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Fall 2021: Therapeutics III > Concepts of Chemotherapy (Dykhuizen) > Flashcards

Concepts of Chemotherapy (Dykhuizen) Flashcards

1
Q

In what ways is chemotherapy used to treat solid tumors?

A
  • Adjuvant therapy: chemo after surgery
  • Neoadjuvant therapy: chemo before surgery
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2
Q

In what ways is chemotherapy used to treat hematological tumors?

A
  • Induction therapy: to eradicate cancer
  • Consolidation therapy: to wipe out any remaining cancer
  • Maintenance therapy: to prevent remission
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3
Q

Explain the 2-hit hypothesis in relation to retinoblastoma.

A

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

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4
Q

What is synthetic lethality?

A

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.

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5
Q

BRCA mutations in breast cancer increase susceptibility to _____________.

A

PARP inhibitors

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6
Q

List four PARP inhibitors.

A

olaparib, rucaparib, niraparib, and talazoparib

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7
Q

What are PARP inhibitors PRIMARILY used for?

A

BRCA 1/2 cancers

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8
Q

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

A

false

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9
Q

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

A

cells > genome > chromosome > genes > DNA

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10
Q

What is the central dogma of biology?

A

DNA (transcription) RNA (translation) protein

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11
Q

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

A

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

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12
Q

What happens in the S phase of the cell cycle?

A

cell replicating/synthesizing DNA

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13
Q

What happens in the G2 phase of the cell cycle?

A

cell assembles machinery for chromosomal segregation and cytokinesis

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14
Q

What happens in the M phase of the cell cycle?

A

mitosis

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15
Q

What drives the cell cycle clock?

A

cyclins paired with CDKs

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16
Q

What is the R point in the cell cycle clock?

A

when cells decide whether or not to enter the cell cycle

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17
Q

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

A

G1-S

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18
Q

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

A

G1​-S

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19
Q

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

A

G1​-S

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20
Q

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

A

S-G2

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21
Q

During what checkpoint is there evaluation for any errors?

A

S-G2

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22
Q

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

A

G2-M

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23
Q

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

A

G2​-M

24
Q

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

A
  • inhibit proteins that drive the cell cycle
  • trigger cell cycle checkpoints to induce apoptosis
25
Q

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

A

S phase

26
Q

What are the “master regulators” of cell cycle initiation?

A

Cyclin D and CDK-4,6

27
Q

List three CDK4/6 inhibitors.

A

palbociclib, abemaciclib, ribociclib

28
Q

What adverse reactions are associated with CDK4/6 inhibitors?

A
  • neutropenia
  • nausea/vomiting
  • fatigue
  • diarrhea
29
Q

What are CDK4/6 inhibitors currently approved for?

A

breast cancers

30
Q

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

A

true

31
Q

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

A

false

32
Q

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

A

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
33
Q

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

A

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

34
Q

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)?

A
  1. repeated administration
  2. continuous infusion
35
Q

A chemotherapy that interferes with DNA synthesis is _____________.

A

cell cycle specific

36
Q

Define growth fraction.

A

the fraction of cells in a tumor that are actively proliferating

37
Q

Describe the trend in which tumor cells grow.

A

exponentially

38
Q

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?

A

30 days

39
Q

Cancer chemotherapy kills tumor cells with _____-order kinetics.

A

first

40
Q

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

A
  • small tumor (or treatment after surgical removal)
  • early diagnosis
  • increased drug intensity
41
Q

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

A

decreases; slows

42
Q

What does the Gompertzian Growth Curve demonstrate?

A

as tumors grow, their doubling time slows

43
Q

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

A

>109 cells (1 g)

44
Q

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

A

1010 cells

45
Q

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

A

1012 cells (1 kg)

46
Q

Most solid tumors double every __________.

A

2-3 months

47
Q

Most lymphomas double _________.

A

every few days

48
Q

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?

A

20 months

49
Q

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

A
  • 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)
50
Q

What physiological changes can promote resistance to chemotherapy?

A
  • 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)
51
Q

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

A

Drug transport out of cells

52
Q

What are the two major limitations of chemotherapy?

A

resistance and toxicity

53
Q

List some major dose-limiting chemotherapy toxicities.

A
  • hematopoeitic (WBC, platelets, RBC)
  • gastrointestinal (N/V, appetite loss)
54
Q

What are some advantages of combination chemotherapy?

A
  • no additive toxicity for drugs with non-overlapping toxicities
  • increased cell killing
  • reduced drug resistance for drugs with independent mechanisms of action
55
Q

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

A

false (for now)

56
Q

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

A

maximal

57
Q

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

A

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

Fall 2021: Therapeutics III (25 decks)

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