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What drug is an aliphatic nitrogen mustard?
aromatic nitrogen mustard?
- Aliphatic - Mustine aka chlormethine
- Aromatic - Chlorambucil and Melphalan
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How does mustine (chlormethine) work against cancer cells?
Intermediate alkylates guanine on DNA and then creates interstrand cross-link in DNA
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What are some common mechanisms of resistance with mustine?
- 1) Increased DNA repair
- 2) Decreased trasnport of the alkylating drug
- 3) Increased production of glutathione and glutathione-associated proteins
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True or False. Moderate doses of mustine can produce severe bone marrow depression w/ leukopenia and thrombocytopenia.
False. Excessive doses can however
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How must mustine be administered?
Must be delivered through fast running IV infusion. It is also prone to extravasation if not careful
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How does chlorambucil and melphalan work?
Alkylates guanine on DNA via SN1 with carbocation. No intermediate is formed
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True or False. Chlorambucil is one of the slowest acting and least toxic nitrogen mustards
True.
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What is a toxicity of melphalan even when you stop the drug?
Delayed bone marrow toxicity
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Chlorambucil is used for what types of cancer?
CLL (chronic lymphocytic leukopenia), non-Hodgkins lymphoma and ovarian cancer
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True/False?
Cyclophosphamide is a pro-drug.
- True.
- It is oxidized in the liver to form two products:
- phosphoramide mustard & acolein
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What is cyclophosphamide's MOA?
Oxidation in the liver gives rise to an active metabolite - phosphoramide mustard - which forms INTER-STRAND DNA links.
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Cyclophosphamide is used for which types of cancer?
- Breast cancer, ovarian cancer, non-Hodgkin's lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilm's tumor.
- *It is also used as an immunosuppressant.
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What are the adverse fx associated with cyclophosphamide?
- - N&V
- - Alopecia
- - *Hemorrhagic cystitis - prevented with adequate hydration and Mesna*
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True/False?
Cyclophosphamide is considered to have mild toxicities.
True.
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Why is cyclophosphamide occassionally responsible for causing hemorrhagic cystitis?
- It's other metablite - acrolein - is a potent electrophile that reacts with nucleophiles on the surfaces of cells that line the bladder.
- * Mesna acts as a sacrificial nucleophile *
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