Medications for EXAM #3

Question 1

What is the difference between traditional chemotherapy and targeted therapy?

Answer 1

Traditional chemo targets ALL dividing cells, while targeted therapies bind antigens or receptors on tumor cells.
L19a #3

Question 2

Name three monoclonal antibody cancer therapies

Answer 2

Bevacizumab, Rituximab, Trastuzumab.
BRT (bert)
L19a #5

Question 3

Name three tyrosine kinase inhibitor cancer therapies

Answer 3

Gefitinib, Imatinib, Lapatinib.
GIL
L19a #5

Question 4

What do the following suffixes for monoclonal antibody cancer treatments mean:

1. ) -mab
2. ) -umab
3. ) -momab
4. ) -ximab
5. ) -zumab

Answer 4

1.) -mab = Monoclonal antibody.
2.) -umab = Human (only human protein).
3.) -momab = Mouse (murine).
4.) -ximab = Chimeric (mix of mouse and human; “x” indicates CROSSED).
5.) -zumab = Humanized (mix of human and mouse, less mouse compared to chimeric).
L19a #7

Question 5

What are the consequences of:

1. ) Caspase 3 activation (2)
2. ) iPLA2 activation (3)

Answer 5

1.) Caspase 3 activation = Apoptotic tumor cell death = Tumor Shrinkage.
2.) iPLA2 activation = Release of PGE2 and AA = Accelerated tumor growth and repopulation = Tumor recurrence.
L19a #9

Question 6

For the following monoclonal antibodies, list what their effect is and what they are specific for:

1. ) Rituximab
2. ) Trastuzumab
3. ) Bevacizumab
4. ) Nivolumab

Answer 6

1.) Direct cytotoxicity; specific for CD20 on B cells.
2.) Growth factor inhibitors; specific for HER2.
3.) Vascular endothelial growth factor inhibitors; inhibits angiogenesis (beV = Vascular).
4.) Program death-1 inhibitors; “Turns on” immune system.
L19a #10

Question 7

What do the following CD molecules identify?
CD20
CD33
CD52

Answer 7

CD20: B cell
CD33: Myeloid cells
CD52: Lymphocytes
L19a #11

Question 8

What is VEGF and what does it do?

Answer 8

Vascular endothelial growth factor – Promotes angiogenesis.

L19a #13

Question 9

What is EGFR and what does it do?

Answer 9

Epidermal Growth Factor Receptor –Promotes cellular proliferation, invasion and metastasis.
L19a #13

Question 10

What is HER2/neu, what does it regulate (4), and what cancer is it over-expressed in?

Answer 10

Human Epidermal Growth Factor Receptor 2: Regulates cell growth, differentiation, migration and adhesion.
Over-expressed in breast cancer
L19a #13

Question 11

What does rituximab target and where, i.e. on which types of cancer cells (3)?

Answer 11

CD 20 found on B cell lymphomas, B cell chronic lymphocytic leukemia, and melanoma stem cells.
L19a #14

Question 12

1. ) What types of cancer is rituximab/rituxan for (2)?

2. ) What are its three possible mechanisms of action?

Answer 12

1.) B cell non-Hodgkin lymphoma, leukemias.
2.)
(a) ADCC (antibody-dependent cell mediated cytotoxicity) –via macrophage, monocyte, or NK cell.
(b) CDC (complement-mediated cytotoxicity) –complement activation followed by cell lysis.
(c) Apoptosis.
L19a #14

Question 13

What are the drugs used for non-Hodgkin lymphoma treatment? (mnemonic)

Answer 13

R-CHOP: 
Rituximab
Cyclophosphamide
Hydroxydaunorubicin (doxorubicin)
Oncovin (vincristine)
Prednisone
L19a #16

Question 14

What is the action of Bevacizumab and what is cancers it used for (3)?

Answer 14

Inhibits the action of VEGF (vascular endothelial growth factor) by binding directly to VEGF receptors on endothelial cells.
-Used for colon cancer (with 5-FU), non-small cell lung cancer, and breast cancer.
L19a #19

Question 15

1. ) What is the action of Trastuzumab and for what cancer?
2. ) What are its two mechanisms?
3. ) What are the risks and precautions with trastuzumab?

Answer 15

1.) Anti-HER2 for breast cancer (can feature uncontrolled HER2 activity).
HER-‘T’wo = ‘T’rastuzumab
2.) Block receptor signaling (PI3K/Akt signaling), and receptor internalization (dephosphorylation and downregulation).
3.) 2-7% incidence of cardiotoxicity during therapy (arrhythmias, heart failure, MI). Must have frequent screening for cardiomyopathy (baseline echocardiograms needed) due to increased risk for cardiac death.
L19a #22

Question 16

What chemo drugs must be used with caution due to risk of causing arrhythmias and heart failure?

Answer 16

ADD
Anthracyclines —> Doxorubicin, Daunorubicin.
L19a #23

Question 17

1. ) What roles do tyrosine kinases play in the cell cycle (6)?
2. ) What is the result of constitutive phosphorylation (3)?

Answer 17

1.) Growth, differentiation, metabolism, adhesion, motility, and death.
2.) Oncogene over-expression, hyperactive kinase activity, and non-regulated growth of cancer cells.
L19a #25

Question 18

What tyrosine kinase is involved in CML? How?

Answer 18

Chronic myelogenous leukemia: Bcr-Abl kinase.
-Chromosomes 9 translocates to Ch22 to make the oncoprotein Bcr-Abl (forms the Philadelphia chromosome).
L19a #27

Question 19

1. ) How does Bcr-Abl directly affect genetic expression (3), and
2. ) What is the result (3)?
3. ) What drug(s) blocks the effects of Bcr-Abl?

Answer 19

1.) Enhanced expression and/or function of RNA binding proteins increases (1) mRNA translation, (2) mRNA export/translation, and (3) transcription/translation.
2.) Growth advantage, enhanced survival, and differentiation arrest.
3.) Imatinib
L19a #28

Question 20

1. ) What does Imatinib target and how does it work (2)?

2. ) What is the result (2)?

Answer 20

1.) Targets Bcr-Abl —> Inhibits c-kit and induces apoptosis.
2.) Decreases rate of cell division and enhances DNA repair.
L19a #30

Question 21

1. ) What is Lapatinib used for?
2. ) When is it used?
3. ) What is one of its main advantages?

Answer 21

1.) Tyrosine kinase inhibitor that inhibits EGFr and HER2/neu in HER2-amplified, trastuzumab refractory breast cancer (i.e. used in patients with HER2 positive breast cancer that has progressed after treatment with trastuzumab).
Used in conjunction with Capecitabine
2.) Used to prolong life of patients with breast cancer after Trastuzumab fails to work well (hence, Trastuzumab-refractory breast cancer).
3.) It crosses the BBB.
L19a #32

Question 22

How does lapatinib work on the receptor level?

Answer 22

Lapatinib binds on the tyrosine kinase (TK) domain, prevents dimerization and phosphorylation; thereby inhibiting the downstream cascade of events.
L19a #33

Question 23

1. ) List four types of epidermal growth factor receptors.
2. ) What is the result of mutation or dysregulation?
3. ) What cancers are they associated with (4)?

Answer 23

1.) EGFr (HER1), HER2/neu, HER3, and HER4.
2.) Uncontrolled cell division and cancer.
3.) Lung, epithelial, colon, and breast cancer.
L19a #34

Question 24

1. ) What is the action of Gefitinib?
2. ) What is its mechanism?
3. ) What type of cancer is it mostly used for? Why?

Answer 24

Gef = EGFr
1.) EGF tyrosine kinase receptor (EGFr) inhibitor.
2.) Binds to the ATP-binding site and inhibits protein phosphorylation.
3.) Used for non-small cell lung carcinoma (and breast cancer) because EGFr (also HER1) is over-expressed in lung and breast cancer.
L19a #35

Question 25

1. ) Give an example of cofactor/coenzyme supplementation in manipulation of metabolism and what it's for. 2. ) It's efficacy is conditional of what?

Answer 25

1.) Sapropterin dihydrochloride (KUVAN) – BH4 cofactor effective in some PKU patients. 2.) Requires at least 12.5% residual enzyme activity. L26 #10

Question 26

Name three medications that treat OTC deficiency through the mechanism of metabolic diversion.

Answer 26

1.) Glycerol phenylbutyrate (Ravicti) 2.) Sodium phenylbutyrate (Buphenyl) *1 and 2 are metabolized to phenylacetate, which conjugates with glutamine, which then mobilizes nitrogen excretion* 3.) Sodium benzoate, Sodium phenylacetate (Ammonul) – Benzoate combines with glycine to form *HIPPURATE*, which is excreted in the urine. L26 #11

Question 27

What medication is an example of enzyme inhibition in the context of metabolic manipulation? Describe (what does it do, what is it for).

Answer 27

Allopurinol: A xanthine oxidase inhibitor used to decrease uric acid production. -Used in Lesch-Nyhan syndrome, which is an HGPRT deficiency in which the body is unable to salvage hypoxanthine or guanine, which results in excessive production of uric acid. L26 #12, p.40 njp

Question 28

1. ) What *class* of medications are an example of enzyme inhibition (metabolic inhibitors) in the context of metabolic manipulation. 2. ) What are they used for? 3. ) How do they work?

Answer 28

1.) Statins – Structural analogs of HMG-CoA. 2.) Used for patients with *familial hypercholesterolemia (heterozygous)* —> Deficiency in functioning LDL receptors, which results in elevated LDL-cholesterol. 3.) Statins are competitive inhibitors of HMG-CoA reductase. L26 #13

Question 29

What type of drug is often used with statins in order to reduce circulating LDL and increase LDL receptors? Give two examples.

Answer 29

Bile acid sequestrants —> Cholestyramine, Colestipol. | L26 #14

Question 30

1. ) What drug utilizes the receptor antagonism mode of metabolism manipulation to exert its effect? 2. ) What is it used for? 3. ) How does it work?

Answer 30

1.) Losartan, an AT II receptor antagonist. 2.) Used to prevent dilatation of the ascending aorta in Marfan syndrome. 3.) Losartan inhibits AT II signaling, which decreases TGF-β (transforming growth factor) activity. Decreased TGF-β activity decreases rate of dilatation of the aorta in individuals with Marfan syndrome. L26 #15, p.41 njp

Question 31

1. ) What is the drug Ataluren most effective at? | 2. ) What two disorders is this drug used for (describe the nature of these disorders)?

Answer 31

1.) Most effective in allowing UGA read-through (i.e. allows skipping over nonsense codons). 2.) (i) Cystic fibrosis: Nonsense mutation of the ∆F508 in the CFTR protein (Arg553). Shows significant improvement in lung function with Ataluren. (ii) Duchenne Muscular Dystrophy (DMD): Helps patients walk an average of 47 meters farther. L26 #20

Question 32

1. ) What is the most common mutation that causes CF and how? 2. ) Besides Ataluren, which other small molecular therapy drug treats Cystic Fibrosis and how? What else does it need?

Answer 32

1.) ∆F508 mutation in CFTR protein (most common of all CF mutations). -Mutant protein trapped in ER and degraded by proteasome (trafficking defect). 2.) Lumacaftor: Drug serves as a pharmaceutical chaperone; it interacts directly with the mutant CFTR and stabilizes the 3D structure. *Not sufficient on its own —> needs to be combined with another drug —> Ivacaftor (serves as a potentiator for Lumacaftor)* L26 #21, p.42 njp

Question 33

A drug is of clinical benefit to cystic fibrosis if it increases ________________ of the cell by 20-25%.

Answer 33

Increases CFTR channels in the apical surface of the cell by 20-25%. L26 #21

Question 34

What is the role of Ivacaftor?

Answer 34

Drug serves as a potentiator for Lumacaftor —> Improves Cl- transport of some mutant CFTR proteins. *FDA approved for 9 CFTR missense mutations* L26 #23

Question 35

Concerning protein/amino acid replacement, what treats hemophilia A and B (2)?

Answer 35

Hemophilia A: Clotting factor VIII. Hemophilia B: Clotting factor IX. L26 #23

Question 36

Concerning enzyme replacement therapy, how do you treat the following: 1. ) Gaucher disease 2. ) Pompe disease 3. ) Fabry disease 4. ) ADA deficient SCID 5. ) Hurler syndrome, MPS I 6. ) Hunter syndrome, MPS II

Answer 36

1.) Beta glucocerebrosidase 2.) Alpha glucosidase 3.) Alpha galactosidase 4.) Adenosine deaminase 5.) Alpha-L-iduronidase (Laronidase; aldurazyme) 6.) Iduronate-2-sulfatase (Idursulfase; elaprase) L26 #23, p.43 njp