Drugs that Target Altered Intracellular Processes

Question 1

What is the general idea behind targeting altered intracellular processes?

Answer 1

• There are many differences between normal and cancer cell that can be targeted with antineoplastics
• In constrast to drugs that target specific proteins (overexpressed/mutated) or growth factor receptors, drugs that target altered intracellular processes tend to be less selective —> THUS THEY HAVE GREATER # OF SIDE EFFECTS
• –These drugs tend to have similarities to cytotoxic drugs that simply target rapidly dividing cells

Question 2

What drugs deplete asparagine?

Answer 2

L-asparaginase

Question 3

How do normal cells get asparagine?

Answer 3

1. Asparagine is converted into aspartate which travels across the membrane
2. Then on other side of the membrane, its converted back to asparagine by asparagine synthetase

Question 4

What happens in some cases of ALL (acute lymphoblastic leukemia - childhood)?

Answer 4

They DO NOT have asparagine synthetase.

This means they’re dependent upon bringing asparagine into the cell.

Question 5

What happens when you treat ALL with L-asparaginase?

Answer 5

• The drug drives asparagine over to aspartate so there isn’t much asparagine available to bring directly into the cell.
• Driving the molecule over to aspartate is an advantage for normal cells!!

Question 6

What is the MOA of L-asparaginase?

Answer 6

-L-Asparaginase causes selective toxicity because some ALL cells lack asparagine synthase (i.e., they require an exogenous source of L-asparaginee for protein synthesis), therefore decreasing the asparagine concentration by administration of L-Asparaginase deprives tumor cells of asparagine

Question 7

What are the side effects associated with L-asparaginase?

Answer 7

-Hypersensitivity reactions: fever, chills, nausea/vomiting, skin rash and urticaria

Question 8

L-asparaginase is often used in combination with other drugs. What is important to remember in these cases?

Answer 8

Sequence of drug administration is critical!!
Example:
-If MTX is given first, you have synergistic cytotoxicity
-If L-asparagine is given first, MTX cytotoxicity is reduced as the MTX cell kill is dependent upon synthesis of the enzymes necessary for DNA synthesis (DHFR and thymidylate synthase, specifically)

Question 9

What drugs inhibit proteosome?

Answer 9

1. Bortezomib

2. Carfilzomib

Question 10

What is the MOA of Bortezomib and Carfilzomib? What one is reversible and what is irreversible?

Answer 10

• Inhibitors of the 26S proteasome: a large protein complex that degrades ubiquinated (esp. misfolded) proteins
• Ubiquitin-26S proteasome pathway regulates intracellular protein concentration, thereby maintaining homeostasis - inhibition affects multiple signaling cascades and TRIGGERS APOPTOSIS
• Bortezomib = reversible
• Carfilzomib = irreversible

Question 11

What are the side effects of Bortezomib and Carfilzomib?

Answer 11

• Thrombocytopenia (low platelets), neutropenia (low WBCs) and/or anemia
• Peripheral neuropathy

Question 12

What drugs inhibit HDAC?

Answer 12

Romidepsin

Vorinostat

Question 13

What is the MOA for Romidepsin & Vorinostat?

Answer 13

1. Histone deacetylases (HDACs) work with histone acetyltransferases to regulate gene expression
   - –Acetylation is associated with euchromatin (“open for transcription”)
   - –Deacetylation is associated with heterochromatin
2. Cancer cells can overexpress/aberrently recruit HDACs, leading to hypoacetylation of histones, condensed chromatin structure and decreased transcription
   - –Causes SILENCING of tumor supressor genes (esp. p53)
3. HDAC inhibitors increase transcription, and lead to cell cycle arrest and apoptosis

Question 14

Why are HDAC inhibitors still under investigation?

Answer 14

• Valproic acid (HDAC inhabit approved for use as mood stabilizer and anti epileptic) is also under investigation for use in cancer
• HDACs are also being investigated for use in Huntington’s disease and ALS

Question 15

What are the side effects of HDAC inhibitors?

Answer 15

• Hematologic: pulmonary embolism, deep vein thrombosis, thrombocytopenia and anemia
• Drug/Drug Interactions:
• –Severe thrombocytopenia and GI bleeding result from co-administration with valproic acid
• –PT and INR are prolonged if given with WARFARIN
• Nausea, vomiting, diarrhea
• Hyperglycemia (esp. in diabetics)
• Fatigue, chills
• Taste disorders (dysgeusia, dry mouth)
• Mutagenic (carcinogenic?)