf, William N. Charmanc, and David Matthewse aBIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand; bDepartment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; cMonash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia; dLondon School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, England; eMedicines for Malaria Venture, 1215 Geneva, Switzerland; and fDepartment of Biochemistry and Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Bangkok 10400, Thailand Edited by Wim Hol, University of Washington, Seattle, WA, and accepted by the Editorial Board September 8, 2012 (received for review March 16, 2012) Malarial dihydrofolate reductase (DHFR) is the target of antifolate target is P. falciparum dihydrofolate reductase (DHFR), which is antimalarial drugs such as pyrimethamine and cycloguanil, the inhibited by the antimalarials PYR and cycloguanil (CG) (Fig. 1). clinical efficacy of which have been -
Effect of Human Fibroblast Interferon on the Antiviral Activity of Mammalian Cells Treated with Bleomycin, Vincristine, Or Mitomycin C1
[CANCER RESEARCH 43, 5462-5466. November 1983] Effect of Human Fibroblast Interferon on the Antiviral Activity of Mammalian Cells Treated with Bleomycin, Vincristine, or Mitomycin C1 Robert J. Suhadolnik,2 Yosuke Sawada,3 Maryann B. Flick, Nancy L. Reichenbach, and Joseph D. Mosca3 Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 ABSTRACT protein kinase (2,9,28,34,36). In addition to the use of interferon in the treatment of cancer (1, 11, 12, 29, 34), combination Bleomycin, vincristine, or mitomycin C, when added to HeLa chemotherapy of interferon and methotrexate, c/s-platinum diam- cells simultaneously with human fibroblast interferon (IFN-0), minedichloride, cyclophosphamide, or 1,3-bis(/i-chloroethyl)-1- caused a decrease in cell density and inhibited DMA synthesis nitrosourea on either tumor cells in culture or in leukemic mice compared with HeLa cells treated with IFN-/3 alone. However, has been reported (5, 7, 10, 25). Furthermore, Stolfi ef al. (37) the IFN-0-induced antiviral processes were unaffected by the reported recently that the administration of mouse interferon to presence of these drugs as determined by in vitro enzyme assays mice following the administration of 5-fluorouracil protected the and the development of the antiviral state in the intact HeLa cell. mice from mortality. Because it is possible to selectively inhibit HeLa cells treated with IFN-/Õalone or with IFN-/3 in combination proliferation of tumor cells with chemotherapeutic drugs, we with bleomycin, vincristine, or mitomycin C were able to induce reasoned that the ability of the normal cell to maintain the antiviral the double-stranded RNA-dependent adenosine triphos- phate:2',5'-oligoadenylic acid adenyltransferase (EC 2.2.2.-) and state might be adversely affected by such drugs and that the antiproliferative action of interferons might affect the activity of the double-stranded RNA-dependent protein kinase. -
Cisplatin, Methotrexate and Bleomycin for Advanced Recurrent Or
: Ope gy n A lo c ro c d e s n s A Yumura et al., Andrology (Los Angel) 2017, 6:2 Andrology-Open Access DOI: 10.4172/2167-0250.1000194 ISSN: 2167-0250 Research Article Open Access Cisplatin, Methotrexate and Bleomycin for Advanced Recurrent or Metastatic Penile Squamous Cell Carcinoma Yumura Y*, Kasuga J, Kawahara T, Miyoshi Y, Hattori Y, Teranishi J, Takamoto D, Mochizuki T and Uemura H Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Japan *Corresponding author: Yasushi Yumura, Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Japan, Tel: +81452615656; Fax: +81452531962; E-mail: [email protected] Received date: December 11, 2017; Accepted date: December 15, 2017; Published date: December 22, 2017 Copyright: © 2017 Yumura Y, et al. 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 Objective: This study aimed to evaluate the efficacy and toxicity of cisplatin, methotrexate, and bleomycin (CMB) chemotherapy in patients with advanced, recurrent, or metastatic penile squamous cell carcinoma (PSCC). Methods: The CMB regimen was administered to 12 patients with advanced (n=7), recurrent (n=4), or metastatic (n=1) PSCC. Patients received a total of 21 cycles of CMB between 2002 and 2009, and were retrospectively reviewed for treatment efficacy and toxicity of the drugs. The mean patient age was 61 (61.0 ± 8.7) years. Patients received 20.0 mg/m2 of cisplatin intravenously on days 2-6; 200.0 mg/m2 of methotrexate intravenously on days 1, 15 and 22; and 10.0 mg/m2 of bleomycin as a bolus on days 2-6. -
The Role of Folate Receptor Alpha (Fra) in the Response of Malignant Pleural Mesothelioma to Pemetrexed-Containing Chemotherapy
British Journal of Cancer (2010) 102, 553 – 560 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 $32.00 www.bjcancer.com The role of folate receptor alpha (FRa) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy *,1 1,3 1 2 1 1,3 1,3 1 JE Nutt , ARA Razak , K O’Toole , F Black , AE Quinn , AH Calvert , ER Plummer and J Lunec 1 2 Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Department of Pathology, Royal 3 Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, UK BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRa). METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI50). FRa expression was determined by western blotting and that of FRa, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT–PCR. Immunohistochemistry for FRa was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. RESULTS: A wide range of GI50 values was obtained for the cell lines, H2452 cells being the most sensitive (GI50 22 nM) and RS5 cells having a GI50 value greater than 10 mM.NoFRa protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. -
Chemotherapy of Ovarian Cancer Directed by the Human Tumor Stem Cell Assay
UC Irvine UC Irvine Previously Published Works Title Chemotherapy of ovarian cancer directed by the human tumor stem cell assay. Permalink https://escholarship.org/uc/item/7fz6p03p Journal Cancer chemotherapy and pharmacology, 6(3) ISSN 0344-5704 Authors Alberts, D S Chen, H S Salmon, S E et al. Publication Date 1981 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Cancer Chemother Pharmacol (1981) 6: 279-285 ancer hernotherapy and harmacology O Springer-Verlag 1981 Chemotherapy of Ovarian Cancer Directed by the Human Tumor Stem Cell Assay David S. ~lberts',H. S. George Chen1,2, Sydney E. salmon1, Earl A. surwit1>3, Laurie young1, Thomas E. ~oon',and Frank L. Meyskens, .Trl, and Co-investigators from the Arizona-New Mexico Tumor Cloning Group" The Cancer Center, College of Medicine, Department of Chemical Engineering, College of Mines, Department of Obstetrics and Gynecology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA Summary. The human tumor stem cell assay ovarian cancer of epithelial type [6, 22, 261. In the (HTSCA) has been used to study the in vitro sensitivity past chemotherapy has been selected on an empirical rates of anticancer drugs used in the treatment of 115 basis, with as many as three or more agents being patients with previously untreated and relapsing combined for the treatment of newly diagnosed ovarian cancer. The data from these studies have patients with stages 111 and IV disease [9, 25, 271. identified patterns of cross resistance and residual When patients relapse following therapy with multi- sensitivity between these agents, and have allowed the ple-drug regimens the response rate to single agents is prospective selection of single agents possessing in in the range of 0-25% [12,21,28].