Concepts of Chemotherapy (Dykhuizen) Flashcards
In what ways is chemotherapy used to treat solid tumors?
- Adjuvant therapy: chemo after surgery
- Neoadjuvant therapy: chemo before surgery
In what ways is chemotherapy used to treat hematological tumors?
- Induction therapy: to eradicate cancer
- Consolidation therapy: to wipe out any remaining cancer
- Maintenance therapy: to prevent remission
Explain the 2-hit hypothesis in relation to retinoblastoma.
There is an assumption that hereditary retinoblastoma already has a single deletion.
What is synthetic lethality?
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.
BRCA mutations in breast cancer increase susceptibility to _____________.
PARP inhibitors
List four PARP inhibitors.
olaparib, rucaparib, niraparib, and talazoparib
What are PARP inhibitors PRIMARILY used for?
BRCA 1/2 cancers
True or false: olaparib can be prescribed with or without genetic testing.
false
Explain general nuclear organization from largest (cells) to smallest (DNA).
cells > genome > chromosome > genes > DNA
What is the central dogma of biology?
DNA (transcription) RNA (translation) protein
What happens in the G0/G1 phase of the cell cycle?
cell is quiescent or accumulating “building blocks” required for cell division
What happens in the S phase of the cell cycle?
cell replicating/synthesizing DNA
What happens in the G2 phase of the cell cycle?
cell assembles machinery for chromosomal segregation and cytokinesis
What happens in the M phase of the cell cycle?
mitosis
What drives the cell cycle clock?
cyclins paired with CDKs
What is the R point in the cell cycle clock?
when cells decide whether or not to enter the cell cycle
During what checkpoint is there evaluation of a mitogenic signal telling the cell to proceed?
G1-S
During what checkpoint is it assessed whether or not there are enough building blocks?
G1-S
During what checkpoint is it assesed whether there is unrepaired DNA damage?
G1-S
During what checkpoint is it assessed whether or not the genome has been replicated?
S-G2
During what checkpoint is there evaluation for any errors?
S-G2
During what checkpoint is it assessed whether the sister chromatid arms have been separated?
G2-M
During what checkpoint is it assessed whether the required machinery is present and assembled for chromosomal segregation and cytokinesis?
G2-M
What are the two most common methods used by tradtional chemotherapies to target the cell cycle?
- inhibit proteins that drive the cell cycle
- trigger cell cycle checkpoints to induce apoptosis
Which phase of the cell cycle is targeted by most kinase inhibitors?
S phase
What are the “master regulators” of cell cycle initiation?
Cyclin D and CDK-4,6
List three CDK4/6 inhibitors.
palbociclib, abemaciclib, ribociclib
What adverse reactions are associated with CDK4/6 inhibitors?
- neutropenia
- nausea/vomiting
- fatigue
- diarrhea
What are CDK4/6 inhibitors currently approved for?
breast cancers
True or false: tumor suppressor genes produce proteins that block the activity of cyclins.
true
True or false: only fast-growing tumors are susceptible to chemotherapies.
false
What happens if a tumor cell that has lost its G1-S checkpoint control is treated with chemotherapy and DNA is damaged?
the cell will not halt in G1 and instead try to replicate, leading to two possibilities:
- attempt triggers apoptosis
- damaged DNA gets replicated, but lethal genetic insults may still occur
What is one major limitation associated with phase-specific chemotherapy agents?
the number of cells killed is limited to the number of cells present in the appropriate phase of the cell cycle
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)?
- repeated administration
- continuous infusion
A chemotherapy that interferes with DNA synthesis is _____________.
cell cycle specific
Define growth fraction.
the fraction of cells in a tumor that are actively proliferating
Describe the trend in which tumor cells grow.
exponentially
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?
30 days
Cancer chemotherapy kills tumor cells with _____-order kinetics.
first
What three factors can increase the success rates for cytotoxic chemotherapy?
- small tumor (or treatment after surgical removal)
- early diagnosis
- increased drug intensity
As tumors grow, their growth fraction _______ and doubling time _______.
decreases; slows
What does the Gompertzian Growth Curve demonstrate?
as tumors grow, their doubling time slows
At what size can a tumor mass be detected by standard imaging or feeling?
>109 cells (1 g)
At what size will a tumor mass’ associated symptoms appear in a patient?
1010 cells
At what size is a tumor mass considered to be lethal?
1012 cells (1 kg)
Most solid tumors double every __________.
2-3 months
Most lymphomas double _________.
every few days
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?
20 months
How can there be decreased chemotherapy accumulation in the cell (drug resistance)?
- 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)
What physiological changes can promote resistance to chemotherapy?
- 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)
What is the most common reason for resistance to multiple chemotherapies at once?
Drug transport out of cells
What are the two major limitations of chemotherapy?
resistance and toxicity
List some major dose-limiting chemotherapy toxicities.
- hematopoeitic (WBC, platelets, RBC)
- gastrointestinal (N/V, appetite loss)
What are some advantages of combination chemotherapy?
- no additive toxicity for drugs with non-overlapping toxicities
- increased cell killing
- reduced drug resistance for drugs with independent mechanisms of action
True or false: a drug that is ineffective when used alone can often be approved for combination studies.
false (for now)
In combination therapy, individual drugs in combination should be used at _______ doses.
maximal
In general, how should one decide which drugs to include in a combination chemotherapy regimen?
use drugs with different mechanisms of action or different cell cycle specificities
