BMS2047 Targeting Replicating Cells Lecture Notes PDF

BMS2047: Targeting replicating cells Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation for the next 2 weeks: Week 1: Thursday 8th February 13.00-14.00 Week 2: Friday 16th February 09.00-10.00 Click here for other weeks Or book an appointment: https://calendly.com/sgbai...

BMS2047: Targeting replicating cells Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation for the next 2 weeks: Week 1: Thursday 8th February 13.00-14.00 Week 2: Friday 16th February 09.00-10.00 Click here for other weeks Or book an appointment: https://calendly.com/sgbailey/15min What is the link between cancer cells and infectious agents? Principles of cancer development How does cancer occur? Encapsulated: Single location Easily treatable low risk Invasive: Al-Zaher (2009) Hematology/Oncology and Stem Cell Therapy 2(1):259-264 Aggressive Cells move outside a tumour “capsule” Metastasis through body Many cancers are diagnosed late → High chance of metastasis Chemotherapy: Where in the cell cycle? Modify DNA structure: Alkylating Agents Antibiotics Inhibition of DNA synthesis: Inhibit DNA polymerase Inhibit Dihydrofolate reductase Methylation of deoxyuridylic to thymidylic acid Inhibit thymidylate synthetase Inhibit topoisomerase Steroid hormones & antagonists of specific proteins: Glucocorticoids, anti-oestrogens, androgens/anti-androgens M-Phase Specific Vinca alkaloids M Taxanes Cell cycle inhibitors: CDK inhibitors S Purines Pyrimidines Many drugs not cell cycle specific specific proteins e.g. G0 Target monoclonal antibodies, inducers of ROS etc Mercaptopurine Adapted from Neal (2016) Medical Pharmacology at a Glance 8th Edn Death by apoptosis How does a cell deal with damaged DNA? Death Receptor e.g. CD95 Controlled Cell Death (Apoptosis) CD95L Extrinsic pathway Pro-caspase 8/10 CD95L Caspase 3, 6, 7 Caspase 8/10 + CD95L Caspase dependent DNAses nucleus Pro-caspase 3,6,7 p p p53 BAX transcription How does a cell deal with damaged DNA? Controlled Cell Death (Apoptosis) Intrinsic pathway Pro-caspase 3,6,7 Caspase 3, 6, 7 Caspase 9 + Caspase dependent DNAses nucleus DNA damage p p Procaspase 9 + Bax, Bad, Bid p53 Apoptosis Extrinsic Pathway Intrinsic Pathway  Signalling from outside the cell, which can be perpetuated by CD95L expression (FasL)  DNA damage causes rapid p53 phosphorylation and activation.  Transcriptional activation of Bcl2 genes BAX, BAD and BID.  Bcl2 proteins form pore in mitochondrial membrane and cytochrome C moves into cytoplasm.  Activation of pro-caspase 9 by proteolytic cleavage.  Activation of Pro-caspase 3,6,7 by caspase 9 (Ca2+ as cofactor).  Caspases activate DNAses in nucleus to cause DNA degradation (→ fragmented nucleus).  Activation of pro-caspases 8 & 10 by proteolytic cleavage.  Activation of Pro-caspase 3,6,7 by caspases 8/10 (Ca2+ as cofactor).  Caspases activate DNAses in nucleus to cause DNA degradation (→ fragmented nucleus).  Activation of p53 (by phosphorylation) can activate intrinsic pathway too. This weeks Lecture Bites: Lecture Bite 4: Targeting DNA synthesis Lecture Bite 5: Targeting DNA synthesis 2 Lecture Bite 6: Other ways of inhibiting DNA replication Week 3: Lecture Bite 1: Targeting cell division Lecture Bite 2: More specific therapies Learning Outcomes Outline the principles of cancer development. Integrate knowledge of cellular signalling involved in both cancer development and cell death to specific drug. mechanisms. Describe treatment strategies, relating it to the principles of cancer development. Explain how treatment strategies can be tailored when there are distinctive features which disseminate normal from cancerous cells. ANTI-INFECTIVES Student feedback and consultation th Week 1: Thursday 8 February 13.00-14.00 Week 2: Friday 16th February 09.00-10.00 Click here for other weeks Antibiotics What are the defining properties of bacteria? What key processes can we target? Inhibition of cell wall synthesis β-Lactam Antibiotics Bacteriocidal Interfere with cell wall biosynthesis (peptidoglycans) Large group including Penicillins, cephalosporins, carbapenems and monobactams Cephalosporins can be used with or without beta-lactamase inhibitor https://apps.who.int/iris/bitstream/handle/10665/ 273826/EML-20-eng.pdf?ua=1 Neal (2016) Medical Pharmacology at a Glance 8th Edn Cephalosporins Anti-Methicillin-resistant Staphylococcus aureus (MRSA) Ceftaroline, ceftobiprole Inhibition of nucleic acid synthesis Bacteria must synthesize folates, but humans can gain from diet. Bacteriostatic Sulphonamides, Trimethoprim, Cotrimoxazole-combo – Sulphonamide use decreased as resistance has increased. – Cotrimoxazole acts at both steps Common side effects: – GI tract hypersensitivity – Rare side effects: Anaphylactic shock Figure 51.2 Rang & Dales Pharmacology (2016) 8th Edition Bacterial DNA replication Requires proteins: DnaA binds at OriC (Origin of replication). DNA gyrase (Topoisomerase II) DNA ligase DnaB works as a helicase. DnaC DNA polymerase III DnaG (primase) Single strand binding proteins Click here for video of prokaryotic DNA replication if you need a refresher DNA Gyrase Inhibitors Bacterial DNA gyrase introduces negative supercoils into a relaxed closed circular DNA molecule DNA gyrase is necessary for DNA synthesis to occur E.g. Nalidixic acid, coumermycin – Active against different subunits of DNA gyrase Bacteriostatic Orally active Useful in cases where bacteria have become resistant to penicillins, cephalosporins or aminoglycosides Common side effect: GI tract hypersensitivity ABOVE: Neal (2016) Medical Pharmacology at a Glance LEFT: Rang & Dales Pharmacology (2016) 8th Edition Inhibition of protein synthesis Neal (2016) Medical Pharmacology at a Glance 8th Edn This weeks Lecture Bites: Lecture Bite 1: Drugs of interest & Antibiotic resistance Lecture Bite 2: Anti-Virals Lecture Bite 3: Anti-virals 2; HIV: a case in point Learning outcomes Explain the rationale behind : – Infective drug design – Identification and exploitation of difference between hostpathogen Be able to provide examples of the different classes of antipathogenic drug classes, including their mode of action – Demonstrate why different drug classes work – Understand the challenge of resistance – How are we trying to mitigate this? Understand the concept of risk verses benefit for drug prescription To post on the discussion board click here References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. Neal (2016) Medical Pharmacology at a Glance 8th Edn (especially for revision) IN MORE DETAIL: WHO ESSENTIAL MEDICINES LIST: https://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1 British National Formulary(BNF) for info on drug:drug interactions, side effects and use for combinations: https://bnf.nice.org.uk/drug/ Fernandes, P., & Martens, E. (2017) Antibiotics in late clinical development. Biochemical Pharmacology 133:152–163 Bryan-Marrugo, O.L. (2015) History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C. Medicina Universitaria. 17(68):165-174 Amarelle, L., Lecuona, E., & Sznajdera, J.I.(2017) Anti-Influenza Treatment: Drugs Currently Used and Under Development. Arch Bronconeumol. 53(1):19–26 Ventola, C.L. (2015) The Antibiotic Resistance Crisis: Part 1: Causes and Threats P T 40(4): 277–283.