Anti-Neoplastic Drugs, Pt. 5 Flashcards
What is apoptosis? What begins the signal to start this process?
regulated process of programmed cell death that depends on the balance of pro-apoptotic and pro-survival signals
internal surveillance molecules detect damaged DNA
What are the 3 biochemical events of apoptosis? What happens at the very end?
- cell shrinkage
- chromatin condensation
- DNA fragmentation
cells are converted into vesicles (apoptotic bodies) that can be removed by macrophages
What 3 things do cancer cells do to avoid apoptosis?
- alter pro-apoptotic proteins that detect problems and induce apoptosis (caspases, Bad, Bax, Bak, Noxa, Puma)
- overproduces anti-apoptotic proteins (BCL2, MCL1, BAG3, HSP27, HSP70, survivin)
- create mutant proteins
What are the 2 pathways of apoptosis? How do they come together?
- extrinsic - apoptosis-inducing ligand binds to death receptors to activate Caspases
- intrinsic - p53, Bax, and Bak induce mitochondrial activation of cytochrome C and Caspases
execution phase - caspases induce apoptosis
(anti-cancer cells want to activate apoptosis in cancer cells)
What is the goal in targeting apoptotic pathways with anti-neoplastics? What are the 2 main types of drugs to do this?
switch the balance towards cell death for cancer cells
- drugs that directly activate pro-apoptotic pathways (Bax, Bak, Bad, Bok) to cause apoptosis
- drugs that deactivate anti-apoptotic proteins (BCL2, BCL-XL) present in cancer cells
What is the mechanism of action of Palladia? What is its main use?
tyrosine kinase inhibitor that has both direct antitumor and anti-angiogenic activity
FDA-approved for dogs with grade II or III recurrent cutaneous mast cell cancer
What are 5 adverse effects of Palladia?
- loss of appetite
- nausea/vomiting
- diarrhea
- low leukocytes
- protein loss through kidneys
What is the mechanism of action of Laversia-CA1? What is it used to treat?
first small-molecule selective inhibitor of nuclear export (SINE) that targets and binds to exportin-1 (XPO1) transporter
first and ONLY oral tablet to treat lymphoma in dogs
What off-label targeted therapy is available as an apoptotic in cats? How is it used?
Gleevac
binds and inhibits several protein-tyrosine kinases in squamous cell carcinoma
What is angiogenesis? What does it do in adults?
blood vessel formation taking place early in development
promotes wound healing and supports female reproductive system in pregnancy
On a cellular level, when does angiogenesis occur? How do cells do this?
when cells are in need of nutrients and oxygen
cell releases proteins that bind to special receptors on the surface of endothelial cells that make up the lining of vessels
What provides nutrients and oxygen to tumors? How are the cancer cells able to do this?
tumor blood vessels
produce high levels of proteins, like VEGF*, MMPs, and HIF-1α that bind to receptors on endothelial cells
What is the goal of anti-angiogenic therapy? What 3 types of drugs are used?
block angiogenesis to starve tumor cells
- drugs that interfere with any tumor cells (indirect inhibitors) and tumor endothelial cells (direct inhibitors)
- drugs that target pro-angiogenic proteins released by the tumor
- drugs that target endothelial receptors
What is thought to be the ideal strategy for cancer therapy? Why?
anti-angiogenics that can target all cancers, since endothelial cells will be the same in all cancers
less drug resistance will occur since endothelial receptors are genetically stable
What are the 2 main anti-angiogenics? How do they work?
- Bevacizumab (Avastin) - anti-VEGF antibody that blocks it from binding to the endothelial receptor
- Sorafenib (Nexavar) - small molecule inhibitor that targets VEGF-R and multiple kinase activity on endothelial receptors
How does immunotherapy work? What 3 side effects differ from those commonly seen in other types of cancer treatment?
trains the immune system to attack cancer rather than attacking the cancer directly - blocks tumor cells from deactivating T-cells
- fatigue
- inflammation of skin, lungs (cough, chest pains), and colon (abdominal pain, diarrhea)
- endocrine: diabetes, pituitary gland inflammation
How does cancer immunotherapy work:
interferes with T cell and cancer cell communication to keep T cells active
- cancer cells exhibit PDL1, which inhibits the immune checkpoint protein PD-1 on T-cells, and inactivates them
- checkpoint inhibitors are able to block this pathway to release the breaks, allowing T cells to fight
How does oncolytic viral therapy work?
virus against tumor is injected (typically into CCSF) allowing it to selectively infect and kill cancer cells and induces an immune response to the virus
What are the 2 approaches to adaptive T cell therapy?
- resected tumor sample is digested into a single cell suspension and cultured in the presence of IL-2 to select for naturally occurring tumor-infiltrating lymphocytes that are then expanded, tested for anti-tumor activity, and reinfused into the patient
- T-cells are harvested from the blood and either a transgenic T-cell receptor or a chimeric antigen receptor is introduced by viral or non-viral transduction, making the cells now able to recognize the tumor and fight it
