Antitumor Antibiotics Flashcards
Antitumor Antibiotics are produced by
Streptomyces bacteria
Antitumar Antibiotic Drugs
o Doxorubicin o Daunorubicin o Bleomycin o Dactinomycin o Mitomycin
Antitumor Antibiotics Functions
o Intercalation (insertion) between base pairs (doxorubicin)
o DNA strand fragmentation (bleomycin)
o Cross-linking the DNA strands (mitomycin)
o Overall they inhibit DNA replication and RNA synthesis
Antitumor Antibiotics Major mechanisms
Topoisomerase II inhibition through DNA intercalation
• Can cut but not ligate
Free radical generation
Inhibition of signal transduction pathways
Antitumor Antibiotics Specificity
CELL CYCLE NON SPECIFIC
Structure of anthracyclines
Have a tetracycline ring + sugar (daunosamine) attached by glycosidic linkage
Also have quinone moieties which accept electrons that forms the hydroxyl quinone which makes the drug unstable and then gives said electron away to oxygens for ROS production
Cardiac Toxicity with anthracyclines
Semiquinone and hydroxyquinone can return to quinone form by donating the electron to oxygen or hydrogen peroxide to form hydroxyl radical which cause DNA damage and lipid peroxidation → desoty the cardiac myocytes
Cardio-Protective Agent
Dexrazoxane (zinecard)
Dexrazoxane (zinecard) Function
Undergoes hydrolysis and accepts the iron from the anthracycline- iron complex and the regeneration of the free doxorubicin
Prevents the formation of the iron version
Given BEFORE doxorubicin administration
Doxorubicin Use
carcinomas, carcomas, hematologic cancers (leukemia, hodgkin’s)
Doxorubicin MOA
- Binds directly to DNA via intercalation between base pairs
- Inhibits topo II which blocks DNA and RNA synthesis and fragmentation of DNA
- Iron-chelator: this complex can bind DNA and membranes better and produce free radicals that immediately cleave DNA
Doxorubicin Drug Interactions
- Barbiturates (phenobarbital) – increased metabolism
* CCB (verapamil) – additive toxicity
Doxorubicin SE
- Cardiovascular
- GI
- Genitourinary (red urine)
- Myelosuppresion
- Hyperuricemia
Dactinomycin (actinomycin-D) Use
rhabdomyosarcoma, eqings sarcoma and wilm’s tumor (kidney cancer)
Dactinomycin MOA
- Intercalates between G-C in DNA
* Dactinomycin-DNA complex blocks transcription of DNA by RNA polymerase