Fitz- Antineoplastics VI

Question 1

Must angiogenesis inhibitors work by decreasing substances that promote angiogenesis like:

Answer 1

VEGF

mTOR

Question 2

What are the 3 things that mTOR does?

Answer 2

reduces cell growth/proliferation
prevent angiogenesis
increase the cytotoxicity of drugs that damage DNA

Question 3

Thalomide is used to treat what two diseases?

Answer 3

Hansen’s disease

multiple myeloma

Question 4

What is the significant teratogenic effect of thalidomide?

Answer 4

phocomelia

Question 5

What is the role of naturally occurring angiogenesis inhibitors in the growth of secondary tumors following surgery?

Answer 5

Some tumors secrete substances that inhibit angiogenesis at other tumor sites, so when a primary tumor is removed, some weeks later, metastases of the tumor can appear throughout the body.

*this indicates they were present all along but too small to be detected

Question 6

What is rebound angiogenesis?

Answer 6

Rapid growth of cancer when an angiogenesis inhibitor is stopped

Question 7

What drug acts on VEGF?

Answer 7

Bevacizumab

Question 8

STIs (pazopanib, sorafenib, sunitinib) inhibit what two proteins?

Answer 8

VEGF-R

PDGF-R

Question 9

What drugs inhibit FGF?

Answer 9

Thalidomide

Interferon

Question 10

What drugs are mTOR inhibitors?

Answer 10

Everolimus

Temsirolilumus

Question 11

What drug induces INFy?

Answer 11

IL-12–> increases inducible protein 10–> angiogenesis inhibtion

Question 12

What drug decreases FGF production?

Answer 12

INF alpha

Question 13

What is the role of VEGF-R in cancer?

Answer 13

VEGF-R is a tyrosine kinase receptor that activates mTOR in order to promote angiogenesis

Question 14

What is mTOR and what does it do?

Answer 14

An intracellular serine/theronine kinase

Plays a central role in the control of cell growth and proliferation

Senses changes the availability of GFs/E sources and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutriet uptake.

Question 15

What proteins are regulated by mTOR?

Answer 15

Cell cycle regulators (cyclin D1)
AA and glucose transporters
proangiogenic factors
enzymes required for DNA repair

Question 16

When is the mTOR pathway activated in cancer cells?

Answer 16

Uncontrolled proliferation

Increased mTOR in cancer cells–> secretion of VEGF and PDGF—> promote angiogenesis by increasing mTOR in vascular cells

Question 17

What happens when you decrease the activity of VEGF-R and mTOR?

Answer 17

Synergistic kill of cancer cells

Question 18

What is the MOA of bevacizumab?

Answer 18

Blocks VEGF

Question 19

What are the SE of bevacizumab?

Answer 19

GI perforation
woud dehiscence
hemoptysis (spitting up blood)–> fatal

Question 20

What drugs inhibit VEGF-R and PDGF-R?

Answer 20

Pazo and Suni- ckit

Sora- raf

Question 21

What STI is associated with:

hepatotoxicity, hemorrhage, GI perforation and hypertension

Answer 21

Pazo

Question 22

What STI is associated with:

hemorrhage, hypertension?

Answer 22

Sora

Question 23

What STI is associated with:

hand-foot syndrome, skin discoloration?

Answer 23

Suni

Question 24

What is the MOA of mTOR inhibitors?

Answer 24

1. Decrease cell growth and proliferation by blocking mTOR (decreasing bioenergetics)
2. Decrease VEGF and PDGF release from cancer cells
3. Increase cytotoxicity w/ drugs that damage DNA (damage w/ alkylating agent then mTOR force to continue cell cycle)

Question 25

What are some of the toxicities associated w/ mTOR inhibitors?

Answer 25

``` hypersensitivity immunosuppression angioedema kidney thrombosis delays in wound healing nephrotoxicity male infertility hyperlipidemia ```

Question 26

What drug shifts the immune system from Th1--> Th2 and is a potent TNFalpha agent?

Answer 26

Thalidomide?

Question 27

What are the SE of thalidomide?

Answer 27

Few in adult M and non-pregnant F N/V, rashes, peripheral neuopathy, increased risk of DVT

Question 28

What are the severe teratogenic effects of thalidomide if women take it 3-4 weeks post conception?

Answer 28

miscarriage birth defects: malforned intestines, hearing defects, ocular/renal defects, phocomelia * children and grand children affected * single dose

Question 29

What are the advantages of combination chemotherapy?

Answer 29

1. Synergistic effect: allowing you to decrease dose and therefore decrease toxicity to the pt 2. Decrease development of resistance--> decreased likelihood of clonal selection 3. Broader cell kill in cancers that consist of heterogenous tumor cell population

Question 30

What strategies are used to select drugs for combination therapy?

Answer 30

1. effective alone 2. diff mechanism of action and diff mechanism of resistance 3. CCNS/CCS 4. Diff toxicities

Question 31

What is pulse therapy? and why is it used?

Answer 31

Intermittent treatment w/ high doses of a drug, followed by free drug periods Allows hematologic and immunologic recovery between treatment cycles

Question 32

What is an example of pulse treatment?

Answer 32

MTX for the tx of choriocarcinoma

Question 33

What is recruitment?

Answer 33

Use a CCNS drug to achieve a significant log kill This causes cancer cells in Go to be recruited back into the cell cycle THEN You administer a CCS drug to kill dividing cells. HUZZAH

Question 34

What are examples of drugs used for recruitment?

Answer 34

CMF in breast cancer DAUNOrubicin and cytarabine in AML

Question 35

What is synchrony?

Answer 35

Use CCS drugs to synchronize cells into simultaneous cell division so that they're more sensitive to drugs/radiation.

Question 36

What are examples of drugs used for synchrony?

Answer 36

Hydroxyurea followed by radiation Vinca alkaloids followed by etoposide MTX follwed by L asparaginase for ALL

Question 37

What is rescue therapy?

Answer 37

Following the administration of toxic doses of a drug, normal cells are rescued by "antidotes" that ONLY they can use

Question 38

What is an example of rescue therapy?

Answer 38

leucovorin following high dose of MTX