MPP Lecture 8: Nucleotide Synthesis & Chemotherapy PDF
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This document covers nucleotide synthesis, different types of chemotherapy and their mechanisms of action. The document describes the various mechanisms by which chemotherapeutic agents inhibit DNA synthesis. It further explains the roles of enzymes and inhibitors in these processes.
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1.Understand the basics of nucleotide synthesis Nucleotides: precursors of DNA and RNA - Purines: Pure As Gold (A & G) - Pyrimidines: C, T, & U General sets of sequential reactions: 1. Synthesis of ribonucleotides 2. Reduction of ribonucleotides to deoxyribonucleotides a. C...
1.Understand the basics of nucleotide synthesis Nucleotides: precursors of DNA and RNA - Purines: Pure As Gold (A & G) - Pyrimidines: C, T, & U General sets of sequential reactions: 1. Synthesis of ribonucleotides 2. Reduction of ribonucleotides to deoxyribonucleotides a. Catalyzed by the enzyme ribonucleotide reductase b. Antimetabolites: inhibit synthesis of nucleotides 3. Formation of DNA precursors 4. DNA is transcribed into RNA 5. RNA translated to proteins Conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP) - Catalyzed by Thymidylate synthase - MTHF is required as a cofactor - DHF reduces THF by dihydrofolate reductase (DHFR) to produce MTHF 2.Categorize, compare and contrast the three classes of traditional chemotherapeutic agents Aspect Inhibitors of DNA Inhibitors of DNA Damaging Synthesis and Microtubule Agents Integrity Function Mechanism Inhibit DNA replication Disrupt microtubule Directly damage DNA Of Action or repair processes dynamics in mitosis (cross-links, breaks) Cell Cycle S-Phase M-Phase All phases Specificity Rapid Dividing Solid tumors Broad, leukemias, cancers solid tumors Target enzymes involved in prevent proper chromo single-strand or nucleotide production segregate double-strand breaks DNA polymerase inhibit the assembly intercalation into DNA function stabilize them cross-linking of DNA misincorporation of excessively strand nucleotides defective cell division apoptosis Examples Antimetabolites Vinca Alkaloids Alkylating agents Topoisomerase Taxanes Antitumor antibiotics Inhibitors Platinum complexes Key Effective during active Highly effective during Effective against both Advantages DNA replication mitosis dividing and non-dividing cells Key Resistance can Neurological side High risk of long-term Disadvantage develop via mutations effects complications like in target enzymes secondary cancers s 3.Describe the mechanism of actions of inhibitors of thymidylate synthase and purine metabolism Antimetabolites: Inhibitors of thymidylate synthesis or Purine Metabolism inhibitors of thymidylate synthase 1. 5-Fluorouracil (5-FU) inhibits DNA synthesis a. Interferes with biosynthesis of thymidylate, U -> T b. Pretends to look like Uracil c. Highly toxic 2. Capecitabine is an orally bioavailable prodrug of 5-FU a. Absorbed and converted to 5-FU Inhibitors of Purine Metabolism 1. 6-Mercaptopurine (6-MP) a. inosine analogues b. inhibit interconversions among purine nucleotides c. Decrease AMP and GMP 2. Azathioprine (AZA) a. Prodrug of 6-MP b. Superior immunosuppressant compared to 6-MP 3. Pentostatin is a selective inhibitor of adenosine deaminase (ADA) a. Enzyme inhibitor b. structural analogue of the intermediate in the reaction catalyzed by ADA and binds to the enzyme with high affinity 4.Know the mechanism of actions of inhibitors of ribonucleotide reductase inhibitors of ribonucleotide reductase 1. Hydroxyurea a. inhibits ribonucleotide reductase using a tyrosyl radical b. Unable to convert nucleotides to deoxynucleotides Purine and pyrimidine Analogues - “Rogue” nucleotides that are incorporated into DNA - 1. Guanine analogues a. Thioguanine i. O atom -> S atom 2. Purine analogues a. Fludarabine phosphate b. Cladribine 3. Cytidine analogues a. Cytarabine i. Pro-drug b. 5-Azacytidine 5.Explain the mechanism of actions of antimetabolites and agents that modify DNA structure 1. Incorporate into DNA Causing: a. Chain termination i. Fludarabine phosphate ii. Cladribine b. Competition for DNA polymerase i. Cytarabine c. Methylation i. 5-Azacytidine 2. Leading to: a. Disruption of DNA structure b. DNA strand breakage c. inhibition of cell growth d. Altered gene expression 6.Explain the mechanism of actions of topoisomerase inhibitors Topoisomerase inhibitors - Interfere with the normal function of topoisomerases - cause topoisomerases to participate in DNA destruction include: Topoisomerase I - Camptothecins Topoisomerase II - Anthracyclines - Epipodophyllotoxins - Combines with cisplatin or bleomycin - Amsacrine 7.Predict the most appropriate chemotherapy given a clinical scenario
