Angiogenesis

Question 1

What two substances are the targets for angiogenesis inhibitors?

Answer 1

VEGF and mTOR

Question 2

What are the actions of mTOR inhibitors?

Answer 2

reduce cell growth and proliferation, prevent angiogenesis, increase cytotoxicity of drugs that damage DNA

Question 3

What are the types of anti-angiogenics?

Answer 3

IFN-alpha, VEGF and VEGF-R inhibitors, mTOR inhibitors, thalidomide

Question 4

What is the role of mTOR in angiogenesis?

Answer 4

senses changes in growth factors and energy sources and induces synthesis of proteins necessary for angiogenesis

Question 5

What is the target for Bevacizumab?

Answer 5

humanized monoclonal Ab against VEGF

Question 6

Toxicity of Bevacizumab

Answer 6

GI perforation, wound dehiscence, and hemoptysis (can be fatal)

Question 7

What drugs inhibit VEGF-R?

Answer 7

Pazopanib, Sorafinib, Sunitinib

Question 8

Why are pazopanib, sorafinib, and sunitinib worse drugs than Imatinib?

Answer 8

much less specific - target multiple kinases

Question 9

What are the pharmacokinetics of VEGF-R inhibitors (same as blockers of Bcr-Abl)?

Answer 9

oral admin, high plasma protein binding, metabolized in liver thru Cyp34A

Question 10

What are the major toxicities for VEGF-R inhibitors?

Answer 10

CHF, myocardial infarction, teratogenic

Question 11

What are the specific side effects for Pazopanib?

Answer 11

severe hepatotoxicity, hemorrhage, QT prolongation, GI perforation, hypertension

Question 12

What are the specific side effects for Sorafenib?

Answer 12

increased risk of hemorrhage, hypertension

Question 13

What are the specific side effects for sunitinib?

Answer 13

skin discoloration, hand-foot syndrome

Question 14

What are the 3 major effects of mTOR inhibitors?

Answer 14

reducing cell growth and proliferation, prevent angiogenesis, synergy with drugs that damage DNA

Question 15

What are the mTOR inhibitor drugs?

Answer 15

everolimus, temsirolimus

Question 16

How do mTOR inhibitors decrease cell cycle progression?

Answer 16

inhibit protein synthesis of cyclin D1, which normally controls progression thru G1/S checkpoint

Question 17

How do mTOR inhibitors reduce bioenergetics?

Answer 17

decreases access to nutrient and metabolic fuel

Question 18

How do mTOR inhibitors push cancer cells thru the cell cycle?

Answer 18

prevents p21-mediated cell cycle arrest (p53 controls transcription of p21)

Question 19

What is the resistance in mTOR inhibitors?

Answer 19

substrate for P-glycoprotein

Question 20

What are the side effects of the mTOR inhibitors?

Answer 20

hypersensitivity, increased risk of lymphomas, infection, angioedema, kidney arterial and venous thrombosis

Question 21

What are the immunomodulatory drugs?

Answer 21

lenalidomide, pomalidomide, thalidomide

Question 22

What is thalidomide approved to treat?

Answer 22

Hansen’s disease (leprosy)

Question 23

What is the major side effect of thalidomide?

Answer 23

phocomelia if taken during pregnancy

Question 24

What is the MOA of thalidomide?

Answer 24

unknown - but alters the ratios of immune cells and changes expression of molecular markers on their surface; also decreases FGF

Question 25

What are the other side effects of thalidomide?

Answer 25

Peripheral neuropathy, DVT esp. in multiple myeloma pts