Angiogenesis Flashcards
What two substances are the targets for angiogenesis inhibitors?
VEGF and mTOR
What are the actions of mTOR inhibitors?
reduce cell growth and proliferation, prevent angiogenesis, increase cytotoxicity of drugs that damage DNA
What are the types of anti-angiogenics?
IFN-alpha, VEGF and VEGF-R inhibitors, mTOR inhibitors, thalidomide
What is the role of mTOR in angiogenesis?
senses changes in growth factors and energy sources and induces synthesis of proteins necessary for angiogenesis
What is the target for Bevacizumab?
humanized monoclonal Ab against VEGF
Toxicity of Bevacizumab
GI perforation, wound dehiscence, and hemoptysis (can be fatal)
What drugs inhibit VEGF-R?
Pazopanib, Sorafinib, Sunitinib
Why are pazopanib, sorafinib, and sunitinib worse drugs than Imatinib?
much less specific - target multiple kinases
What are the pharmacokinetics of VEGF-R inhibitors (same as blockers of Bcr-Abl)?
oral admin, high plasma protein binding, metabolized in liver thru Cyp34A
What are the major toxicities for VEGF-R inhibitors?
CHF, myocardial infarction, teratogenic
What are the specific side effects for Pazopanib?
severe hepatotoxicity, hemorrhage, QT prolongation, GI perforation, hypertension
What are the specific side effects for Sorafenib?
increased risk of hemorrhage, hypertension
What are the specific side effects for sunitinib?
skin discoloration, hand-foot syndrome
What are the 3 major effects of mTOR inhibitors?
reducing cell growth and proliferation, prevent angiogenesis, synergy with drugs that damage DNA
What are the mTOR inhibitor drugs?
everolimus, temsirolimus
How do mTOR inhibitors decrease cell cycle progression?
inhibit protein synthesis of cyclin D1, which normally controls progression thru G1/S checkpoint
How do mTOR inhibitors reduce bioenergetics?
decreases access to nutrient and metabolic fuel
How do mTOR inhibitors push cancer cells thru the cell cycle?
prevents p21-mediated cell cycle arrest (p53 controls transcription of p21)
What is the resistance in mTOR inhibitors?
substrate for P-glycoprotein
What are the side effects of the mTOR inhibitors?
hypersensitivity, increased risk of lymphomas, infection, angioedema, kidney arterial and venous thrombosis
What are the immunomodulatory drugs?
lenalidomide, pomalidomide, thalidomide
What is thalidomide approved to treat?
Hansen’s disease (leprosy)
What is the major side effect of thalidomide?
phocomelia if taken during pregnancy
What is the MOA of thalidomide?
unknown - but alters the ratios of immune cells and changes expression of molecular markers on their surface; also decreases FGF
