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37 Cards in this Set
- Front
- Back
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When is DNA repair occurring in the cell?
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DNA repair is constantly going on in the cell and protects the genome from damage and harmful mutations
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Which is more serious Single Strand or Double Strand DNA damage?
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Double Strand DNA Breaks
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Why is double strand DNA damage more severe than single strand DNA damage?
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When only one of the strands has a defect, the other strand can be used as a template to guide the correction of the damaged strand. While a break in both strands is very hazardous to DNA
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What are the two mechanisms by which DNA repair of ssDNA can take place?
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1) Direct Reversal of Damage
2) Excision Repair Mechanisms |
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What are the two types of Excision Repair Mechanisms?
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1) Base Excision Repair (BER)
2) Nucleotide Excision Repair (NER) |
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What is Mismatch Repair?
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Corrects errors of DNA replication and recombination that result in mispaired nucleotides following DNA replication
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What are the two mechanisms of DNA repair of dsDNA?
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1) Homologous Recombination
2) Non Homologous End Joining |
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What is Homologous Recombination?
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Repairs dsDNA breaks, requires an identical/nearly identical sequence to be used as the template for repair of the break.
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When does Homologous Recombination occur?
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Done during the phases of the cell cycle when the DNA is replicating or has completed its replication
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What is Non Homologous End Joining?
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Rejoins the two ends of the break in absence of a template sequence. However there is often DNA sequence loss during this process and so the repair can be mutagenic
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When does Non Homologous End Joining occur?
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This can occur at all stages of the cell cycle and is the main repair mechanism for dsDNA breaks in mammalian cells
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How do DNA damaging agents work in anticancer chemotherapy?
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By overwhelming the capacity of the cell to repair DNA damage and resulting in cell death
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Which type of cells are more sensitive to DNA damaging agents?
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Cells that are most rapidly dividing (such as cancer cells) are preferentially affected. (side effects include, affecting stem cells and bone marrow)
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What are examples of Alkylating Agents? (3)
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1) Nitrogen Mustards: Cyclophosphamide.
2) Chlorambucil 3) Bulsulfon |
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What is the MOA of Alkylating Agents?
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By attacking nucleophilic sites, cross linking being the most damaging. Mainly through the N7 atom of Guanine (although other moieties can also be alkylated)
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What is the most commonly used Alkylating Agent?
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Cyclophosphamide
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Is cyclophosphamide a pro drug?
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Yes, requires activation by the CYP2B6 in the liver. The active form is Arolein
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What are the toxcities of Alkylating Agents? (2)
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1) Bone Marrow and Myelosuppression
2) Hemorrhagic Cystitis |
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How do you reduce Hemorrhagic Cystitis caused by Cyclophosphamide?
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Can be reduced by hydration and administering Mesna (which contains Sulfahydryl)
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What are the resistance mechanisms of Alkylating Agents? (2)
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1) Increased metabolism by glutathione transferase
2) Increased metabolism by aldehyde dehydrogenase |
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What are the examples of Platinum Compounds? (3)
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1) Cisplatin
2) Carboplatin 3) Oxaliplatin |
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What is the MOA of Platinum Compounds?
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Acts similarly to alkylating agents; by cross-linking DNA strands. Targets nucleophilic centers in Guanine, Adenine and Cytosine creating intra-strand cross-links between the drug and neighbouring Guanines
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Which platinum compound is the most efficacious in the treatment of Testicular and Ovarian Cancer?
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Cisplatin
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Why is Carboplatin is less reactive and less toxic compared to Cisplatin?
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Due to the slower hydrolysis
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"Platinum Compounds are given IV only" True or False?
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TRUE
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What are the toxcities of Platinum Compounds? (3)
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1) Myelosuppression (Cisplatin and Carboplatin) 2) Nephrotoxcitiy (Cisplatin)
3) Anemia and Peripheral Sensory Neuropathy (Oxaliplatin) |
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What are the resistance mechanisms of Platinum Compounds? (3)
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1) Increases metabolism by glutathione conjugation or by other sulfahydryls conjugation 2) Decreased intracellular concentrations [decrease uptake or increased efflux via P-GP)
3) Increased DNA repair capacity |
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What are examples of Anthracycline Antibiotics? (2)
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1) Doxorubicin
2) Epirubicin |
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What are the three mechanisms of Cytotoxcity due to Antrhacycline Antibiotics?
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1) Intercalate DNA
2) Tripartite complex with Topo II leading to dsDNA breaks 3) Generates free radicals and induces oxidative stress |
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Where are Anthracyclines normally synthesized from?
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From the fungus streptococcus peucetius
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"Doxorubicin is widely used to treat ______"
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Solid Tumors
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What are the major toxcities of Anthracycline Antibiotics? (2)
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1) Myelosuppression
2) Cardiac Toxcities (dose dependent) related to free radical production, where 1-10% of patients develop Irreversible CHF |
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How do liposomal formulations of Doxorubicin and Epirubicin compare to the orginal formulations?
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Liposomal formulations are related to fewer cardiac toxicites
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What agent can theoretically prevent/reduce cardiac toxcities?
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Dexarazoxane (an iron chelating agent)
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"Epirubicin appeared to have reduced cardiac toxicity when compared to Doxorubicin treatments in early clinical tests" True or False?
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TRUE
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"Dose limiting toxcitiy of myelosuppression is similar in Epirubicin to those observed with Doxorubcin treatments" True or False?
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TRUE
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What are the resistance mechanisms of Anthracycline Antibiotics? (3)
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1) Increased expression of P-GP
2) Decreased Topoisomerase II activities 3) Increased metabolism by Glutathione Perioxidase |
