The rest of Fitz drugs - Fitz Flashcards
Drugs Targeting Protein Functions:
What classes do we have?
- Tyrosine Kinase Inhibitors
- Drugs targeting altered intracellular processes
Types of tyrosine Kinase Inhibitors?
What are we targeting?
- Signal Transduction Inhibitors (STIs) = -nib
- Monoclonal Antibodies = -mab
**Targeting proteins taht are mutated or overexpressed in cancer cells!
What does tyrosine kinase do?
- Important regulators of i_ntracellular signal transduction pathways_ responsible for development and multicellular communication
- They phosphorylate tyrosine residues
-Receptor TKs can be mutatued/overexpressed in cancers
Inhibitors of EGFR:
MOA:
Cetuximab, Panitumumab
EGFR is overexpressed in epithelial-derived cancers
MOA: prevent actions of EGFR
identify cells that are expressing the receptor as foreign
Side effects of Cetuximab/ Panitumumab
(EGFR inhibitors)
They are antibodies so think about it….
- Common Ab S.E:
-
Infusion/hypersensitivity reactions
- HAMA
- Infections
-
Infusion/hypersensitivity reactions
-
Unique toxicities:
- skin (rash, photosensitivity, necrotizing fascitis)
- Lung (interstitial lung disease)
*well doesn’t that make sense if they are targeting epithelial cells and epithelial derived cancers (skin, GI cancers..)? —way to reason that out bud!
Inhibitors of HER2:
- What are the drugs?
- What cancer over express HER2?
- Trastuzumab
- Pertuzumab
- Ado-Trastuzumab Emtansine
- HER2: specific TK that is overexpressed in aggressive breast cancers
- and don’t respond to other treatments (doxorubicin)
Trastuzumab MOA:
Fitz says the old fashion approach :)
- binding of antibody interferes with HER2 signaling
2. Identifies HER2 overexpressing cells as foreign
—>boom immune system will kill them
Pertuzumab MOA:
Prevents HER2 from dimerizing with other HER receptors
Dimerization inhibitor
(the 1st of its class)
*more complete MOA than trastuzumab
Ado-Trastuzumab Emtansine MOA:
(I like to think of this as a trojan horse- give one drug but 2 drugs end up in cells)
- internalized into cell (how cool!)
- Marks HER2 in internal vesicles so it targets them before its even expressed!
- lysosome degrades it into 2 parts:
- Trastuzumab –> you know about this Morgz
- DM1 –> inhibitor that disrupts microtubule networks by binding tubulin
HER 2 Inhibitor
Resistance:
Toxicities:
Resistance: change HER2 so Ab doesn’t recognize it
Toxicities: (infusion, hypersensitiviy rxns, HAMA, infections, birth defects/fetal loss
Unique SE: ventricular dysfunction and congestive heart failure
Drugs that target altered intracellular procesess
General concepts:
tend to be less selective and have greater number of side effects
L-Asparaginase MOA:
Deplete Asparagine
What’s the deal with Asparagine and Aspartate?
- Cells not good at getting Asparagine across membranes
- Asparagine –> Aspartate to get it into cell by enzyme L-Asparaginase
- Aspartate —-> Asparagine by enzyme Asparagine synthase
- Asparagine needed for protein synthesis
Asparagine/Aspartate in childhood ALL?
Tx?
- No Asparagine synthetase enzyme :(
- Get asparagine across by transporters that are hella ineffective
Tx:
- give more L-asparaginase –>drives reaction to right to make lots of Aspartate
- deprives cancer cells of asparagine they need to make proteins.
How does L-asparaginase cause selective toxicity in
acute lymphoblastic leukemia of children?
Cancer cells don’t have asaparagine synthase to convert aspartate into asparagine
Normal cells do :)
Give L-asparaginase enzyme to drive rxn to aspartate
Sucks to suck if you are a cancer cell b/c you don’t have asparagine for protein synthesis
L-Asparaginase side effects:
-Hypersensitivity: fever, chills, n/v, skin rash, urticaria
What is important when using L-asparaginase in combo with other drugs?
sequence of drug administration is critical!!
-if you give MTX first —>synergistic cytotoxicity
-L-Asparaginase first —> MTX cytotoxicity is reduced b/c MTX cell kill depends on synthesis of enzymes necessary for DNA synthesis (DHFR, TS)
Bottom line: ________Give MTX first
Drugs that Inhibit Proteosome?
MOA?
Bortexomib, Carfilzomib
-inhibitors of 26S proteasome (degrades ubiquitinated proteins)
–this pathway maintains homeostatis
If we inhibit the proteasome –> trigger apoptosis
What’s the big difference between Bortezomib and Carfilzomib?
Bortezomib == reversible
Carfilzomib == irreversible
Side effects of Bortezomib and Carfilzomib
(26S proteosome inhibitors)
-thrombocytopenia, neutropenia, and/or anemia
-peripheral neuropathy
Drugs that inhibit HDAC:
Drugs?
Importance of HDAC?
Romidepsin & Vorinostat
- HDACs=histone deacetylases
- work with histone acetyltransferases to regulate gene expression
- acetylation –>euchromatin
- deacetylation –>heterochromatin
HDAC in cancer cells?
Cancer cells overexpress HDAC
—>heterochromatin
–> condensed chromatin, decreased transcription
–>silencing of tumor suppressor genes like p53
Romidepsin and Vorinostat MOA:
increase transcription –>cell cycle arrest –>apoptosis
*decreases efficacy of alkylating agents
Romidepsin and Vorinostat side effects:
-
Hematologic: pulmonary embolism, deep vein thrombosis
- throbocytopenia, anemia
- So give Warfarin
-
Drug/drug interactions:
- Warfarin- these cancer drugs increases effectiveness of warfarin
- Valproic acid- severe thrombocytopenia and GI bleeding
- N/v, diarrhea
- Hyperglycemia
- fatigue, chills
- Taste disorders
- mutagenic
