Hall 27 - Chemotherapy

Question 1

How do most chemo agents work?

Answer 1

Affect DNA synthesis or function

Question 2

For most chemo drugs what does the dose-response relationship look like?

Answer 2

Similar to RT
Initial shoulder followed by exponential relationship between surviving fraction and dose

Best case: first order kinetics (dose kills constant fraction of cells)

Higher chance of cure if small cell population

Higher sensitivity variation than RT

Question 3

How does chemo resistance develop?

Answer 3

Faster than RT
Decreased drug accumulation
Increased drug efflux
Elevated glutathione (free radical scavenger)
Increased DNA repair

Question 4

What is spatial cooperation?

Answer 4

RT treats local disease burden, chemo treats systemically

Question 5

What is synergism?

Answer 5

Chemo accumulates cells at more radiosensitive cell cycle phase (G2/M) or impedes repair of DNA damage by RT

Question 6

How does lack of cross-resistance support combining chemo and RT?

Answer 6

Resistance to chemo does not usually produce resistance to RT

Question 7

Why are chemo agents combined?

Answer 7

Exploits tumor heterogeneity (target different cell subpopulations)
Limits drug resistance

Question 8

What is the mechanism of action of alkylating agents?

Answer 8

Highly reactive compounds that add alkyl groups to DNA

Cell cycle nonspecific

Bulky adducts repaired by NER

Nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, triazine derivatives, nitrosureas, TMZ

Question 9

What is the mechanism of action of procarbazine?

Answer 9

Hydrazine derivative

Question 10

What is the mechanism of action of cisplatin?

Answer 10

Binds to DNA and causes interstrand and intrastrand DNA crosslinks

Cell cycle nonspecific

Radiosensitizer via inhibiting DSB repair

Question 11

What is the mechanism of action of antibiotics (MMC)?

Answer 11

Binds to DNA and inhibits DNA/RNA synthesis

Cell cycle nonspecific

MMC creates DNA crosslinks - bioreductive and tends to be more toxic to hypoxic cells

Question 12

What is the mechanism of action of antimetabolites?

Answer 12

Metabolite analogues

Ex) MTX (folate antagonist), 5-FU (thymine analogue), Xeloda (5-FU prodrug), hydroxyurea (anti-ribonucleotide reductase)

Question 13

What chemo class is cell cycle specific?

Answer 13

Nucleoside analoges

Ex) Gemcitabine, cytarabine, 5-azacytidine

Question 14

What is the mechanism of action of vinca alkaloids?

Answer 14

Inhibit microtubule polymerization > block in late G2

Question 15

What is the mechanism of action of taxanes?

Answer 15

Microtubule stabilizers (opposite vinca alkaloids) > block/prolong G2/M transition > increase radiosensitivity

Question 16

What is the mechanism of action of topoisomerase inhibitors?

Answer 16

Inhibit DNA resealing/religation by enzymes that reduce DNA supercoiling as a result of transcription, replication, or HR repair

Question 17

What is the mechanism of action of irinotecan?

Answer 17

Camptothecin, topotecan, irinotecan - inhibit topoisomerase I (breaks/rejoins a singe strand of DNA to let the broken strand rotate around the intact strand)

Question 18

What is the mechanism of action of doxorubicin?

Answer 18

Etoposide, anthracyclines (doxorubicin, daunorubicin), mitoxantrone - inhibit tomoisomerase II (cuts BOTH strands of DNA helix simultaneously to resolve DNA tangles and supercoils)

Question 19

How do PARP inhibitors work?

Answer 19

Decreased BER > ssDNA breaks > collapse of S-phase replication forks > DSBs

*Synthetic lethality if cells deficient in BRCA1/2 - cannot undergo HR repair of DSBs

Question 20

Where is PD-L1 located?

Answer 20

PD-L1 and PD-L2 on tumor
Bind to PD-1 on T cell
» T cell activation

Question 21

What are pembrolizumab and nivolumab?

Answer 21

PD-1 inhibitors (on T cells)

Question 22

What are durvalumab and atezolizumab?

Answer 22

PD-L1 inhibitors (on tumor cells)

Question 23

What is ipilimumab?

Answer 23

CTLA-4 inhibitor

Question 24

What is LAG-3?

Answer 24

A cell-surface molecule on T cells that binds MHC-II > downregulates immune response (like CTLA-4 and PD-1)