Anti-Neoplastics #5 Flashcards
Describe apoptosis in a normal, healthy cell.
▪ It is a highly regulated process
▪ Depend on the balance of pro-apoptotic and pro-survival signals
▪ Internal surveillance molecules detect damaged DNA and
signal cells for suicide
▪ Biochemical events of apoptotic cell: cell shrinkage, chromatin
condensation, DNA fragmentation etc
▪ Cells convert to vesicle that can be removed by macrophages
One of the major characteristics of chemotherapy drugs is can they induce apoptosis.
Describe apoptosis in a cancerous cell.
▪ Cancer cells alter pro-apoptotic proteins that detect problems and induce apoptosis (Caspases, Bad, Bax, Bak, Noxa, Puma)
▪ Overproducing anti-apoptotic proteins (belonging to the following classes: BCL-2, MCL-1, BAG-3, HSP 27 and 70, survivin etc)
▪ Creating mutant proteins. Even if there is pro-apoptotic protein, it can be mutated in cancer cells; does not do its job aka cause apoptosis
In the process of apoptosis, the extrinsic pathway and intrinsic pathway come together and form the execution phase.
Activation of apoptotic pathways are avoided in cancer. We want to activate this pathway which is the key mechanisms by which cytotoxic drugs kill cancer cells.
What is the major goal of apoptotic pathway? What are these drugs classified as?
The Goal: Switch the balance towards cell death for cancer cells
▪ Drugs that directly activate pro-apoptotic pathways (Bax, Bak, Bad, and Bok) to cause apoptosis
▪ Drugs that deactivate anti-apoptotic proteins (BCL-2, Bcl-xl) present in cancer cells
What is Palladia?
What is its generic name?
What is its MOA?
What is it used for?
**What are the adverse effects?
Targeted drugs are more often used as a primary treatment for some cancers but more often used in combination with surgery, radiation, standard chemo.
What is Laversia-CA1R (Verdinexor)?
Laversia-CA1R (Verdinexor): is the first small-molecule selective inhibitor of nuclear export (SINE), which targets and binds to Exportin-1 (XPO1) transporter. This transporter is important for cell functioning.
It is the first and ONLY oral tablet to treat lymphoma in dogs.
What drug is used off-label as a form of targeted therapy in cats?
GleevacR (Imatinib) is used in cats (off label): binds and inhibits several protein-tyrosine kinases in squamous cell carcinoma
What is Angiogenesis?
What is the role of this process in adults?
What nutrients does this process need?
What do these new cells release?
▪ Angiogenesis is increased BV formation. It is a highly regulated process, takes place in early development.
▪ In adults: promote wound healing and support female reproduction system in pregnancy
▪ On cellular level angiogenesis happen when cell is in need of nutrients & O2
**▪ Cell releases proteins that bind to special receptors in the surface of endothelial cells (EC) that make up the lining of the vessels. Endothelial cells line the vessels and these cells express pro-angiogenic factors. Therefore, drugs will take action on these EC. This is the difference between other targeted drugs.
What is the role of angiogenesis in cancer cells?
▪ Tumor blood vessels provide nutrition and oxygen
▪ Cancer cells “attract” angiogenesis by producing high levels of proteins such as VEGF, MMPs, HIF-1α
▪ Endothelial cells (EC) express receptors that respond to this proteins
Drugs, MABS, act to neutralize the growth promoting effect of the tumor micro-environment which can affect the immune system and other systems in the body.
What is the goal of Anti-Angiogenic Therapy?
What are the two classes of drugs used in this form of therapy?
What other classes of drugs can be used?
What is the ideal anti-angiogenic drug?
The Goal: Block angiogenesis to starve tumor. May be an ideal strategy for cancer therapy b/c it can have less effects on other normal cells than chemotherapy.
▪ Drugs that interfere with any tumor cells (indirect inhibitors –> block activity of angiogenesis inducers = cytokines, oncogenes, growth factors, cells in tumor microenv, etc.) and tumor endothelial cells (EC) (direct inhibitors –> tatget EC cells). Anti-angiogeneic are usually used as combination therapy b/c we still do not have ideal drug.
▪ Drugs that target pro-angiogenic proteins released by tumor (ligand)
▪ Drugs that target endothelial receptors (EC)
▪ Ideal anti-angiogenic drug can target all cancers (EC are the same in all cancers)
▪ Less drug resistance since EC are genetically stable
What is AvastinR (Bevacizumab)?
target VEGF, so it is an anti-VEGF antibody
What is NexavarR (Sorafenib)?
target VEGF-R and has kinase activity (small molecule inhibitor)
Describe how you can use anti-angiogenic therapy to prevent angiogenesis?
VEG-F binds to VEGF-R and promotes signaling pathway –> angiogenesis. If you block the ligand, VEG-F, or block the receptor with Sorafenib and Sorafenib, angiogenesis is inhibited.
Anti-Angiogenic mAbs may be therapeutically efficacious
in?
inhibiting the growth of canine sarcomas
What is the mechanism of action of Bevacizumab (AvastinR)?
Inhibit binding of VEGF to its receptor
on EC
How does a cancerous tumor trick T cells?
How does immunotherapy work?
What are the functions of the following drugs:
Ipilimumab, Nivolumab, Pembrolizumab?
What is Adaptive Cell Therapy (ACT)?
Main idea: activation and expansion of antitumor immunce cells in vivo by doing exvivo things.
You resect tumor samples and prepare single cell suspension which has more immune abilities to fight tumor. You grow them in lab and put back into the dog, and humans too. This can be done in diff ways, either T cells harvested from blood of patient and manipulating them to become more active and putting back into patient so immune cells can fight tumor.
Used in leukemias, lymphomas; bone marrow toxicity, GI side effects. Very expensive.
