DNA Cross-Linking and Alkylation Quiz
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Questions and Answers

How do alkylating agents primarily lead to disruption of protein structure and function?

  • By enhancing protein folding
  • By inhibiting protein synthesis
  • By directly binding to protein molecules
  • By causing alteration in the amino acid sequence of proteins (correct)
  • What is the consequence of DNA cross-linking by drugs with two alkylating groups?

  • Enhancement of DNA replication
  • Stabilization of protein structures
  • Formation of interstrand and intrastrand DNA cross-links (correct)
  • Inhibition of apoptosis
  • What can result from disruption of the template function of DNA due to intrastrand and interstrand DNA cross-linking?

  • Enhanced DNA repair mechanisms
  • Improved protein function
  • Cell proliferation
  • DNA destruction and cell death (correct)
  • Why do alkylating agents affect tumor cells more drastically than normal cells?

    <p>Tumor cells divide more rapidly than normal cells</p> Signup and view all the answers

    What is a drawback of alkylating drugs despite their usefulness in cancer treatment?

    <p>They can be mutagenic and carcinogenic</p> Signup and view all the answers

    How do alkylating agents act on proteins in addition to DNA?

    <p>By alkylating nucleophilic groups on proteins</p> Signup and view all the answers

    What is the mechanism of action of Mesna in protecting the bladder?

    <p>Inhibiting aziridine formation</p> Signup and view all the answers

    How does Thiotepa differ from Mechlorethamine in terms of reactivity?

    <p>Thiotepa's thiophosphoryl group increases reactivity</p> Signup and view all the answers

    What is the consequence of Thiotepa being converted to TEPA by desulfuration in vivo?

    <p>Decreased stability</p> Signup and view all the answers

    How does Thiotepa interact with DNA?

    <p>Forms cross-links through aziridine ring hydrolysis</p> Signup and view all the answers

    What role does oxidative desulfuration play in the activation of Thiotepa?

    <p>Forms the active triethylenephosphoramide metabolite</p> Signup and view all the answers

    Why is Thiotepa considered less reactive than many other alkylating agents?

    <p>Presence of electron-withdrawing group</p> Signup and view all the answers

    Which of the following statements is correct regarding nitrogen mustards?

    <p>They are bis-β-chloroethylamines that act as DNA cross-linking agents and alkylating agents.</p> Signup and view all the answers

    What is the primary mechanism of inactivation for alkylating agents in the body?

    <p>Reaction with water, displacing the leaving group and forming an alcohol.</p> Signup and view all the answers

    Which of the following statements accurately describes the structure-activity relationship of nitrogen mustards?

    <p>Increasing the electron-withdrawing nature of the substituents enhances their reactivity.</p> Signup and view all the answers

    How do aromatic mustards compare to aliphatic mustards in terms of reactivity and toxicity?

    <p>Aromatic mustards are less reactive and less toxic than aliphatic mustards.</p> Signup and view all the answers

    What is the primary route of administration for nitrogen mustards in the treatment of cancers of the blood?

    <p>Intravenous (IV) administration</p> Signup and view all the answers

    Which of the following types of cancers are nitrogen mustards commonly used for palliative care?

    <p>Leukemia, lymphoma, and multiple myeloma</p> Signup and view all the answers

    What is the mechanism by which cisplatin binds preferentially to DNA?

    <p>Formation of covalent Pt-DNA cross-links at N-7 of two adjacent guanine units</p> Signup and view all the answers

    What is the role of water molecules in the mechanism of action of cisplatin?

    <p>Displace the chloro substituents to give reactive, positively charged species trapped in cells</p> Signup and view all the answers

    Why is the cis orientation of chloride and water molecules essential for cisplatin's DNA cross-linking activity?

    <p>It facilitates the formation of intrastrand covalent Pt-DNA cross-links</p> Signup and view all the answers

    Which of the following accurately describes the role of acrolein in cyclophosphamide and ifosfamide toxicity?

    <p>Acrolein, a byproduct of cyclophosphamide and ifosfamide activation, causes bladder and kidney toxicity by alkylating cysteine residues of cell proteins.</p> Signup and view all the answers

    Which of the following agents can be used to reduce bladder toxicity associated with cyclophosphamide and ifosfamide?

    <p>Sodium-2-mercaptoethane sulfonate (mesna)</p> Signup and view all the answers

    Which type of cross-linking is most common in organoplatinum compounds like cisplatin?

    <p>Diguanosine dinucleotides cross-linking</p> Signup and view all the answers

    What is the role of mismatch repairing-enzymes (MMR) in cancer cell apoptosis induced by cisplatin?

    <p>Enhance cell survival in response to cisplatin treatment</p> Signup and view all the answers

    What is the mechanism by which mesna reduces bladder toxicity associated with cyclophosphamide and ifosfamide?

    <p>Mesna reacts with and detoxifies acrolein, forming a water-soluble adduct that is readily excreted in urine.</p> Signup and view all the answers

    Why is the trans isomer of diaquo analogs therapeutically inactive?

    <p>It does not bind to DNA</p> Signup and view all the answers

    Which of the following statements about cyclophosphamide and ifosfamide is true?

    <p>Cyclophosphamide and ifosfamide are nitrogen mustard prodrugs that require metabolic activation to exert their cytotoxic effects.</p> Signup and view all the answers

    Which of the following agents can react with carbinolamine and aziridinium cation, potentially inactivating cyclophosphamide and ifosfamide?

    <p>Glutathione and N-acetylcysteine</p> Signup and view all the answers

    Which of the following enzymes are involved in the inactivation metabolism of cyclophosphamide and ifosfamide?

    <p>CYP3A4 and CYP2B6</p> Signup and view all the answers

    Study Notes

    DNA Cross-Linking Agents

    • Alkylating agents can react with a nucleic acid base on each chain or on the same chain of DNA to form interstrand or intrastrand DNA cross-links.
    • DNA alkylation, intrastrand and interstrand DNA cross-linking disrupt the template function of DNA, including replication and transcription, and result in DNA destruction and cell death.
    • Potential mechanisms of cell death after DNA-alkylation include disruption of the template function of DNA and activation of apoptosis caused by p53.

    Alkylating Agents

    • These agents have poor selectivity and toxic side effects, and can also alkylate nucleophilic groups on proteins.
    • Alkylating agents have been useful in the treatment of cancer, as tumour cells often divide more rapidly than normal cells and are more drastically affected by disruption of DNA function.
    • However, these drugs can be mutagenic and carcinogenic in their own right.

    Thiotepa

    • Thiotepa is an aziridine-based DNA cross-linker, which is active intact, but is also converted by oxidative desulfuration to an active triethylenephosphoramide metabolite.
    • Thiotepa incorporates a less reactive aziridine ring compared with that formed in mechlorethamine, due to the adjacent thiophosphoryl being electron withdrawing and reducing the reactivity of the aziridine ring system.
    • Thiotepa is metabolically converted to TEPA by desulfuration in vivo, and forms cross-links with DNA by sequential reactions of thiotepa itself with DNA.

    Aromatic (R = aryl) Mustards

    • These are much weaker electrophiles, less toxic, and less reactive than other alkylating agents.
    • They are most commonly administered orally for the palliative care of patients with leukemia, lymphoma, or multiple myeloma.

    Inactivation of Alkylating Agents

    • Inactivation of the alkylating agent is possible by reaction with water, which represents the nucleophile that is present in greatest abundance in the body.
    • Reaction involves displacement of the leaving group on the electrophile by the nucleophile (water) with the formation of an alcohol.

    Organoplatinum Compounds

    • Once inside cells, cisplatin undergoes aquation, where the chloro substituents are displaced by neutral water molecules to give reactive, positively charged species trapped in cells.
    • These species bind to DNA preferentially at the N-7 of two adjacent guanine units of a same strand, forming intrastrand covalent Pt-DNA cross-links.
    • Cross-linking results in altered normal base-pairing, inhibits DNA-transcription and replication, and results in cell apoptosis.

    Cyclophosphamide and Ifosfamide

    • These agents are nitrogen mustard prodrugs, which are relatively non-toxic and can be taken orally without causing damage to the gut wall.
    • However, acrolein, an electrophilic byproduct of cyclophosphamide and ifosfamide activation, has been associated with bladder and kidney toxicity.
    • Bladder toxicity can be reduced by co-administrating sulphydryl donors such as mesna, which reacts with and detoxifies acrolein.

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    Description

    Test your knowledge on DNA cross-linking and alkylation processes that disrupt the template function of DNA, affecting replication and protein structure. Learn about the effects of miscoding and alteration in amino acid sequences caused by alkylating agents.

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