Cancer Chemotherapy- Natural Products Flashcards
List the general Classes of Natural Product chemo agents and examples of each
- Anthracyclines (Doxorubicin, Daunorubicin)
- Bleomycin
- Topoisomerase Inhibitors (Irinotecan, Etoposide)
- Mitotic Inhibitors (Vincristine, Vinblastine, Paclitaxel, docetaxel)
What are the alternate names for Doxorubicin
- Adriamycin
- Hydroxydaunorubicin
What are the Mechanisms of action of Anthracyclines
- DNA intercalation
- inserted between base pairs to block DNA and RNA synth, alter the structure of and unwind DNA which activates DNA repair enzymes and damages DNA
- inhibits DNA topoisomerase II (POISON)
- Complexes with Topoisomerase II inhibiting religation and causing dna strand breakage
- Generates ROS
- Damages DNA, proteins, and membranes
How are anthacyclines :
- Administered
- Absorbed/Distributed (CNS?)
- Metabolized
- Eliminated
- Parenteral
- Well distributed but DO NOT cross BBB
- Metabolized in liver to active and inactive products
- Mostly Biliary Excretion, but some Urinary excretion
- MAY NOTE RED URINE
What are the common clinical uses/combination therapies for Daunorubicin and what other anthra is similar to it
- NOT EFFECTIVE FOR SOLID TUMORS
- Idarubicin has similar activity to Daunorubicin (with less cardiotoxicity)
What are the common clinical uses/combination therapies for Doxorubicin and what other anthra is similar to it
- Breast Cancer
-CA: (Cyclophosphamide, Adriamycin) - Non Hodgkins
-CHOP-R (H) - Hodgkins
-ABVD (adriamycin, Bleomycin, Vinblastine, Darcarbazine) - Lung Cancer
- CAV (cyclophosphamide, Adriamycin, Vincristine)
- CAE (cyclophosphamide, Adriamycin, Etoposide)
EPIRUBICIN has similar activity to Doxorubicin
List 5 Adverse effects of Anthracycline treatments
- Cardiotoxicity
- Vesicant blistering and ulceration
- Myelosuppression (dose limiting)
- ALopecia
- Hand foot syndrome (liposomal formulations)
Describe the pathophysiology and the prevention/treatment for the Cardiotoxicity of Anthracyclines
- Primarily seen as CHF (mostly irreversible)
- Likely caused by Free radical damage to cardiomyocytes
- Prevention
- Dexrazoxane: Chelating agent
- Idarubicin use: less toxic can use higher doses
- Liposomal formulations (doxo): less toxic
Describe the pathophysiology and the prevention/treatment for the Vesicant blistering and ulcerations of Anthracyclines
- Extravasation tissue damage, which is concentration dependent and can be delayed up to 5 months
- likely caused by free radical tissue damage
- Prevention/Treatment
- Dexrazoxane: chelating agent
- Liposomal forumlations: less tissue damage, cardiotoxicity, and myelosuppression (can see hand foot synd though)
What are 3 mechanisms of resistance to Anthracyclines
- Dec Drug accumulation: (inc efflux via MDR1/MRP)
- Inc Drug Inactivation: Glutathione
- Altered Drug Target: DNA topoisomerase II change
From what is Bleomycin isolated and how are the drug preps made
- Isolated from Streptomyces Verticillus
- Drug Preps are 60% Bleo A2 and 30% Bleo B2
Describe the Mechanism of action of Bleomycin
- Has free radical formation through association with Fe2+ or Cu2+ and oxygen and has migration to Nucleus
- Once migrated to nucleus has sequence specific DNA Intercalation
- G(T/C)
- This causes DS and SS DNA damage
How is Bleomycin:
- Administered
- Absorbed/Distributed (CNS?)
- Metabolized
- Eliminated
- Parenteral
- Well Distributed (concetrates in skin and lung)
- Crosses BBB maybe?
- active and inactive metabolites
- RENAL excretion
What are the common clinical uses/combination therapies for Bleomycin
- Hodgkins Lymphoma
- ABVD (adriamycin, bleomycin, vinbastin,darcarbazine)
