Anticancer Therapy II

Question 0

What does intrinsic resistance mean?

Answer 0

That cancer cells were unresponsive from the initial treatment.

Question 1

What are the two main types of drug resistance?

Answer 1

1. Intrinsic Resistance

2. Acquired Resistance

Question 2

What does acquired resistance mean?

Answer 2

That cells were initially responsive to treatment but developed resistance over time.

Question 3

What are the seven key mechanisms of drug resistance?

Answer 3

1. Decreased drug uptake.
2. Increased drug efflux.
3. Decreased drug activation.
4. Increased drug inactivation.
5. Decreased apoptosis.
6. Increased cellular repair.
7. Altered cellular targets.

Question 4

What occurs during the development of multidrug resistance?

Answer 4

Cells develop cross resistance to structurally and functionally unrelated drugs. This occurs through over-expression of the P-glycoprotein (Pgp) drug efflux pump in tumour cells.

Question 5

Where is Pgp normally expressed?

Answer 5

In the kidney, gut and blood brain barrier.

Question 6

What is the overall problem with Pgp-mediated MDR?

Answer 6

Increased drug efflux, leading to decreased intra-tumour drug concentration and therefore decreased therapeutic effect.

Question 7

What are the potential solutions to Pgp-mediated MDR?

Answer 7

Combine Pgp inhibitor and cytotoxic drug.

Question 8

What are the current limitations to finding a solution for Pgp-mediated MDR?

Answer 8

1. Pgp inhibitor toxicity (the drugs do other things).

2. Inhibitors lack specificity for tumour-associated Pgp.

Question 9

What is the number one strategy for biological approaches to cancer treatment?

Answer 9

Strategies to increase apoptosis.

Question 10

What are the three key points associated with Cytochrome C mediated apoptosis as a targeted cancer treatment?

Answer 10

1. Cytochrome C is normally sequestered in mitochondria.
2. Drugs promote Cytochrome C release which leads to apoptosis.
3. Bcl-2 blocks Cytochrome C release and increase resistance.

Question 11

What two general types of proteins are part of the Bcl-2 family of transmembrane proteins?

Answer 11

1. PRO-apoptotic members (eg. Bax)

2. ANTI-apoptotic members (eg. Bcl-2)

Question 12

What are the indications of Bcl-2 over-expression in cancers?

Answer 12

1. Poor prognostic marker.

2. Correlated with inherent and acquired drug resistance.

Question 13

What is one approach to overcome Bcl-2 mediated resistance?

Answer 13

Antisense RNA. Oblimersen made it to phase III trials.

Question 14

What are two examples of tyrosine kinase receptors?

Answer 14

1. Epidermal growth factor receptor (EGF-R).

2. Vascular endothelial growth factor receptor (VEGF-R)

Question 15

What are the different things that can result from a loss of regulation of tyrosine kinase receptors in cancer cells?

Answer 15

1. Increased receptor number.
2. Increased ligand number.
3. Mutated receptor active without ligand.
4. Receptor dimerized permanently.

Question 16

What are three tyrosine kinase targeted therapies?

Answer 16

1. Tyrosine kinase inhibitors.
2. Monoclonal antibodies vs. extracellular portion of receptor.
3. Monoclonal antibodies vs. ligand.

Question 17

What are the two drugs that inhibit the TK domain of tyrosine kinase receptors?

Answer 17

Erlonitib and Imanitib

Question 18

What are the two monoclonal antibodies that bind the extracellular portions of tyrosine kinase receptors?

Answer 18

Cetuximab and Trastuzumab

Question 19

What is the monoclonal antibody that bind the ligand of tyrosine kinase receptors?

Answer 19

Bevacizumab

Question 20

What are matrix metalloproteinaes?

Answer 20

Enzymes secreted by activated endothelial cells that degrade the extracellular matrix and allow the cells to migrate.

Question 21

What are the to antiangiogenic therapies?

Answer 21

1. Block endothelial cell activation.

2. Block endothelial cell migration.

Question 22

What drug is used to block endothelial cell activation?

Answer 22

Bevacizumab

Question 23

What antiangiogenic agents are used to block endothelial cell migration?

Answer 23

Matrix metalloproteinase inhibitors.