Concepts of Chemotherapy (Dykhuizen)

Question 1

In what ways is chemotherapy used to treat solid tumors?

Answer 1

• Adjuvant therapy: chemo after surgery
• Neoadjuvant therapy: chemo before surgery

Question 2

In what ways is chemotherapy used to treat hematological tumors?

Answer 2

• Induction therapy: to eradicate cancer
• Consolidation therapy: to wipe out any remaining cancer
• Maintenance therapy: to prevent remission

Question 3

Explain the 2-hit hypothesis in relation to retinoblastoma.

Answer 3

There is an assumption that hereditary retinoblastoma already has a single deletion.

Question 4

What is synthetic lethality?

Answer 4

Inactivation of either of two genes individually has little effect on cell viability, but loss of function of both genes simultaneously leads to cell death.

Question 5

BRCA mutations in breast cancer increase susceptibility to _____________.

Answer 5

PARP inhibitors

Question 6

List four PARP inhibitors.

Answer 6

olaparib, rucaparib, niraparib, and talazoparib

Question 7

What are PARP inhibitors PRIMARILY used for?

Answer 7

BRCA 1/2 cancers

Question 8

True or false: olaparib can be prescribed with or without genetic testing.

Answer 8

false

Question 9

Explain general nuclear organization from largest (cells) to smallest (DNA).

Answer 9

cells > genome > chromosome > genes > DNA

Question 10

What is the central dogma of biology?

Answer 10

DNA (transcription) RNA (translation) protein

Question 11

What happens in the G₀/G₁ phase of the cell cycle?

Answer 11

cell is quiescent or accumulating “building blocks” required for cell division

Question 12

What happens in the S phase of the cell cycle?

Answer 12

cell replicating/synthesizing DNA

Question 13

What happens in the G₂ phase of the cell cycle?

Answer 13

cell assembles machinery for chromosomal segregation and cytokinesis

Question 14

What happens in the M phase of the cell cycle?

Answer 14

mitosis

Question 15

What drives the cell cycle clock?

Answer 15

cyclins paired with CDKs

Question 16

What is the R point in the cell cycle clock?

Answer 16

when cells decide whether or not to enter the cell cycle

Question 17

During what checkpoint is there evaluation of a mitogenic signal telling the cell to proceed?

Answer 17

G₁-S

Question 18

During what checkpoint is it assessed whether or not there are enough building blocks?

Answer 18

G₁​-S

Question 19

During what checkpoint is it assesed whether there is unrepaired DNA damage?

Answer 19

G₁​-S

Question 20

During what checkpoint is it assessed whether or not the genome has been replicated?

Answer 20

S-G₂

Question 21

During what checkpoint is there evaluation for any errors?

Answer 21

S-G₂

Question 22

During what checkpoint is it assessed whether the sister chromatid arms have been separated?

Answer 22

G₂-M

Question 23

During what checkpoint is it assessed whether the required machinery is present and assembled for chromosomal segregation and cytokinesis?

Answer 23

G₂​-M

Question 24

What are the two most common methods used by tradtional chemotherapies to target the cell cycle?

Answer 24

• inhibit proteins that drive the cell cycle
• trigger cell cycle checkpoints to induce apoptosis

Question 25

Which phase of the cell cycle is targeted by most kinase inhibitors?

Answer 25

S phase

Question 26

What are the "master regulators" of cell cycle initiation?

Answer 26

Cyclin D and CDK-4,6

Question 27

List three CDK4/6 inhibitors.

Answer 27

**_palbo_**ciclib, **_abema_**ciclib, **_ribo_**ciclib

Question 28

What adverse reactions are associated with CDK4/6 inhibitors?

Answer 28

* neutropenia * nausea/vomiting * fatigue * diarrhea

Question 29

What are CDK4/6 inhibitors currently approved for?

Answer 29

breast cancers

Question 30

True or false: tumor suppressor genes produce proteins that block the activity of cyclins.

Answer 30

true

Question 31

True or false: only fast-growing tumors are susceptible to chemotherapies.

Answer 31

false

Question 32

What happens if a tumor cell that has lost its G₁-S checkpoint control is treated with chemotherapy and DNA is damaged?

Answer 32

the cell will not halt in G₁ and instead try to replicate, leading to two possibilities: 1. attempt triggers apoptosis 2. damaged DNA gets replicated, but lethal genetic insults may still occur

Question 33

What is one major limitation associated with phase-specific chemotherapy agents?

Answer 33

the number of cells killed is limited to the number of cells present in the appropriate phase of the cell cycle

Question 34

How can you increase the number of cells present in the appropriate phase of the cell cycle to maintain therapeutic levels of a drug over a longer period with phase-specific chemotherapies (two possibilities)?

Answer 34

1. repeated administration 2. continuous infusion

Question 35

A chemotherapy that interferes with DNA synthesis is \_\_\_\_\_\_\_\_\_\_\_\_\_.

Answer 35

cell cycle specific

Question 36

Define growth fraction.

Answer 36

the fraction of cells in a tumor that are actively proliferating

Question 37

Describe the trend in which tumor cells grow.

Answer 37

exponentially

Question 38

A patient has a tumor that doubles in size every 10 days. The first course of chemotherapy reduces the tumor to 12.5% of its original size. How long will it take for the tumor to return to its original size?

Answer 38

30 days

Question 39

Cancer chemotherapy kills tumor cells with \_\_\_\_\_-order kinetics.

Answer 39

first

Question 40

What three factors can increase the success rates for cytotoxic chemotherapy?

Answer 40

* small tumor (or treatment after surgical removal) * early diagnosis * increased drug intensity

Question 41

As tumors grow, their growth fraction _______ and doubling time \_\_\_\_\_\_\_.

Answer 41

decreases; slows

Question 42

What does the Gompertzian Growth Curve demonstrate?

Answer 42

as tumors grow, their doubling time slows

Question 43

At what size can a tumor mass be detected by standard imaging or feeling?

Answer 43

\>10⁹ cells (1 g)

Question 44

At what size will a tumor mass' associated symptoms appear in a patient?

Answer 44

10¹⁰ cells

Question 45

At what size is a tumor mass considered to be lethal?

Answer 45

10¹² cells (1 kg)

Question 46

Most solid tumors double every \_\_\_\_\_\_\_\_\_\_.

Answer 46

2-3 months

Question 47

Most lymphomas double \_\_\_\_\_\_\_\_\_.

Answer 47

every few days

Question 48

A patient detects a lump. Her cancer has a doubling time of 2 months. How long does she have before the tumor threatens to be lethal?

Answer 48

20 months

Question 49

How can there be decreased chemotherapy accumulation in the cell (drug resistance)?

Answer 49

* reduced transport into the cell (loss of importer) * decreased prodrug activation * detoxification of drug molecule * increased transport out of cell (efflux pumps like PgP or MRP)

Question 50

What physiological changes can promote resistance to chemotherapy?

Answer 50

* refuge of cancer cells in drug-protected sites (i.e., the brain) * massive stromalization * refuge of cancer cells in a site that provides protective trophic signals * passage through an EMT (epithelial mesenchymal transition)

Question 51

What is the most common reason for resistance to multiple chemotherapies at once?

Answer 51

Drug transport out of cells

Question 52

What are the two major limitations of chemotherapy?

Answer 52

resistance and toxicity

Question 53

List some major dose-limiting chemotherapy toxicities.

Answer 53

* hematopoeitic (WBC, platelets, RBC) * gastrointestinal (N/V, appetite loss)

Question 54

What are some advantages of combination chemotherapy?

Answer 54

* no additive toxicity for drugs with non-overlapping toxicities * increased cell killing * reduced drug resistance for drugs with independent mechanisms of action

Question 55

True or false: a drug that is ineffective when used alone can often be approved for combination studies.

Answer 55

false (for now)

Question 56

In combination therapy, individual drugs in combination should be used at _______ doses.

Answer 56

maximal

Question 57

In general, how should one decide which drugs to include in a combination chemotherapy regimen?

Answer 57

use drugs with different mechanisms of action or different cell cycle specificities