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