Flashcards in LEC 27,28 - Anti-Neoplastics Deck (163):
What replicative phase do most mature animals enter?
G0 - will then reactivate with injury
What cells in the body have constant replication?
Skin/hair follicles, GI epithelium, Bone marrow, and male gametes
What is the normal progression through the cell cycle regulated by?
Presence of growth signals and check points
What are the six replication check points?
G1 to S, during S phase, during G2 (DNA damage and replication checkpoint), Antephase checkpoint, and spindle assembly checkpoint
What happens in the spindle checkpoint.
Make sure that things are seperating correctly
What happens in the antephase checkpoint?
Check the environment (ie. presence of ROS) to make sure conditions are okay for replication
What happens in the DNA checkpoint in the middle of the S phase?
Proofread the daughter cell for DNA mistake
Where are the two most common places that cancer cells have mutations in?
Oncogenes or tumor suppressor genes
What are oncogenes?
Activating mutations allow cells to grow in absence of signals
What are tumor suppressor genes?
Inactivating mutations overriding checkpoints that prevent growth or cause cell death
What happens to the dividing cells of a tumor as it increases in size?
The number of dividing cells decrease
Why do you need multiple rounds of chemo?
Inactive cells can go into remission but can reactivate down the raod
Where do most cancer metastasize to? Why?
Liver and lungs - increased capillary beds so pressure/speed is lower then the rest of the body. Gives tumor cells time to set up shop
How are ways that cancer cell mutations act on the cancer cell itself?
Genome instabilty/mutation, resisting cell death, deregulating cellular energetics, sustained proliferative signaling, and enabling replicative immortality
What are ways that cancer cell mutations act with the environment?
Evading growth suppressors, avoiding immune destruction, tumor promoting inflammation, inducing angiogenesis, and activating invasion/metastasis
What are the three major goals of cancer treatment?
Cure, induce remission, and palliative treatment
Elimination of ALL cancer cells from the body
Why is it hard to know if you CURED the cancer?
All it takes is one cell, and there is no test to determine if there was any cells left after treatment
Induce remission -
Absence of clinical signs of disease
Palliative treatment -
Pain reduction to improve quality of life
When is palliative treatment your best option?
Remission is unattainable or elderly patient where they couldn't undergo treatment
What are the advantages of chemotherapy?
Good for treatment of diffuse disease, treatment of areas in difficult anatomic locations, and can improve the surgical outcome
What are the downsides to chemotherapy?
Solid tumors are resistant, cancer is constantly changing so might stop working, lots of adverse effects, and expensive
Drugs for: Anal sac adenocarcinomas
Doxorubicin, mitoxantrone, toceranib
Drugs for: TCC
Prioxicam + Mitoxantrone, carboplatin, gemcitabine; vinblastine, mitomycin C
Drugs for: Multiple myeloma
melphalan + prednisone
Drugs for: Osteosarcoma
Doxorubicin, carboplatin, cisplatin, and gemcitabine
Drugs for: Mast cell tumors
Toceranib and mastinib
Drugs for: SSC
Paclitaxel and mitomycin C
Drugs for: Lymphoma, remission
CHOP protocol (Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisone)
Drugs for: Lymphoma, rescue
ALL DA DRUGS
Why is it important do do chemotherapy with osteosarcoma even if you have amputated the leg?
95 to 100% of dogs where symptoms of osteosarcoma are present have mets to the lungs already
What are the six groups of chemotherapy drugs?
Alkylating agents, anthracyclines, pyrimidine analogs, drugs affecting tubulin, tyrosine kinase inhibitors, and three other drugs
What are the four types of alkylating agents?
Nitrogen mustards, platinum agents, methylating agents, and 2 other drugs
Alkylating agents - Nitrogen mustards:
Cyclophosphamide, mechlorethamine, and melphalan
Alkylating agents - Platinum agents:
Cisplatin and carboplatin
Alkylating agents - Methylating agents
Dacarbazine, procarbazine, and temozolomide
Alkylating agents - Others:
Mitomycin C and lomustine
Doxorubicin, mitoxantrones, and dactinomycin
Cytarabine and gemcitabine
Drugs affecting tubulin:
Vincristine, vinblastine, and paclitaxel
Tyrosine kinase inhibitors:
Toceranib and mastinib
What are the three chemotherapy agents that dont really belong to a specific group?
Asparaginase, prednisone, and piroxicam
What is the chemical structure of the alkylating agents that allows them to be reactive?
How do the alkylating agents work?
Causes crosslinking in the DNA strand. DNApol can no longer read the DNA. Leads to replication and transcription inhibition, cell-cycle arrest, DNA repair, and cell death
What is the major target within the DNA for the alkylating agents?
G N7 position
What are the drugs that cause single cross links?
Dacarbizine, procarbazine, and temozolamide
What are the drugs that cause double cross links?
Cyclophosphamide, mechlorethamine, melphalan, cisplatin, carboplatin, lomustine, and mitomycin C
What direct effects does the alkylating agents have on the DNA strand?
Deletion of modified G's from DNA during replication. Mispairing of modified G's to T rather than C. Leads to so many mutations it causes cellular apoptosis.
What allows the alkylating agents to work so well?
Can effect the cell at ALL stages because will effect protein synthesis as well.
Which of the akylating agents are given PO?
Lomustine, melphalan, procarbazine, and cyclophosphamide
Which of the alkylating agents gets absorbed by the liver, bone, and GI tissue the best?
Which of the alkylating agents crosses the BBB?
How are the platinum alkylating agents metabolize in the body?
They are not actively metabolized, eliminated as the parent drug
Which of the alkylating agents have active metabolites?
Lomustine and cyclophosphamide
Which of the alkylating agents is metabolized in the plasma? How?
Melphalan - via hydrolysis
How are the platinum compounds excreted?
Active renal secretion, both parent drug and free platinum are excreted
What is the major downside of using platinum compounds?
They are secreted in the urine as an active compound for 5 days post treatment making disposal of waste hard.
Dose limiting toxicity -
Dose that causing the most severe toxic effects taht doesn't kill a patient
What is the most dose limiting effect of Lomustine, mechlorethamine, melphalan, and procarbazine? Why?
Myelosuppression, increases the risk the patient might get an infection which they will not be able to fight off
What are the adverse effects of Lomustine, mechlorethamine, melphalan, and procarbazine? When do you start to see these effects?
Myelosuppression and thromnbocytopenia. Delayed effect because it is affecting the immature cells so won't see problems till these cells mature.
Which of the alkylating agents myelosuppression is additive?
What are the adverse effects of cyclophosphamide?
Necrotizing hemorrhagic cystitis
What are the adverse effects of cisplatin?
Leukopenia and acute nephrotoxicity in dogs
What happens in cats that are given cisplatin?
Lethal pulmonary edema
What are the adverse effects of carboplatin?
Only causes leukopenia
What causes there to be a vesicant effect of the alkylating drugs?
Active form of these drugs cause free radicals. If these free radicals are able to get outside the circulation they cause severe tissue damage.
What are three ways that a tumor cell becomes resistant to a drug?
Increase production of molecules that inactivate drug, increase DNA repair enzymes, or reduce the intracellular drug concentrations
How is melphalan taken up by the cell?
Leucine transport system
How is mechlorethamine taken up by the cell?
Chloine transport system
Besides reducing expression of enzymes that transport the drug into the cell what is another way a tumor cell can have less drug in the cell?
Increase the export enzymes (P-gp)
What inactivates cyclophosphamide?
What competes with DNA for the alkylating drugs?
What is the most common antracyclines?
How does doxorubicin cause oxygen radicals?
DNA damage leading to apoptosis. Lipid peroxidation of cell membranes
What does lipid peroxidation do to the cell?
Makes it leaky and therefor causes cell death
What drugs inhibit topiosomerase II?
Doxorubicin and mitoxantrone
What happens when Topoisopermase II is inhibited?
Blocks DNA replication and reduces RNA/protein synthesis
What does Dactionmycin inhibit?
DNA-Dependent RNA synthesis
How are anthracyclines administered?
All given IV, IP can be done for more of a local deposition.
Where do anthracyclines not distribute to? Why?
CNS, due to P-gp
Where are anthracyclines metabolized?
What is the major metabolite of antracyclines?
How is doxorubicin eliminated?
Excreted in feces for the most part, 10% is excreted in the urine
How long is doxorubicin detected in the waste of an animal?
How is mitoxanthrone eliminated?
100% unchanged within the urine
How is Dactinomycin eliminated?
Most of it is eliminated unchanged in the urine and feces
What are the adverse effects of doxorubicin in the early stages of administration (
Nausea, vomiting, histamine release, ventricular arrythmia, and acute GI toxicity
What happens if you are getting ventricular arryhtmias with doxorubicin adminstration?
Slow the adminstration of the medication
What are the intermediate (1d to 2 weeks) adverse effects of doxorubicin use?
Alopecia, thrombocytopenia, neutropenia, tissue inflammation/necrosis
What is the dose limiting adverse effect when it comes to doxorubicin?
Thrombocytopenia and neutropenia
When do you see tissue inflammation and necrosis with doxorubicin?
When it gets out of the circulatory system during administration due to the creation of free radicals
What are the chronic side effects of doxorubicin effects in dogs?
How does DCM occur in dogs on doxorubicin?
Oxygen radicals damage cardiomyocyte sarcoplasmic reticulum, damage accumulates and DCM occurs
Is DCM a dose limiting effect on doxorubicin treatment?
No, it is a treatment limiting effect though. If it occurs then treatment must be stopped and another drug needs to be used.
What dogs are most susceptible to DCM from doxorubicin?
What does chronic doxorubicin use in cats cause?
Chronic renal failure
How does chronic renal failure occur in cats using doxorubicin?
Oxygen radicals damage podocytes of renal glomeruli, damage accumulates. Need to monitor closely because known at what dose this occurs.
What are the adverse effects of Dactinomycin?
Myelosuppression, diarrhea, ulcerative stomatitis, urate stone formation, and vesicant
What are the adverse effects of Mitoxantrone?
Vomiting, diarrhea, anorexia, and myelosuppression
How does resistance form against anthracyclines?
Increased p-gp expression. Increased glutathione expression for doxo and dactino.
What is the base used in pyrimidine analogs?
At what phase do the pyrimidine analogs work?
S phase only! Due to the affecting the creating of a DNA strand
How do the pyrimidine analogs work?
DNA polymerase can't read modified sugar nucleosides. Bases are "repaired" leading to an increasing amount of mutations. Ends with the death of the daughter cell
Which of the pyrimidine analogs are most effective?
How are pyrimidine analogs administered?
IV or SC (Gemcitabine is IV only)
What determines how much pyrimidine analog gets into the CNS?
CRI > Bolus, making CNS adverse effects more prominent with CRI's
How are pyrimidine analogs metabolized?
Converted to Ara-U in liver and kidneys by cytosine deaminase
How are pyrimidine analogs eliminated?
What are the adverse effects of the pyrimidine analogs?
Myelosuppression, leukopenia is most common. But anemia and thrombocytopenia can occur as well
How does resistance occur against pyrimidine analogs?
Increased expression of p-gp. increased expression of cytosine deaminase
What are the two types of chemotherapy agents that affect tubulin dynamics?
Vinca alkaloids and taxanes
Vinca alkaloids -
Vincristine and vinblastine
How do the drugs that affect tubulin dynamics work?
Act to stabilize microtubules. Prevent proper breakdown of mitotic spindle during cytokinesis. Induce apoptosis and immune clearance.
At what phase of cell replication do tubulin dynamic drugs work?
Which of the tubulin dynamic drugs may work synergistically? Why?
Vincristine and paclitaxel sites differ so they can attack two different locations.
How are the tubulin dynamic drugs administered?
How are the tubulin dynamic drugs distributed throughout the body?
Plasma protein binding occurs. But excluded from the CNS via p-gp
How are tubulin dynamic drugs metabolized?
How are tubulin dynamic drugs metabolized?
Fecal, in biphasic manner
What does the biphasic response of tubulin dynamic drugs suggest?
Slow elimination following tissue accumulation
What are the major adverse effects seen when using tubulin dynamic drugs?
Neurotoxicity and histamine release
What is the dose limiting toxicity for the tubulin drugs?
Which of the tubulin drugs is the most neurotoxic?
What neuro symptoms are seen with toxicity caused by tubulin drugs
Difficulty with movement, paresis, and voice change. Improvement does occur when drugs are discontinued
Which of the tubulin drugs causes a histamine release?
What must be given with Paclitaxel?
What causes the histamine release when paclitaxel is adminstered?
Due to the vechile that the drug is dissolved in
What is the catch-22 with Paclitaxel adminstration?
Rapid infusion - histamine release. But slow infusion causes myelosuppression.
Which of the tubulin drugs is more myelosuppressive?
How do cancer cells become resistant to tubulin drugs?
p-gp mutations and other
What does the activation of tyrosine kinase receptors cause?
Many cellular responses. Most common being: proliferation and protein synthesis.
What phase of the cycle is affected by drugs that target receptor tyrosine kinases?
What is c-kit?
Oncogene, responsible for a receptor tyrosine kinases (CD117). This is a stem cell growth factor receptor. Driving leukopoesis.
Where are c-kit mutations most commonly seen?
Mast cell tumors
What happens when the c-kit oncogene is turned on?
Causes continous signaling from the receptor, even without a ligand. Leading to unregulated cell proliferation.
How do the receptor tyrosine kinases inhibitors work?
Act as a competitive antagonist of ATP binding to the kinase domain of c-kit
What are the targets of masitinib?
c-kit, PDGF-R, and Lyn
What are the targets of tocerinib?
c-kit, and 50 more tyrosine kinases
What is the route of elimination for mastinib?
How are the tyrosine kinases metabolized?
What are the adverse effects of toceranib?
Diarrhea, anorexia, weight loss, melena, lameness, anemia, neutropenia, and thromboembolism
What are the adverse effects of masitinib?
Vomiting, diarrhea, hepatotoxicity, neutropenia, renal toxicity, anemia
What is prednisone?
Glucocorticoid with broad anti-inflammatory effects
What is the DOC for TCC?
How does piroxicam work?
Nonspecific cyclooxygenase inhibitor
How is piroxicam metabolized?
How is piroxicam eliminated?
What are the adverse effects of piroxicam?
GI ulceration, renal papillary necrosis
How does asparaginase work?
Stops Asp --> ASN in lymphoid tumors
At what point of the cell cycle does asparaginase work?
How is asparaginase adminstered?
How is asparaginase distributed in the body
Confined to the plasma
How long do asparagine levels remain low when a patient is given asparaginase?
23 days post administration
How is asparaginase used metabolized?
Hydrolyzed into amino acids and then used for new protein synthesis
What are the two major toxic side effects of asparaginase use?
Hypersensitivity and protein synthesis abnormalities
What are the signs of protein synthesis abnormalities caused by asparaginase?
Hepatotoxicity, coagulation defects, hemorrhagic pancreatitis, and hyperglycemia
What part of the cell cycle does prednisone and piroxicam work on?
Cell cycle independent
Drugs that - Work on cellular energetics
Drugs that - Effect the proliferative signaling
Receptor tyrosine kinase inhibitors
Drugs that - Affect tumors cells resistance to death
Alkylating agents, anthracyclines, pyrimidine analogs, and microtubule stabilizers