BMS2047_03_Anti Cancer treatments_2024 - Copy.pdf

BMS2047: Anti-Cancer treatments Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation Week 2: Friday 16th February 09.00-10.00 Week 3: Thursday 22nd February 13.00-14.00 Click here for other weeks Learning Outcomes Outline the principles of cancer development. Integrate...

BMS2047: Anti-Cancer treatments Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation Week 2: Friday 16th February 09.00-10.00 Week 3: Thursday 22nd February 13.00-14.00 Click here for other weeks 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. Targeting DNA synthesis Lecture bite 4 DNA synthesis inhibitors: DNA damaging agents Alkylating agents: formation of covalent bond in DNA → impedes replication.  Intra-strand linking and crosslinking  N7 & O6 of adjacent guanines become crosslinked  Failure of DNA strands to separate  Most susceptible in late G1 and S phase of cell cycle INTRA STRAND Figure 56.3 Rang & Dales Pharmacology (2016) 8th Edition DNA synthesis inhibitors: DNA damaging agents Platinum based: cisplatin, carboplatin, oxaloplatin  Water-soluble  Slow IV or infusion  Usually used in solid tumours e.g. testes and ovary  SIDE EFFECTS: Highly nephrotoxic, low myelotoxicity, lots of vomiting and nausea.  REFINED MODEL (2nd Generation) = Carboplatin, less side effects except increase in myelotoxicity Figure 56.3 Rang & Dales Pharmacology (2016) 8th Edition DNA damaging agents: Alkylation Nitrogen mustards: E.g. Cyclophosphamide Activated by Phase I metabolism (liver) Effective on lymphocytes Administration is orally or intravenous (IV) Nitrosoureas: E.g. Lomustine Lipid soluble → cross blood-brain barrier Figure 56.4 Rang & Dales Pharmacology (2016) 8th Edition Severe effect replicative capacity of bone marrow Targeting DNA synthesis (2) Lecture bite 5 DNA synthesis inhibitors: Anti-metabolites Block one or more metabolic pathways involved in DNA synthesis Folate antagonists – Methotrexate (MTX) Inhibition of dihydrofolate reductase Competitive inhibitor; higher affinity than dihydrofolate ↑Folate from diet → resistance Low lipid solubility Administration: Oral, IV, IT, IM. SIDE EFFECTS: Bone Marrow depression Epithelial/mucosal layer damage Used in combination therapy Figure 56.5 Rang & Dales Pharmacology (2016) 8th Edition DNA synthesis inhibitors: Anti-metabolites Tetrahydrofolate polyglutamate = FH4(glu)n, 2′-deoxythymidylate = DTMP, 2′-deoxyuridylate = DUMP Figure 56.6 Rang & Dales Pharmacology (2016) 8th Edition DNA synthesis inhibitors: Anti-metabolites Pyrimidine analogues: O  Inhibition of Thymidylate synthetase 5-FU  Activation of DNA damage response 5-FdUMP Thymidylate synthetase  E.g. Fluorouracil Analogue of uracil 5-FUTP 5-FdUTP DNA damage RNA damage p p p53 Nucleotide pool imbalances Prevents methylation of the uracil analogue → no generation of dTMP SIDE EFFECTS: Myelotoxicity Epithelial/mucosal layer damage Nausea & vomiting Adapted from Avendaño and Menéndez (2015) DNA synthesis inhibitors: Anti-metabolites Purine analogues: e.g. Fludarabine Metabolised to a trisphosphate form Used as a substrate for DNA polymerase and inhibits active site. SIDE EFFECTS: Myelosuppression Inhibition of purine deaminase: e.g. Penostatin Inhibits adenosine deaminase Prevents purine metabolism DNA synthesis inhibitors: Nucleoside analogues Nucleoside analogues  E.g. Cytarabine (pyrimidine)  Analogue of 2’-deoxycytidine  Enters cell and is phosphorylated to cytosine arabinoside trisphosphate  cytosine arabinoside trisphosphate binds DNA polymerase and inhibits its action.  SIDE EFFECTS: Bone Marrow depression Epithelial/muscosal layer damage Nausea & vomiting Figure 56.7 Rang & Dales Pharmacology (2016) 8th Edition Other ways of inhibiting DNA replication Lecture bite 6 Cytotoxic antibiotics affect nucleic acid structures  Main mechanism is through DNA modification Topoisomerase inhibitors Alkylating agents Inhibitors of DNA & RNA polymerase  Not recommended for use in combination with radiation Cytotoxic antibiotics Anthracyclines e.g. Doxorubicin  Inhibits topoisomerase II  Also binds DNA, inhibits DNA/RNA polymerase  Lymphomas and solid tumours  Given by IV infusion  SIDE EFFECTS: Nausea & vomiting Loss of hair myelosuppression cardiotoxicity problems  Others include Bleomycin Plant Derivatives  Naturally occurring products  Often (but NOT always) target microtubules  Types include: Vinca alkaloids (Derived from periwinkle plant) Taxanes (from bark of Pacific Yew tree) Others e.g. Etoposide (from mandrake root) Plant derivatives: Topoisomerase inhibitors E.g. Etoposide  Semi-synthetic plant analogues  Block cells in late S or G2  Binds to the complex formed between DNA and topoisomerase  Block cells in late S or G2  Eventually leads to double stranded DNA breaks Pommier (2009)Chem Rev To post on the discussion board click here References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. IN MORE DETAIL: Or come and talk to me  Starobova, H., and Vetter, I. (2017) Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. Frontiers in Molecular Neuroscience 10(174):1-21  Kolch, W & Pitt, A. (2010) Functional proteomics to dissect tyrosine kinase signalling pathways in cancer. Nat Rev Cancer 10(9):618-29  Patel, H.K., & Bihani, T. (2018) Selective Eoestrogen Recptor Modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacology & Therapeutics 186:1–24  Foster, T., et al. (2011) The economic burden of metastatic breast cancer: a systematic review of literature from developed countries. Cancer Treatment Reviews 37: 405-415  Barthelemy, P., LeBlanc, J., Goldbarg, V., Wendling, F., & Kurtz, J-E. (2014) ANTICANCER RESEARCH 34: 14831492  Barbier, P., Tsvetkov, P.O., Breuzard, G., & Devred, F. (2014) Deciphering the molecular mechanisms of antitubulin plant derived drugs. Phytochemistry Reviews 13(1): 157–169  Weaver, B.A. (2014) How Taxol/paclitaxel kills cancer cells. Molecular Biology of the Cell 25: 2677-81  Khan et al., (2015) Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors by Modulating PGlycoprotein through Dietary Nutraceuticals. Asian Pac J Cancer Prev. 16(16):6831-6839  Holohan, C., Van Schaeybroeck, S., Longley, D.B., & Johnston, P.G. (2013) Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer 13: 714–726  Agneyo Ganguly et al. (2007) Betulinic Acid, a Catalytic Inhibitor of Topoisomerase I, Inhibits Reactive Oxygen Species–Mediated Apoptotic Topoisomerase I–DNA Cleavable Complex Formation in Prostate Cancer Cells but Does Not Affect the Process of Cell Death. Cancer Res 67:11848-11858  Pommier, Y. (2009) DNA Topoisomerase I Inhibitors: Chemistry, Biology and Interfacial Inhibition. Chem Rev. 109(7): 2894–2902.