Podcast
Questions and Answers
How do alkylating agents primarily lead to disruption of protein structure and function?
How do alkylating agents primarily lead to disruption of protein structure and function?
What is the consequence of DNA cross-linking by drugs with two alkylating groups?
What is the consequence of DNA cross-linking by drugs with two alkylating groups?
What can result from disruption of the template function of DNA due to intrastrand and interstrand DNA cross-linking?
What can result from disruption of the template function of DNA due to intrastrand and interstrand DNA cross-linking?
Why do alkylating agents affect tumor cells more drastically than normal cells?
Why do alkylating agents affect tumor cells more drastically than normal cells?
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What is a drawback of alkylating drugs despite their usefulness in cancer treatment?
What is a drawback of alkylating drugs despite their usefulness in cancer treatment?
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How do alkylating agents act on proteins in addition to DNA?
How do alkylating agents act on proteins in addition to DNA?
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What is the mechanism of action of Mesna in protecting the bladder?
What is the mechanism of action of Mesna in protecting the bladder?
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How does Thiotepa differ from Mechlorethamine in terms of reactivity?
How does Thiotepa differ from Mechlorethamine in terms of reactivity?
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What is the consequence of Thiotepa being converted to TEPA by desulfuration in vivo?
What is the consequence of Thiotepa being converted to TEPA by desulfuration in vivo?
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How does Thiotepa interact with DNA?
How does Thiotepa interact with DNA?
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What role does oxidative desulfuration play in the activation of Thiotepa?
What role does oxidative desulfuration play in the activation of Thiotepa?
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Why is Thiotepa considered less reactive than many other alkylating agents?
Why is Thiotepa considered less reactive than many other alkylating agents?
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Which of the following statements is correct regarding nitrogen mustards?
Which of the following statements is correct regarding nitrogen mustards?
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What is the primary mechanism of inactivation for alkylating agents in the body?
What is the primary mechanism of inactivation for alkylating agents in the body?
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Which of the following statements accurately describes the structure-activity relationship of nitrogen mustards?
Which of the following statements accurately describes the structure-activity relationship of nitrogen mustards?
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How do aromatic mustards compare to aliphatic mustards in terms of reactivity and toxicity?
How do aromatic mustards compare to aliphatic mustards in terms of reactivity and toxicity?
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What is the primary route of administration for nitrogen mustards in the treatment of cancers of the blood?
What is the primary route of administration for nitrogen mustards in the treatment of cancers of the blood?
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Which of the following types of cancers are nitrogen mustards commonly used for palliative care?
Which of the following types of cancers are nitrogen mustards commonly used for palliative care?
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What is the mechanism by which cisplatin binds preferentially to DNA?
What is the mechanism by which cisplatin binds preferentially to DNA?
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What is the role of water molecules in the mechanism of action of cisplatin?
What is the role of water molecules in the mechanism of action of cisplatin?
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Why is the cis orientation of chloride and water molecules essential for cisplatin's DNA cross-linking activity?
Why is the cis orientation of chloride and water molecules essential for cisplatin's DNA cross-linking activity?
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Which of the following accurately describes the role of acrolein in cyclophosphamide and ifosfamide toxicity?
Which of the following accurately describes the role of acrolein in cyclophosphamide and ifosfamide toxicity?
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Which of the following agents can be used to reduce bladder toxicity associated with cyclophosphamide and ifosfamide?
Which of the following agents can be used to reduce bladder toxicity associated with cyclophosphamide and ifosfamide?
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Which type of cross-linking is most common in organoplatinum compounds like cisplatin?
Which type of cross-linking is most common in organoplatinum compounds like cisplatin?
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What is the role of mismatch repairing-enzymes (MMR) in cancer cell apoptosis induced by cisplatin?
What is the role of mismatch repairing-enzymes (MMR) in cancer cell apoptosis induced by cisplatin?
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What is the mechanism by which mesna reduces bladder toxicity associated with cyclophosphamide and ifosfamide?
What is the mechanism by which mesna reduces bladder toxicity associated with cyclophosphamide and ifosfamide?
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Why is the trans isomer of diaquo analogs therapeutically inactive?
Why is the trans isomer of diaquo analogs therapeutically inactive?
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Which of the following statements about cyclophosphamide and ifosfamide is true?
Which of the following statements about cyclophosphamide and ifosfamide is true?
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Which of the following agents can react with carbinolamine and aziridinium cation, potentially inactivating cyclophosphamide and ifosfamide?
Which of the following agents can react with carbinolamine and aziridinium cation, potentially inactivating cyclophosphamide and ifosfamide?
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Which of the following enzymes are involved in the inactivation metabolism of cyclophosphamide and ifosfamide?
Which of the following enzymes are involved in the inactivation metabolism of cyclophosphamide and ifosfamide?
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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.