Antineoplastics VI

Question 1

Angiogenesis inhibitors

Answer 1

–Most work by interfering w/actions of substances that promote angiogenesis (esp. VEGF and mToR).

Question 2

mTOR inhibitors

Answer 2

–Reduce cell growth and proliferation, prevent angiogenesis and increase the cytotoxicity of drugs that damage DNA

Question 3

Which tissues secrete subtances that promote or inhibit angiogenesis?

Answer 3

All tissues (including tumors)

Question 4

When must a cancer cell develop a blood supply in order to grow?

Answer 4

1-2mm. Blocking angiogenesis limits size of tumor growth

Question 5

Rebound angiogenesis

Answer 5

• -rapid growth of cancer when an angiogenesis inhibitor is stopped
• -observed in patients with gliomas, where there is rapid, aggressive regrowth of the tumours after BEVACIXIMAB treatment is stopped

Question 6

VEGF and VEGF-R drugs

Answer 6

• Bevacizumab

- Pazopanib, sorafenib, sunitinib

Question 7

mTOR inhibitor drugs

Answer 7

-Everolimus, temsiroliumus

Question 8

Types of anti-angiogenics

Answer 8

Interferon-alpha.
VEGF and VEGF-R
mTOR inhibitors

Question 9

mTOR function

Answer 9

• is a serine/threonine kinase that plays a role in the control of cell growth and proliferation
• senses changes in availability of growth factors and/or energy sources, and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutrient uptake

Question 10

Proteins regulated by mTOR

Answer 10

• Cell cycle regulators (cylin D1)
• Amino acid and glucose transporters
• Proangiogenic factors
• Enzymes required for DNA repair

Question 11

VEGF-R

Answer 11

Tyrosine kinase receptor that activates mTOR to promote angiogenesis

Question 12

mTOR and cancer cells

Answer 12

Increased mTOR activity in cancer cells–>secretion of VEGF and PDGF–>angiogenesis due to increased mTOR activity in vascular cells–> decreasing activity of VEGF/VEGF-R and mTOR can result in synergistic cell kill

Question 13

Bevacizumab

Answer 13

• -humanized monoclonal antibodydirected againstvascular endothelial growth factor (VEGF)
• -approved (in combination with5-FU) for first-line treatment of metastatic colorectal cancer, lung cancer, breast cancer (controversial

Question 14

Bevacizumab side effects

Answer 14

• -Can cause GI perforation, wound dehiscence, hemoptysis (can be fatal). May worsen coronary or peripheral artery disease (preventing sprouting of new vessels)
• -Also causes side effects common to antibodies

Question 15

STIs of VEGF-R

Answer 15

• -Receptors for VEGF and PDGF are receptor tyrosine kinases.
• -Less specific than Imatinib (block multiple kinases
• -1st line treatment for renal cell carcinoma

Question 16

Sorafenib

Answer 16

Raf.

Question 17

Pazopanib, sunitinib

Answer 17

c-KIT.

Question 18

STIs of VEGF-R (Pazopanib, sorafinib, sunitinib) pharmacokinetics

Answer 18

• -Same PKs as forSTIs that block Bcr-Abl and HER2:
• -oral administration; good bioavailability
• -highly plasma protein bound
• -metabolized in the liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)

Question 19

STIs of VEGF-R (Pazopanib, sorafinib, sunitinib) generla side effects

Answer 19

Same general toxicities as forSTIs that block Bcr-Abl and HER2:

• -relativelyminor side effects: nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions
• -can causecongestive heart failureand decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/ormyocardial infarction
• -teratogenic

Question 20

Pazopanib side effect (specific)

Answer 20

Severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension

Question 21

Sorafenib side effects (specific)

Answer 21

Increased risk of hemorrhage, hypertension

Question 22

Sunitinib side effects (specific)

Answer 22

Skin discoloration, hand-foot syndrome

Question 23

mTOR inhibitor drugs

Answer 23

Everolimus, temsirolimus

Question 24

mTOR inhibitor drugs MOA

Answer 24

1. Reducing cell growth and proliferation (decreased cell cycle progression, reduced bioenergetics)
2. Prevention of angiogenesis
3. Synergy with drugs that damage DNA

Question 25

mTOR inhibitor drugs pharmacokinetics

Answer 25

- -oral administration; must be taken consistently (either with or without food) in order to minimize variability in drug concentration - -metabolized by CYP 3A4 (drug interactions) - -substrate for P-glycoprotein

Question 26

mTOR inhibitor drug side effects

Answer 26

- hypersensitivity--  increased risk of lymphomas, --particularly of the skin and infection - angioedema - kidney arterial and venous ----thrombosis - delays in wound healing - hyperlipidemia - nephrotoxicity and proteinuria - male infertility

Question 27

immunomodulatory drug names

Answer 27

Lenalidomide, pomalidomide, thalidomide

Question 28

Thalidomide uses

Answer 28

- Hansen's disease | - Multiple myeloma

Question 29

Thalidomide side effects

Answer 29

- -relatively few side effects in adult males and non-pregnant females, other than nausea, rashes, constipation and peripheral neuropathy - -increased risk of deep vein thrombosis, particularly in multiple myeloma patients (most patients are placed on WARFARIN when THALIDOMIDE treatment is initiated) - -Significant teratogenic effects (esp. arond 3-4 weeks postconception).

Question 30

Thalidomide MOA

Answer 30

- -In Hansen's disease: suppresses immune and inflammatory reactions (as soon as treatment stopped, symptoms reappear). - Antieoplastic: alters ratios of various types of immune cells and changes that expression of molecular markers on their surfaces - -sedating and improves well being--restores appetite and decreases wasting

Question 31

Thalidomide pharmacokinetics

Answer 31

Oral | Renal excretion of metabolites

Question 32

Treatment strategies

Answer 32

Antineoplastic agents are almost always given in combination. Correct selection of drugs in a regimen can result in decreased development of resistance, synergistic effects and decreased toxic effects. 

Question 33

Pulse therapy

Answer 33

- -intermittent treatment with very high doses of a drug, followed by drug-free periods - -allow hematologic and immunologic recovery between treatment cycles Example: METHOTREXATE for the treatment of choriocarcinoma

Question 34

Rescue therapy

Answer 34

--following administration of toxic doses of a chemotherapeutic agent, normal cells can be rescued by giving "antidotes" that only they can use Example: LEUCOVORIN following high dose METHOTREXATE treatment

Question 35

Principles of drug selection

Answer 35

- Active when used alone - Different mechanisms of action and/or different chemical classes (CCNS vs. CCS or active in different stages of cell cycle) - Enables use of more specific strategies

Question 36

Results of appropriate drug selection

Answer 36

- -Synergistic effects (ex. cytarabine +6-thioguanine) - -decreased development of resistance - -broader cell kill in cancers that have heterogeneous tumor cell production

Question 37

Recruitment

Answer 37

- -use a CCNS drug to achieve a significant log kill - -cause cancer cells in G0 to be recruited back into the cell cycle - -administer a CCS drug to kill dividing cells

Question 38

Synchrony

Answer 38

- -using CCS drugs to synchronize cells into simultaneous cell division, so that they are more sensitive to other drugs or radiation - -timing the delivery of drugs so that the action of one drug doesn't interfere with the actions of another

Question 39

Synchrony examples

Answer 39

- -HYDROXYUREA followed by radiation - -VINCA ALKALOIDS (M phase) followed by another CCS drug like ETOPOSIDE (S phase) - -METHOTREXATE followed by L-ASPARAGINASE for the treatment of acute lymphocytic leukemia

Question 40

Recruitment examples

Answer 40

CMF in breast cancer | DAUNORUBICIN + CYTARABINE in AML