Angiogenesis Inhibitors

Question 1

True or false: tumors differ from normal cells in that they do not secrete angiogenesis inhibitors

Answer 1

false - they do actually!

they often inhibit angiogenesis at metastatic sites, so when the doc removes the primary tumor, they stop the inhibition and metastases crop up like crazy

Question 2

What is the concern of rebound angiogenesis?

Answer 2

it’s rapid growht of ccancer when an angiogenesis inhibitor is stopped (esp with gliomas)

Question 3

How do most angiogenesis inhibitors work?

Answer 3

they decrease the action of substances that promote angiogenesis, like VEGF and mTOR

Question 4

What is mTOR specifically

Answer 4

it’s an intracellular serine/threonine kinase that plays a central role in the control of cell growth and proliferation

(direct control on cyclin D1, VEGF and PDGF and DNA repair enzymes)

Question 5

What tyrosine kinase receptor will activate mTOR in order to promote angiogenesis?

Answer 5

VEGF-Receptor

(so the mTOR secreted by the cancer cell promotes secretion of VEGF, which goes and binds to the VEGF-R on the vascular cell, hwich promose activity of mTOR in the vascular cell, leading to angiogenesis

Question 6

How does interleukin 12 work as an angiogenesis inhibitor?

Answer 6

It induces IFN gamma, which results in the produciton of inducible protein 10, which has anti-angiogenic effects

Question 7

Interferon alpha has anti-tumor activity thorugh three different mechanisms - which one inhibit angiogenesis?

Answer 7

Decreases the production of fibroblast growth factor (FGF), which is angiogenic

Question 8

What drug is a humanized monoclonal antibody directed against VEGF?

Answer 8

Bevacizumab

Question 9

What are the specific serious side effects of bevacizumab?

Answer 9

GI perforation, wound dehiscence and hemoptysis

all of which can be fatal

Question 10

What are the three signal transduction inhibitors that block VEGF-R and PDGF-R?

Answer 10

pazopanib
sunitinib
sorafenib

Question 11

In general, the STIs have relatively minor side effects, but what concerning one is common to al three?

Answer 11

cardiomyopathy

Question 12

Whatst he specific side effects for paxopanib?

Answer 12

severe (fatal) hepatotoxicity, hemorrhage, QT prolongation, GI perforation and HTN

Question 13

WHat’s the specific side effects for sorafenib?

Answer 13

hemorrhage, HTN

Question 14

What are the specific side effects of sunitinib?

Answer 14

skin discoloration and hand-foot syndrome

Question 15

What are the two mTOR inhibitors used to inhibit angiogenesis?

Answer 15

Everolimus

Temsirolimus

Question 16

What are the two general ways mTOR inhibitors prevent angiogenesis?

Answer 16

1. decrease synthesis and release of angiogenic growth facotrs like VEGF from cancer cells
2. blocks growth and proliferation of vascular cells

Question 17

How do the mTOR inhibitors block cell growth and proliferation?

Answer 17

mTOR regulates protein synthesis of cyclin D1which controls progression through the G1/S checkpoint

mTOR also increases expression of amino acid nand glucose transporters, so without it, you have reduced bioenergetics

Question 18

How do the mTOR inhibitors increase the cytotoxicity of the drugs that damage DNA?

Answer 18

mTOR regulates p21 translation, which is the cell cycle inhibitor controlled by p53 to allow for DNA repair. WIthout mTOR< you dont get p21 translation, so you incresae the liklihood that the DNA-damaged cell will progress through the cell cycle and die without repairing itself

Question 19

What is the main use for thalidomide? how does it work for that?

Answer 19

Hansen’s disease - specifically erythema nodosum leprosum in Hansen’s disease
main function for this is immune and inflammatory suppression

Question 20

How does thalidomide have antitumor effects?

Answer 20

Not completely sure - blocks production of FGF, so it decreases angiogenesis, but also may have some sort of immune cell modulatory effect (increases Th2 response over Th1)

Question 21

What are the side effects of thalidomide?

Answer 21

in males and non-pregnant females: pretty mild - nausea, peripheral neuropathy, constipation, increased risk of DVT

in pregnant women: phocomelia