Cancer MOAs Flashcards
Which classes of drugs are cell-cycle specific?
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
What classes of drugs are cell-cycle independent?
1) Alkylating Agents
2) Anthracyclines
Good for large tumors with low growth fractions. They work in a dose-dependent fashion
What order kinetics do chemo drugs follow? Do they work best on high or low burden tumors?
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)
What is IC50?
The concentration of drug that kills half of tumor cells
What is the main mechanism of drug resistance? What gene is it on and how does it work?
P-glycoprotein, a membrane-bound ATPase efflux pump that pumps cytotoxic chemicals out of a cell.
From mdr1 (multi drug resistance) gene
What traits are desirable in a combination therapy
1) Different targets in the cell cycle
2) Non-overlapping toxicity
3) Different means of resistance
4) Different mechanisms of action
Anti-metabolites
Mimic building blocks of nucleotide/DNA synthesis, one way or another disrupting the process without directly damaging the DNA
Folate analogues
- 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
Pyrimidine/Purine Analogues
1) Compete for synthetic enzymes
2) Incorporate into nucleic acids and terminate the chain
5-fluorouracil
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
Hydroxyurea
A ribonucleotide reductase inhibitor, binds active site iron residue, preventing conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates.
Alkylating agents (and one unique one)
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
Platinum Compounds
Called alkylating agents, but bind through interactions with platinum ions. Bulky leaving groups in the drug keep them in circulation longer
Antitumor Antibiotics
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
L-asparaginase
Cleaves asparagine to aspartate - tumors do not have asparagine synthase and other cells do, so tumors starve for asparagine
Antimitotic Agents
Block topoisomerase or microtubule function. Derived from plants and things found in nature
Vinca Alkyloids
- 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
Taxanes
- Bind the mitotic spindle, preventing dissociation of tubulin dimers and disrupting dynamic instability
- Most active in M phase
Estramustine
- 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)
Topoisomerase II Inhibitors
- Binds the topoisomerase II-DNA complex, preventing passage of DNA polymerase and causing a permenant double strand break.
- Most active in S phase
Topoisomerase I Inhibitors
- Bind to the complex of topoisomerase I and DNA. When replication fork arrives, it causes a double strand break.
- Most active in S phase.
Hormonal Agents
Affect signaling through steroid receptors.
Predisone/Cortisol
Used for lymphomas and leukemias to deplete the aberrant immune cells
Progestins
Bind progesterone receptors. Useful for promoting immature cells in endometrial cancer
