16 and 17 - Antieoplastic Agents I and II

Question 1

What specific criteria are important for cells to pass the G1/S checkpoint?

Answer 1

• Are cell nutrition, size and environment favorable?
• Is all DNA intact?

If so, the cell will prepare for DNA replication and enter S phase

Question 2

What specific criteria are important for cells to pass the G21/M checkpoint?

Answer 2

Is DNA completely replicated?

If so, the cell will enter mitosis

Question 3

What specific criteria are important for cells to pass the metaphase/anaphase checkpoint?

Answer 3

• Is all DNA intact?
• Are all chromosomes attached to the mitotic spindle?

If so, the cell will begin chromatid separation and prepare for cytokinesis

Question 4

What do tumor suppressor genes do?

Answer 4

• They encode proteins that are important components of checkpoints
• Tumor suppressors can halt the cell cycle and induce apoptosis if ideal conditions are not met

Question 5

What is the key tumor suppressor?

Answer 5

p53

Cells that become cancerous often have reduced function in this key tumor suppressor

Question 6

What are oncogenes?

Answer 6

Oncogenes are mutated versions of genes that support normal cellular proliferation (proto-oncogenes)

Question 7

What are the three mechanisms by which oncogenes form?

Answer 7

1 - Point mutation
2 - Fusion-protein
3 - Proto-oncogene duplication or amplification

Question 8

Describe how a point mutation can form an oncogene

Answer 8

• A mutation in one of the nucleotides that causes a change in an amino acid in a regulatory region in the protein product of the gene
• An amino acid substitution (called a point mutation) can cause the protein to be hyperactivated or resistant to normal degradative mechanisms that prevent too much expression of the protein
• Hyperactivity or resistance can lead to uncontrolled proliferation

Question 9

Describe how a fusion-protein can form an oncogene

Answer 9

• A fusion protein is when a chromosomal translocation causes a fusion of two genes
• The fusion-protein can have increased activity
  )

Question 10

Give an example of a fusion-protein

Answer 10

Example

• Philadelphia chromosome
• Fusion between chromosomes 9 and 22
• This causes a fusion between the ABL gene and the BCR gene
• The normal protein product of ABL is a tyrosine kinase that promotes cellular growth
• BCR-ABL fusion protein causes a significant increase in the tyrosine kinase activity of ABL
• This leads to uncontrolled proliferation of myeloid cells causing chronic myeloid leukemia (CML

Question 11

Describe how duplication or amplification can form an oncogene

Answer 11

When a proto-oncogene is duplicated or amplified, it causes the formation of many extra chromosomal copies

Question 12

What does it mean to say that the killing of cancer cells is “first order”?

Answer 12

It means that chemo drugs kill a constant PERCENTAGE of cancer cells, not a constant number

Question 13

Give an example of first order killing

Answer 13

If a drug kills 99 % of cells with the first dose, it will not kill the remaining 1% with the second dose (it will only kill 99 % of the remaining cells).

Question 14

What are the four goals of cancer therapy?

Answer 14

1 - Curative intent
2 - Adjuvant therapy
3 - Neoadjuvant therapy
4 - Palliative care

Question 15

What is curative intent?

Answer 15

When we begin treating some cancers, we intend to cure them

• Acute lymphocytic leukemia (ALL)
• Testicular cancer
• Acute myelogenous leukemia (AML)

Question 16

What is adjuvant therapy?

Answer 16

• Drug therapy is given after the primary treatment (typically surgery, but can also be radiation)
• After surgery or radiation there are remaining cancer cells and those are the ones we are trying to treat
• This is done to decrease the chances that the cancer will return

Question 17

What is neoadjuvant therapy?

Answer 17

• Drug therapy that is done to shrink a tumor before surgical resection
• This can be done to allow a previously unoperable tumor to become operable

Question 18

What is palliative care?

Answer 18

• Palliative care provides temporary improvement of quality of life by reducing
  symptoms.
• Therapies with combinations of drugs with different mechanisms of cytotoxicity and different adverse
  effects are often administered to maximize cell kill, while minimize side-effects.
• This is most often the rule rather
  than the exception

Question 19

How do tumor cells become resistant to chemotherapy treatments?

Answer 19

• Tumor cells often have genetic instability, which allows them to become resistant to chemotherapy
• Gene duplications of the multi-drug resistant (MDR) transporter can cause cell to survive despite chemotherapy
• This is because they are able to pump many different cytotoxic agents out of the cell
• This can enable the tumor cell count to grow despite treatment

Question 20

What is epithelial-mesenchymal transition (EMT)? How does this induce resistance to chemotherapy?

Answer 20

• The process by which cells lose adhesive properties and become motile
• Changes that occur during EMT cause the cells to become resistant to drugs

Question 21

What are other ways that resistance can occur?

Answer 21

The tumor is able to…

• Undergo epigenetic changes
• Induce drug efflux
• Repair DNA damage
• Inhibit cell death
• Metastasize via EMT
• Alter the drug
• Inactivate the drug