Anticancer Abx Flashcards
Anthracenedione
Mitoxantrone
Anthracyclines (5)
Doxarubicin Duanorubicin Idarubicin Epirubicin Valrubicin
Actinomycin
Dactinomycin
Mitomycin anti cancer antibiotic
Mitomycin
Bleomycin anti cancer antibiotic
Bleomycin
Anticancer ABX General MOAs
Cell cycle non specific, dose dependent, Anti tumor Abx
- Intercalation w/ DNA
- Inhibition of topoisomerase II activity
- Generation of free radicals that cause single strand DNA breaks
Superoxide dismutase
Protective. Detoxifies ROS. Enzyme converts superoxide into hydrogen peroxide
Catalase
Protective. Takes hydrogen peroxide and converts it to 2H2O and O2
Fenton rxn
Hydrogen peroxide in the presence of Fe2+ will produce hydroxyl free radicals (responsible for ssDNA breaks)
Anthracyclines acute cardiotoxicity
Cardiac tissue does not contain catalase enzyme so all hydrogen peroxide produced from quinone + NADPH/CYP450 reductase rxn gets channeled to form hydroxyl radical
Acute cardiotoxicity reduced by administering with dexrazoxane drug will chelate with iron to prevent Fenton rxn
Anthrcyclines ADR
Acute and chronic toxicity Myelosuppression N/V Mucositis Alopecia
Anthracyclines chronic cardiotoxicity
Aldoketoreductase enzyme reduces C13 keto grp to 2’ OH (rubicinol). Smaller R-group, Faster conversion to 2’OH, increased concentration of active drug accumulating in cardiomyocytes leading to cardiomyopathy
Benefits of anthracycline liposomal formulations
Slow plasma clearence Increase uptake in tumor cells Decrease uptake in cardiac tissues Decreased conversion to 2'OH Decrease extravasation
EPIrubicin benefits
EPImer. Faster glucuronidation, eliminated faster. Less ROS generation because of steric hindrance of 4-beta-OH. Less cardiotoxicity than duanorubicin and doxorubicin
How does valrubicin void cardiotoxicity?
It is directly delivered into bladder to treat BCG-refractory cancer
Mitoxantrone differences from anthracyclines
Lacks l-duanosamine sugar
3 rings instead of 4
Limited ROS formation bc quinone structure in drug is involved in hydrogen bonding
Resistant to NADPH/CYP450 reduction–> dec. Cardiotoxicity
Glucuronide conjugate causes DARK BLUE sclera, fingernails, & urine
Anthracyclines MOA
- Intercalation w/ DNA
2. Inhibition of topoisomerase II activity
Anthracenedione (mitoxantrone) MOA
- Intercalation w/ DNA
2. Inhibition of topoisomerase II activity
Actinomycin (dactinomycin) MOA
- Intercalation w/ DNA
3. Generation of free radicals that cause single strand DNA breaks
Dactinomycin toxicities
Drug is Used in wilms tumor in children
Dose limiting myelosuppression Severe vesicant N/V Hyperpigmentation Rhabdomyolysis (*avoid HMG-coA reductase inhibitors) *Radiation recall*
Mitomycin MOA
- Generation of free radicals that cause single strand DNA breaks (from quinone structure)
Also involved in DNA cross linking (rRNA target?)
Mitomycin toxicity
Severe myelosuppression
Skin necrosis
Fatal pulmonary toxicty
Bleomycin MOA
- Generation of free radicals that cause single strand DNA breaks
Bleomycin toxicity
- Pulmonary toxicity*
- Skin toxicity*
- NO MYELOSUPPRESSION
- bleomycin in is inactivated by bleomycin hydrase* (amide to carboxylate to lose DNA binding affinity)
Mechanisms of Resistance to Anticancer Abx
- Decrease uptake into tumor cells
- P-go mediated efflux of drug
- Reduced expression of target enzyme or mutation of enzyme that decreases binding of drug (I.e topo II)
- Trapping of ROS (cancer cell can increase glutathione production to decrease ROS)
