Anti-neoplastic Pharm Flashcards
what are the three mainstays of cancer treatment?
- Surgery
- Radiation
- Chemotherapy
Define the M-phase
This is the phase of the cell cycle in which mitosis occurs. This phase is quite short in all cells, typically lasting less than 1 hour.
Define G1 phase
RNA transcription and protein synthesis occur during this phase, which is extremely variable in length, ranging from 7 to 170 hours (7 days).
Define S phase
DNA synthesis, in preparation for chromosome duplication, occurs during this phase. S-phase generally lasts 8 to 30 hours.
Define G2 phase
This phase, which precedes the following mitotic event, is short (1-4 hours).
Define G0 phase
This ‘phase’ is used to describe cells that are not actively cycling. For example, certain cell types such as skeletal muscle or neurons enter this phase and never replicate again. Other cells, such as hepatocytes, proliferate or cycle in young, growing animals, then cease cycling at maturity. However, hepatocytes are capable of re-entering the cell cycle again if
regeneration is necessary. The length of this phase is highly variable (can be years).
what is meant by “log kill kinetics” with regards to chemotherapeutic drugs
they (cancer drugs) kill a constant fraction of cells, not a constant number of cells
what 4 responses can you get from a given chemotherapy treatment, and what do they mean?
And, after how many cycles should you address this response?
After 2 cycles of chemotherapy you can classify your treatment response to be…..
Complete response: Resolution of all clinically apparent neoplastic disease for at least 1 month.
Partial response: Reduction in measurable tumor dimensions of at least 50% for at least 1 month.
Stable disease: No change or < 50% reduction in measurable tumor dimensions.
Progressive disease: Progressive growth of a tumor or appearance of new lesions.
what general mechanisms of resistance can a tumor portray?
- Failure to reach target
- Inactivation of drug
- Altered target
- Failure to undergo apoptosis
what are me reasons that a drug might fail to reach it’s target?
- can’t maintain adequate concentration within tumor because of transport pumps
- multidrrug resistance pumps
- P-glycoprotein
- MRP
- LRP (lung resistance protein)
what is an example of a drug inactivating agent of a tumor?
glutathione/glutathione-S-transferase system (GST’s).
This system has been shown to be clinically important in mediating resistance to alkylating
agents such as cyclophosphamide
How might a target be altered within a tumor?
DNA topoisomerases are nuclear enzymes that play essential roles in DNA replication, transcription, chromosome segregation and DNA recombination
Anticancer agents that act to block topoisomerase activity include doxorubicin (one of the most commonly used agents in veterinary medicine), mitoxantrone, etoposide,
camptothecin analogues, and others
How might a tumor cell avoid apoptosis despite the presence of anticancer drugs?
It has been shown that tumor cells that overexpress genes responsible for suppressing apoptosis, such as BCL-2, are resistant to chemotherapy-induced apoptosis (so are clinically chemoresistant). Additionally, cells that have mutations in the tumor suppressor gene p53 tend to be resistant to apoptosis caused by DNA-
damaging chemotherapeutic agent
what is the goal of a phase I trial?
to determine the maximal tolerated dosage of a drug with even just a slight efficacy.
what is the goal of a phase II trial
to determine they tumor type for which a drug shows activity.
The drug is typically given to patients with very advanced Dz
what is the goal of a Phase III trial
to determine if a drug can be used in combination with other drugs to improve treatment.
what is the KM? and what is its value for a dog and cat?
is the metabolic constant for a given species
Cat 10.0
Dog 10.1
what is the “BAG” effect?
Toxicity to rapidly deviding cells predictably produces
- Bone myelosuppression; infertility
- Alopecia.
- Gastrointestinal signs (anorexia, vomiting, diarrhea)
what is the first cell line typically suppressed and why?
Cells with the shortest lifespan in the circulation are neutrophils, thus neutropenia is almost always the first hematologic toxicity observed in
response to chemotherapy.
What the 6 common classes are chemotherapy agents used in Veterinary Medicine
- Alkylating Agents
- Mitotic Inhibitors
- Anti-Tumor antibiotics (anthracyclines)
- Platinum compounds
- Antimetabolites
- Tyrosine Kinase Inhibitors
What is the MOA of Alkylating agents
they cause chemical cross links to occur in DNA which will interfere with DNA replication by alkylating
What are the most common Alkylating agents used, and which ones are labeled for use veterinary species
First there are no labeled drugs for use in veterinary medicine
- Cyclophosphamide (cytoxan)
- Chlorambucil
- Lomustine
- melphalan
what is the nadir, side effects, and considerations taken while for using cyclophosphamide?
- BAG, in paticular neutropenia is around 7-14 days.
- Patients should drink lots of water to encourage bladder emptying often (often combind with furosemide)
- Frequent monitoring of UA for presence of blood or other signs of nephropathy is important
If cost is not an issue what drug can you use to minimize the nephrotoxic effect of cyclophosphamide?
MESNA
is a bladder protectant and can be used with anticancer drugs. it is a bit expensive. but works great
what is a common adverse irreversible sequela of use of lomustine?
Thrombocytopenia and neutropenia with repeated long term use
What organs are typically affected with use of lomustine?
it is Hepatotoxic and nephrotoxic
what primary chemistry perameters should be monitored when using lomustine?
ALT and Creatinine every 2 months
what alternative drug is an option for patients with an intolerance for cyclophosphamide
Chlorambucil
what are the primary clinical uses for Alkylating agents?
generally used for lymphoma protocols, but can also be used for multiple myeloma.
what alkylating agent is use as a rescue drug for lymphoma and histiocytic sarcoma?
Lomustine
What alkylatin agent is commonly used as part of a combination protocol for mast cell tumors
Lomustine
what is the MOA for Mitotic Inhibitors what what part of cell cycle to they effect?
- They bind to microtubles and interfere with mitosis.
- generally specific for the M phase of the cell cycle
what are the two common mitotic inhibitors used?
- vincristine
- vinblastine
what class of chemo agent MUST be intraveniously administered
all of your vinca alkaloids (vincristine, vinblastine) will cause severe tissue damage and necrosis
when is the nadir for mitotic inhibitors
BAG between 7-14 days
which chemo drug requires special consideration in some border collies and why?
these are substrates for P-glycoprotein –
- mitotic inhibitors (vincristine and vinblastine)
- Doxorubicin
MDR1 genotyping should be preformed prior to dosing
what is the most common use in VetMed for mitotic inhibitors?
- Lymphoma
- vinblastine is used in cobminations for other tumors
- used as a single agent in many vanereal tumors
- vinblastine used in some mast cell tumor protocols
What is a BIG difference to take note of when using vinblastine vs vincristine
the dose for vinblastine is significantly higher than vincristine
DON’T CONFUSE
what is the MOA for anthracyclines
other wise known as anti-tumor antibiotics interfere with DNA replication and RNA synthesis
what anti-tumor antibiotics are used in VetMed
- doxorubicin
- mitoxantrone
what is the most common side effect and nadir for the anti-tumor antibiotics
nadir is 7-10 days and hemorrhagic colitis is the most common GI related adverse side effect
what is a cumulative (dose/time dependent) irreversible toxicity of doxorubicin and what is it’s limit?
cardiac toxicity
the total life time dose should be limited to 180-240 mg/m2
you have a cat that comes in for it’s doxorubicin treatment, you find that the IV catheter is not properly places and some is administered extra-vascular….
what initial reaction should be avoided at all costs?
NEVER try to infiltrate the area with saline in efforts to dilute. It will not work, and only aid is spreading the agent to a bigger area
what is the most common uses of doxorubicin
- lymphoma protocols
- carcinomas
- sarcomas
- as a single agent is very effective against lymphoma
if you have an MDR1 mutation in a patient with lymphoma, what might you substitute for doxorubicin
mitoxantrone
what is the MOA of platinum compounds?
causes intrastrand cross linking of DNA leading to apoptosis
what are the common platinum compounds used
- cisplatin
- carboplatin
what chemotheraputic agent is generally considered the most emetogenic?
cisplatin causes very severe vomiting urges
what is the nadir of the platinum compounds?
there are typically considered to be 2 different times
- around day 6
- around day 15
what is a good pre-cisplatin administration protocol to use and why
cisplatin is very nephrotoxic
start diuresis ~4 Hr prior and at least 2 Hr after administration.
Why is cisplatin not used in cats?
it can cause fulminant fatal pulmonary edema
what is the clinical use for platinum compounds?
- osteosarcoma in dogs (sometimes combind with dixorubicin)
- carcinomas
- intralesional use in horses (sarcoids)
what is the MOA of the antimetabolites?
- they interfere with purine and pyrimidine synthesis and incorporation into DNA
- 5 FU is the pyrimidine analog that is incorporated
what are some common used antimetabolites?
- methotrexate
- 5FU
- cytosine arabinoside
what are the side effects of 5 FU
- BAG
- central neurotoxicity
can be fatal in cats even after topical administration
what modalities can 5-FU be given
- topically
- intralesionally (mast cell tumors in dogs)
- IV
- SQ
how is methotrexate administered
- orally
- IV
what class of chemo agent does cystosine arabinsoide belong to and how is it administered
antimetabolite
- IV
- SQ (allows for greater duration of action)
what is the clinical use for antimetabolites?
generally used in lymphoma protocols
azathioprine (immune mediated Dz)
cytosine arabinoside ( acute leukemia, canine non infectious encephalitis, lymphoma in horses, enters CNS)
what is a profound side effect of cytosine arabinoside
myelosupression
what is the MOA by which NSAIDS are utilized in cancer treatment
- COX-2 is overexpressed in many tumors
- Help enhance apoptotic effects
- Decrease invasiveness
- Block angiogenessis
what is the MOA of tyrosine kinase inhibitors
they are an enzyme that transferes phosphate groups from ATP to proteins within the cell.
Many tumor cells have tyrosine kinase mutations that result in altered cell signaling
these agents block this aberrant signaling and thus decrease signaling for angiogenesis and cell division
what chemotherapy agent in the tyrosine kinase inhibitor is used in VetMed what what is it used for
Toceranib phosphate (palladia)
used for treating Grade II and III mast cell tumors
what was the first FDA approved drug for treating cancer in dogs
Toceranib Phosphate or Palladia
used for treating Grade II and III mast cell tumors
what are the common side effects of Toceranib Phosphate
- neutropenia
- anemia
- GI ulceration (especially when used with NSAIDs)
- vasculitis (+/- thromboembolic Dz)
- PLN
what is the MOA of the Canine melanoma vaccine
- it contains a plasmid DNA that encodes a fragment of the human tyrosinase protein.
- once taken up it triggers a host immune response.
the hosts immune system will start to recognize tyrosinase on melanoma cells as foreign - resulting in tumor cells killing by immune mechanisms
What is the basic rule of thumb for dosage reductions for patients with a known MDR1 genotype mutation?
- 50% reduction for MDR1 mutant/mutant
- 25% reduction for MDR1 mutant/normal
how does metronomic chemotherapy differ to a normal chemotherapy protocol?
metronomic chemotherapy involves frequent administration of much lower doses of the chemotherapeutic drug.
the idea is that giving the drug and a lower dose more consistently can exhibit antiangiogenic effects.
what is the primary go to drug for the control of emisis during chemotherapy protocols.
Maropitant (cerenia)
what is the MOA for maropitant
it is an NK-1 inhibitor which will block the terminal step in the vomiting pathway which will controll most of the nausea from both central or peripheral stimuli.
what two important decisions should be addressed when confronted with a neutropenic patient at nadir from chemotherapy treatment?
- should we continue further chemotherapy treatment, or at least delay it.
- consider starting prophylactic antibiotic therapy