Cancer Chemotherapeutic Agents Lecture 5 - Dr. M Casely-Hayford: Antimetabolites and DNA Topoisomerases
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Questions and Answers

What is the biological function of DNA topoisomerases?

  • Methylating deoxyuridine monophosphate to give dTMP (correct)
  • Modulating drug treatment for cancer
  • Catalyzing the synthesis of thymine and purine bases
  • Acting as targets for cancer drug development

    • What is the essential role of folinic acids in the synthesis of thymine and purine bases?

  • Preventing cell death
  • Accelerating cell division
  • Catalyzing DNA synthesis (correct)
  • Increasing the affinity of methotrexate to enzymes

    • How do classical antifolates differ from nonclassical antifolates?

  • Presence of glutamic acid side chains vs. presence of lipophilic substituents (correct)
  • Inhibition of thymidylate synthase vs. inhibition of DHFR
  • Folic acid analogues vs. natural ligand replacements
  • Stronger affinity to enzyme vs. lack of hydrogen bonds

    • Why does Aminopterine have a stronger affinity to enzymes compared to natural substrate folic acid?

    <p>Additional hydrogen bonds due to replacing (- NH2 ) group with (=O)</p> Signup and view all the answers

    What is the main consequence of DHFR inhibition?

    <p>Blockage of DNA synthesis</p> Signup and view all the answers

    Which statement about 5-Fluorouracil (5FU) is correct?

    <p>It is a thymidylate synthase inhibitor</p> Signup and view all the answers

    What is the lead structure of Topoisomerase I inhibitors?

    <p>Camptothecin</p> Signup and view all the answers

    How does Topoisomerase I work to release supercoiled tension in DNA?

    <p>By breaking one DNA strand and rotating it around the enzyme</p> Signup and view all the answers

    Which chemical modification was done to improve the water solubility of camptothecin, resulting in topotecan?

    <p>Addition of hydroxyl and dimethylaminomethyl substituents</p> Signup and view all the answers

    What is the mechanism of action of camptothecin derivatives like irinotecan in inhibiting Topoisomerase I?

    <p>Stabilizing the cleavable DNA-enzyme complex</p> Signup and view all the answers

    What is the active metabolite of irinotecan, a derivative of camptothecin?

    <p>SN-38</p> Signup and view all the answers

    Which type of cancer is topotecan, a derivative of camptothecin, used to treat?

    <p>Ovarian cancer</p> Signup and view all the answers

    What is the primary reason for the absence of dTMP in the fluorinated ternary complex?

    <p>The complex cannot breakdown due to the stable C5-F bond</p> Signup and view all the answers

    Which type of DNA topoisomerase enzyme breaks both strands and requires ATP for full activity?

    <p>Topoisomerase II</p> Signup and view all the answers

    What is the significance of the 'cleavable complex' in the action of DNA topoisomerase enzymes?

    <p>It is the form of the enzyme during DNA cleavage</p> Signup and view all the answers

    What is the main function of DNA topoisomerases in DNA transcription and replication?

    <p>Winding and unwinding of supercoiled DNA</p> Signup and view all the answers

    What is the primary mechanism by which 5-fluorouracil acts as an anticancer drug?

    <p>It inhibits the synthesis of dTMP</p> Signup and view all the answers

    What is the significance of the 'topo-isomers' in the context of DNA topology?

    <p>They refer to DNA loops with different numbers of twists</p> Signup and view all the answers

    What is the role of tyrosine residues in the action of DNA topoisomerase enzymes?

    <p>They are involved in the cleavage of DNA</p> Signup and view all the answers

    What is the primary mechanism by which DNA topoisomerase enzymes regulate the 3D geometry of DNA?

    <p>They regulate DNA supercoiling</p> Signup and view all the answers

    What is the primary role of oral prodrugs in the context of 5-fluorouracil treatment?

    <p>They bypass the need for intravenous administration</p> Signup and view all the answers

    What is the primary role of DNA topoisomerase enzymes in DNA transcription?

    <p>They facilitate DNA relaxation</p> Signup and view all the answers

    What is the mechanism of action of 5-FU in inhibiting DNA synthesis?

    <p>Acts as a suicide substrate for thymidylate synthase</p> Signup and view all the answers

    Why does 5-FU show selectivity for cancer cells over normal skin cells?

    <p>Presence of fluorine atom accelerates formation of ternary complex in cancer cells</p> Signup and view all the answers

    Which step in the dTMP synthesis pathway involves the breaking of the imidazolidine ring and release of N10 from the co-factor?

    <p>Step 3</p> Signup and view all the answers

    Why does the fluorinated ternary complex formed by 5-FU prevent the breakdown into dTMP?

    <p>Fluorine atom stabilizes the C5 alkene bond</p> Signup and view all the answers

    What is the primary target of methotrexate's mechanism of action?

    <p>Thymidylate synthase enzyme</p> Signup and view all the answers

    In what way does methotrexate differ from aminopterine in its pharmacokinetic properties?

    <p>Affinity to enzyme</p> Signup and view all the answers

    What role does co-factor N5, N10-methylene FH4 play in the dTMP synthesis pathway?

    <p>Abstraction of a proton from C5 position</p> Signup and view all the answers

    What attribute of C6 position on FdUMP makes it more electrophilic than the normal substrate?

    <p>+I effect of fluorine atom</p> Signup and view all the answers

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