MPP lecture 8
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Questions and Answers

Which enzyme catalyzes the reduction of ribonucleotides to deoxyribonucleotides?

  • Thymidylate synthase
  • Dihydrofolate reductase
  • Ribonucleotide reductase (correct)
  • DNA polymerase

    • What is the primary mechanism of action for antimetabolites?

  • Inhibiting microtubule dynamics
  • Directly damaging DNA
  • Inhibiting nucleotide synthesis (correct)
  • Promoting apoptosis

    • Which of these chemotherapeutic agents are classified as inhibitors of microtubule function?

  • Topoisomerase inhibitors
  • Taxanes (correct)
  • Alkylating agents
  • 5-Fluorouracil

    • Which phase of the cell cycle do inhibitors of DNA synthesis primarily target?

    <p>S-Phase</p> Signup and view all the answers

    Which of the following is a known risk associated with DNA damaging agents?

    <p>Secondary cancers</p> Signup and view all the answers

    What role does MTHF play in the conversion of dUMP to dTMP?

    <p>It is a cofactor</p> Signup and view all the answers

    Which of the following best describes the target of alkylating agents?

    <p>Double-strand breaks and intercalation</p> Signup and view all the answers

    What specific class of drugs does 5-Fluorouracil belong to?

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

    Which of the following cell cycle phases is directly affected by inhibitors of microtubule function?

    <p>M-Phase</p> Signup and view all the answers

    Which type of chemotherapeutic agent is effective against all phases of the cell cycle?

    <p>DNA damaging agents</p> Signup and view all the answers

    What is the primary action of Hydroxyurea in chemotherapy?

    <p>Inhibits ribonucleotide reductase using a tyrosyl radical</p> Signup and view all the answers

    How does Pentostatin function as a chemotherapy agent?

    <p>Selectively inhibits adenosine deaminase</p> Signup and view all the answers

    Which statement correctly describes 6-Mercaptopurine (6-MP)?

    <p>It is a purine analogue that decreases levels of AMP and GMP.</p> Signup and view all the answers

    Which agent serves as a prodrug for 5-Fluorouracil (5-FU)?

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

    What mechanism does 5-Azacytidine utilize to exert its effects on DNA?

    <p>Methylation of DNA, leading to altered gene expression</p> Signup and view all the answers

    Which of the following accurately describes the action of Camptothecins?

    <p>Inhibit topoisomerase I, causing DNA strand breakage</p> Signup and view all the answers

    Which agent is classified as a selective inhibitor of topoisomerase II?

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

    What is the role of Azathioprine in cancer treatment?

    <p>It acts as a prodrug for 6-Mercaptopurine with superior immunosuppressive effects.</p> Signup and view all the answers

    What outcome results from the incorporation of purine and pyrimidine analogues into DNA?

    <p>Disruption of DNA structure and cell growth inhibition</p> Signup and view all the answers

    What is a prominent feature of 5-Fluorouracil's mechanism of action?

    <p>It interferes with thymidylate synthesis by mimicking uracil.</p> Signup and view all the answers

    What effect does Hydroxyurea have on ribonucleotide reductase?

    <p>It inhibits the enzyme, preventing nucleotide conversion.</p> Signup and view all the answers

    What is a consequence of the incorporation of purine and pyrimidine analogues into DNA?

    <p>Disruption of DNA structure and potential cell death.</p> Signup and view all the answers

    How do Azathioprine and 6-Mercaptopurine (6-MP) primarily differ in their usage?

    <p>Azathioprine is a superior immunosuppressant compared to 6-MP.</p> Signup and view all the answers

    What mechanism does 5-Azacytidine employ to modify DNA?

    <p>Methylation leading to gene silencing.</p> Signup and view all the answers

    Which of the following accurately describes the role of Pentostatin in chemotherapy?

    <p>It is a structural analogue that inhibits adenosine deaminase.</p> Signup and view all the answers

    Which of the following accurately represents a characteristic of 6-Mercaptopurine?

    <p>It decreases levels of AMP and GMP.</p> Signup and view all the answers

    What distinguishes Fludarabine phosphate in its action as a purine analogue?

    <p>It incorporates into DNA causing chain termination.</p> Signup and view all the answers

    Which of the following statements correctly applies to Camptothecins as topoisomerase inhibitors?

    <p>They interfere with the function of topoisomerase I.</p> Signup and view all the answers

    Which of the following accurately describes the role of ribonucleotide reductase in nucleotide synthesis?

    <p>It catalyzes the reduction of ribonucleotides to deoxyribonucleotides.</p> Signup and view all the answers

    What is a key disadvantage associated with the use of antimetabolites in chemotherapy?

    <p>They lead to misincorporation of nucleotides.</p> Signup and view all the answers

    Which mechanism do DNA damaging agents primarily utilize to exert their effects?

    <p>Directly inducing DNA strand breaks</p> Signup and view all the answers

    In the context of chemotherapy, which of the following correctly categorizes the use of platinum complexes?

    <p>They are classified as DNA damaging agents effective in multiple cell cycle phases.</p> Signup and view all the answers

    What role does dihydrofolate reductase (DHFR) play in nucleotide synthesis?

    <p>It catalyzes the generation of MTHF from DHF.</p> Signup and view all the answers

    Which class of pharmacological agents is primarily aimed at disrupting the dynamics of mitosis?

    <p>Vinca alkaloids</p> Signup and view all the answers

    Which statement best describes the action mechanism of topoisomerase inhibitors in chemotherapy?

    <p>They prevent the ligation of DNA nicks.</p> Signup and view all the answers

    Which aspect of antimetabolites may contribute to their resistance in cancer treatment?

    <p>Mutations in target enzymes for nucleotide production</p> Signup and view all the answers

    Which is a requirement for the function of thymidylate synthase in nucleotide conversion?

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

    What is a common target for inhibitors of purine metabolism in cancer therapy?

    <p>Ribonucleotide reductase</p> Signup and view all the answers

    Study Notes

    Nucleotide Synthesis Basics

    • Nucleotides are the building blocks of DNA and RNA.
    • Purines consist of Adenine (A) and Guanine (G).
    • Pyrimidines include Cytosine (C), Thymine (T), and Uracil (U).
    • Ribonucleotides are synthesized, then reduced to deoxyribonucleotides by ribonucleotide reductase.
    • Steps: formation of DNA precursors → transcription of DNA to RNA → translation of RNA to proteins.
    • Thymidylate synthase converts deoxyuridylate (dUMP) to deoxythymidylate (dTMP) using MTHF, a cofactor derived from DHF.

    Traditional Chemotherapeutic Agents

    • Inhibitors of DNA Synthesis and Integrity

      • Mechanism: inhibit DNA replication/repair.
      • Cell cycle specificity: active during S-phase.
      • Targets: enzymes in nucleotide production, DNA polymerase function, and misincorporation of nucleotides.
      • Examples: Antimetabolites, Topoisomerase Inhibitors.

    • Inhibitors of Microtubule Function

      • Mechanism: disrupt microtubule dynamics during mitosis.
      • Cell cycle specificity: effective during M-phase.
      • Examples: Vinca Alkaloids, Taxanes.

    • DNA Damaging Agents

      • Mechanism: directly damage DNA via cross-links and breaks.
      • Cell cycle specificity: affect all phases.
      • Examples: Alkylating agents, Antitumor antibiotics, Platinum complexes.

    Mechanism of Action: Inhibitors of Thymidylate Synthase and Purine Metabolism

    • Inhibitors of Thymidylate Synthase

      • 5-Fluorouracil (5-FU): disrupts thymidylate biosynthesis, mimics Uracil, highly toxic.
      • Capecitabine: prodrug of 5-FU, converted in the body.

    • Inhibitors of Purine Metabolism

      • 6-Mercaptopurine (6-MP): inosine analogue, decreases AMP and GMP levels.
      • Azathioprine (AZA): prodrug for 6-MP, stronger immunosuppressant.
      • Pentostatin: selective adenosine deaminase inhibitor, binds tightly to the enzyme.

    Mechanism of Action: Inhibitors of Ribonucleotide Reductase

    • Hydroxyurea: inhibits ribonucleotide reductase, preventing conversion of ribonucleotides to deoxynucleotides.

    Analogues Affecting Nucleotide Function

    • Guanine analogue: Thioguanine replaces oxygen with sulfur.
    • Purine analogues: Fludarabine phosphate and Cladribine used for therapy.
    • Cytidine analogues: Cytarabine (pro-drug) and 5-Azacytidine.

    Mechanism of Action: Antimetabolites and DNA Structure Modification

    • Incorporation into DNA can lead to:
      • Chain termination (e.g., Fludarabine phosphate, Cladribine).
      • Competition for DNA polymerase (e.g., Cytarabine).
      • Methylation modification (e.g., 5-Azacytidine).
    • Consequences: DNA structure disruption, strand breakage, inhibition of growth, altered gene expression.

    Mechanism of Action: Topoisomerase Inhibitors

    • Topoisomerase inhibitors interfere with topoisomerases, causing DNA destruction.
    • Topoisomerase I inhibitors include Camptothecins.
    • Topoisomerase II inhibitors include Anthracyclines, Epipodophyllotoxins, and Amsacrine.

    Predicting Appropriate Chemotherapy

    • Selection of chemotherapy should be based on understanding the specific mechanisms, cell cycle targeting, and the unique profile of cancer tissues.

    Nucleotide Synthesis Basics

    • Nucleotides are the basic building blocks of DNA and RNA.
    • Purines include adenine (A) and guanine (G); pyrimidines include cytosine (C), thymine (T), and uracil (U).
    • Ribonucleotide synthesis involves sequential reactions, leading to deoxyribonucleotide production via ribonucleotide reductase.
    • Conversion of dUMP to dTMP is facilitated by thymidylate synthase, requiring MTHF as a cofactor; DHF is reduced to THF by dihydrofolate reductase.

    Traditional Chemotherapeutic Agents

    • Inhibitors of DNA Synthesis and Integrity:
      • Target enzymes for nucleotide production; active during the S-phase; include antimetabolites.
    • Inhibitors of Microtubule Function:
      • Disrupt microtubule dynamics in mitosis; effective during M-phase; examples include Vinca Alkaloids and Taxanes.
    • DNA Damaging Agents:
      • Cause direct DNA damage; affect all cell cycle phases; include alkylating agents and antitumor antibiotics.
    • Key advantages and disadvantages vary among the classes, from effectiveness and resistance development to side effects and long-term complications.

    Mechanism of Action: Thymidylate Synthase Inhibitors

    • 5-Fluorouracil (5-FU):
      • Mimics uracil and interferes with thymidylate biosynthesis; highly toxic.
    • Capecitabine:
      • Oral prodrug converted to 5-FU post-absorption.
    • Inhibitors of Purine Metabolism:
      • 6-Mercaptopurine (6-MP): Inhibits purine nucleotide interconversion, decreasing AMP and GMP.
      • Azathioprine (AZA): Prodrug of 6-MP; stronger immunosuppressant.
      • Pentostatin: Selectively inhibits adenosine deaminase by mimicking the substrate.

    Inhibitors of Ribonucleotide Reductase

    • Hydroxyurea:
      • Inhibits ribonucleotide reductase, preventing conversion of ribonucleotides to deoxynucleotides.

    Purine and Pyrimidine Analogues

    • Incorporate into DNA, acting as rogue nucleotides.
    • Examples include thioguanine (guanine analogue), fludarabine phosphate and cladribine (purine analogues), and cytarabine and 5-azacytidine (cytidine analogues).

    Mechanism of Action: Antimetabolites and DNA Modifiers

    • Antimetabolites can cause:
      • Chain termination (e.g., fludarabine phosphate, cladribine).
      • Competition for DNA polymerase (e.g., cytarabine).
      • Methylation leading to altered gene expression (e.g., 5-azacytidine).
    • Effects include DNA structure disruption, strand breakage, and inhibited cell growth.

    Mechanism of Action: Topoisomerase Inhibitors

    • Interfere with topoisomerase function, promoting DNA damage.
    • Topoisomerase I inhibitors: Camptothecins.
    • Topoisomerase II inhibitors: Include anthracyclines, epipodophyllotoxins, and Amsacrine.

    Clinical Application of Chemotherapy

    • Designing appropriate chemotherapy requires understanding the cancer type, target mechanisms, and potential side effects of agents.

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    Related Documents

    MPP Lecture 8: Nucleotide Synthesis & Chemotherapy PDF
    MPP Lecture 8. PDF

    Description

    Explore the fundamental processes of nucleotide synthesis, including the distinction between purines and pyrimidines. This quiz covers the synthesis of ribonucleotides, their reduction to deoxyribonucleotides, and the formation of DNA and RNA. Test your understanding of these essential biochemical reactions.

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