Cancer MOAs

Question 1

Which classes of drugs are cell-cycle specific?

Answer 1

1) Antimetabolites
2) Topoisomerase Inhibitors
3) Antimitotic Agents

These require specific scheduling to allow cells to come out of G0 - only work on proliferating cells, work best on tumors with high growth fraction

Question 2

What classes of drugs are cell-cycle independent?

Answer 2

1) Alkylating Agents
2) Anthracyclines

Good for large tumors with low growth fractions. They work in a dose-dependent fashion

Question 3

What order kinetics do chemo drugs follow? Do they work best on high or low burden tumors?

Answer 3

First order - kill a certain percentage of cells at a given dose (called Log Kill).

Low tumor burden - a given treatment leaves absolutely less cells than if there were lots of cells (high burden)

Question 4

What is IC50?

Answer 4

The concentration of drug that kills half of tumor cells

Question 5

What is the main mechanism of drug resistance? What gene is it on and how does it work?

Answer 5

P-glycoprotein, a membrane-bound ATPase efflux pump that pumps cytotoxic chemicals out of a cell.

From mdr1 (multi drug resistance) gene

Question 6

What traits are desirable in a combination therapy

Answer 6

1) Different targets in the cell cycle
2) Non-overlapping toxicity
3) Different means of resistance
4) Different mechanisms of action

Question 7

Anti-metabolites

Answer 7

Mimic building blocks of nucleotide/DNA synthesis, one way or another disrupting the process without directly damaging the DNA

Question 8

Folate analogues

Answer 8

• Look like folate but with varying length glutamyl chains. They are taken up inefficiently by tumor cells, so we give high doses, then rescue with Leucovorin (folate-type building block), which is also taken up inefficiently by tumors
• Analogues are compeitive inhibitors of dihydrofolate reductase, depleting THF - without THF the tumor cannot synthesize purines or thymine

Question 9

Pyrimidine/Purine Analogues

Answer 9

1) Compete for synthetic enzymes

2) Incorporate into nucleic acids and terminate the chain

Question 10

5-fluorouracil

Answer 10

A purine (thymidine) analogue, competes with thymidylate synthase preventing dUMP conversion to dTMP, starves body for thymine

-secondarily can inhibit RNA processing or can incorporate into nucleic acids

Question 11

Hydroxyurea

Answer 11

A ribonucleotide reductase inhibitor, binds active site iron residue, preventing conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates.

Question 12

Alkylating agents (and one unique one)

Answer 12

Covalently bind and form alkylated adducts with DNA (and other macromolecules)

Many have chloroethyl groups, which form reactive groups, facilitating adducts

BCNU: Splits apart, with one DNA alkylating agent and another residue that binds proteins (at Lys) disrupting structures

Question 13

Platinum Compounds

Answer 13

Called alkylating agents, but bind through interactions with platinum ions. Bulky leaving groups in the drug keep them in circulation longer

Question 14

Antitumor Antibiotics

Answer 14

Disrupt DNA Structure and Function - synthesized by fungi to protect against bacteria

1) Flat rings intercalate with DNA, blocking and disrupting topo-II, causing ds breaks
2) Generate oxygen free radicals, which attack and damage DNA
3) Hydrophobic, so incorporate in and disrupt membranes

Question 15

L-asparaginase

Answer 15

Cleaves asparagine to aspartate - tumors do not have asparagine synthase and other cells do, so tumors starve for asparagine

Question 16

Antimitotic Agents

Answer 16

Block topoisomerase or microtubule function. Derived from plants and things found in nature

Question 17

Vinca Alkyloids

Answer 17

• Disrupts dynamic instability of microtubules in the mitotic spindle, leading to either arrest and apoptosis, or nondisjunction and apoptosis.
• Do so by binding tubulin dimers, forming complexes that cannot assemble appropriately
• Arrest in M phase

Question 18

Taxanes

Answer 18

• Bind the mitotic spindle, preventing dissociation of tubulin dimers and disrupting dynamic instability
• Most active in M phase

Question 19

Estramustine

Answer 19

• Steroid backbone with dichlorethylamine residue, but binds tubulin and microtubule-associated proteins, inhibiting the microtubule.
• Most active in M phase
• Has steroid side effects (nausea, gynecomastia)

Question 20

Topoisomerase II Inhibitors

Answer 20

• Binds the topoisomerase II-DNA complex, preventing passage of DNA polymerase and causing a permenant double strand break.
• Most active in S phase

Question 21

Topoisomerase I Inhibitors

Answer 21

• Bind to the complex of topoisomerase I and DNA. When replication fork arrives, it causes a double strand break.
• Most active in S phase.

Question 22

Hormonal Agents

Answer 22

Affect signaling through steroid receptors.

Question 23

Predisone/Cortisol

Answer 23

Used for lymphomas and leukemias to deplete the aberrant immune cells

Question 24

Progestins

Answer 24

Bind progesterone receptors. Useful for promoting immature cells in endometrial cancer

Question 25

Anti-estrogens

Answer 25

Partial antagonistic effect on estrogen receptors, useful for ER+ tumors

Question 26

Aromatase Inhibitors

Answer 26

Prevents estrogen production from steroid precursors (in fat, ovaries, etc.) depriving ER+ cells of estrogen.

Question 27

Antiandrogens

Answer 27

Antagonists of androgen receptors, blocking signaling in androgen receptor positive tumors (prostate cancer)

Question 28

GnRH/LHRH Analogues

Answer 28

Analogues of GnRH - when the receptors are over-stimulated, they become desensitized, producing a chemical castration.

Question 29

Cytokines

Answer 29

Immune system stimulators

• Interferon alpha - stimulates NK cells and macrophages
• IL-2 - induces activity of lymphoid (T) cells

Question 30

What are signaling inhibitors

Answer 30

Block critical signaling pathways in the cell - perhaps the most specific treatment we have - can block cancers

• nib = orally ingested small molecule inhibitor of a tyrosine kinase that binds ATP site
• mab = humanized monoclonal antibody
• mib = proteasome inhibitor