Cancer Chemotherapy III: Specific Drugs and Safety Flashcards
L-asparaginase drugs act by doing what? how is this effective against tumors?
they deplete L-asparagine in the blood. tumors are generally deficient in L-asparagine synthetase; thus depleting L-asparagine leads to inhibition of protein synthesis!
what are L-asparaginase drugs derived from
purified enzyme from E. coli is used
administering L-asparaginase
- IM, IP, SQ
- half life in blood is long
- hypersensitivity reactions can occur though, leading to decreased half-life from increased clearance
toxicities of L-asparginase
- anaphylaxis, pancreatitis, DIC are big ones
- minimally myelosuppressive
platinum agents drugs
cisplatin, carboplatin
similarities between cisplatin and carboplatin
- both IV dosed
- eliminated primarily renally, carboplatin clearance correlates with GFR
- carboplatin is preferred to cisplatin because of decreased renal toxicity!
cisplatin is contraindicated in what species
cats!! cisplatin splats cats!!
what were platinum agents primarily used for
testicular cancer
cisplatin
- intra/interstrand DNA cross links
- IV delivery thru polymer delivery systems
cisplatin toxicities
- BAG acutely, neurotoxicity, ototoxicity, nephrotoxicity
- FATAL pulmonary edema in cats!
what is cisplatin used to treat
osteosarcoma, transitional cell carcinoma, nasal, squamous cell carcinoma, testicular, ovarian
primarily osteosarc and TCC
carboplatin
- intra/interstrand DNA cross-links
- IV or intracavitary
INCLUDE GFR FOR DOSING DETERMINATION !! CLEARANCE IS CORRELATED FOR RENAL FX
what toxicities can be observed with carboplatin?
BAG, nephrotoxicity is rare, neurotoxicity
preferred over cisplatin
what is carboplatin used to treat
OSA, TCC, carcinomas
topoisomerase inhibitors
antracyclines like doxorubicin and mitoxantrone can also inhibit toposiomerase II but they have so many MOAs
- this group of molecules, the epipodophyllotoxins etoposide & teniposide inhibit topoisomerase II resulting in single and double strand DNA breaks
how are the topoisomerase inhibitors similar to the taxanes?
excipients are needed for IV dosing; leading to delivery issues
oral bioavailability is low and highly variable. this limits their utility
they are not first line, more like salvage therapies of lymphoma
hydroxyurea
- inhibits ribonucleotide reductase = depletion of deoxyribonucleotide pools = inhibition of DNA synthesis
- orally dosed, distributes to all tissues
- clinically used for bone marrow disorders like polycythemia vera and granulocytic leukemias
what is the only FDA approved chemo drug for dogs?
tanovea
tanovea
- FDA approved: novel double prodrug of antiproliferative analog PMEG
- administration results in accumulation of PMEG in lymphoid cell and low levels in plasma and organs of toxicity
- inhibits proliferation of myeloid and lymphoid lines in vitro
PMEG
known proliferative effects but severe DLTs when given systematically
- drug tanovea is a prodrug of PMEG; leads to accumulation of PMEG in lymphoid cells
toxicities of tanovea
- manageable (BAD) and relatively minor
- unique toxicities: dermatopathy and pulmonary fibrosis
- skin toxicities include erythema, alopecia, pruritis of ears, dorsum, axillae, inguinal area
molecularly targeted agents
new in vetmed: targeted to block pathways considered to be more cancer specific: block signaling molecules involved in tumor cell proliferation and survival
a vast majority of molecular target agents are targeted towards what type of reactions?
kinase reactions! used in cellular signaling. a lot of oncogenes are tyrosine kinases!
dysregulation of RTKs in cancer
- overexpression
- activating mutations
- oncogenic fusions
- ligand dysregulation
first targeted TKI based chemotherapy
imatinib (Gleevec)
- fusion protein BCR/ABL causes chronic myelogenous leukemia: this protein is a tyrosine kinase! the chemotherapy blocks the TK of BCR/ABL
TKI in vetmed cancer therapy
- not super effective because such a specific target; unsure if those are present in K9 tumors
TKIs in vetmed
- toceranib was a “backup”
- Palladia is approved for treatment of mast cell tumors in dogs: inhibits c-Kit, common in activating mutation in mast cell tumors
- Palladia also has activity against other tyrosine kinases! useful for other things
what is toceranib used to treat?
mast cell tumors
how does toceranib work
some mast cell tumors have alteration in KIT gene: leading to activation in absence of ligand. this leads to autophosphorylation and downstream events leading to cell proliferation. toceranib inhibits the autophosphorylation and activation of this
tumor biopsies from dogs treated with toceranib leads to decreased activation of what
MAPK proteins
toxicities associated with toceranib
GI toxicity and neutropenia
how are TKs being worked on in veterinary oncology?
- ID appropriate targets: cell line work
- apply drugs that hit the target: in Vivo studies
- review responders and non-responders (clinical studies and trials)
future of cancer therapy in veterinary medicine
- TKI utilization as more come off patent and become cheaper
- optimization and introduction of novel combo therapies
- precision therapy
- immunotherapies
2 essential elements about chemotherapy safety
Education and training of all staff involved in the handling of any aspect of cytotoxic drugs
* Biological safety cabinet for preparation
– In absence of biological safety cabinet, an appropriate respirator is the only way to prevent inhalation of a carcinogen.
handling of chemo drugs
Work with cytotoxic drugs must be carried out on disposable, plastic-backed paper which is changed every day (at a minimum).
* Syringes and IV sets with Luer-lock fitting should always be used and syringes should always be large enough that they never need to be more than 3⁄4 full.
* Ideally, the closed system is used
– Prevents contamination and exposure from the preparation
to the patient delivery steps
– Prevents handling and recapping of needles
* If not using closed system, sterile gauze should be wrapped around needles and vial tops when withdrawing solutions to catch aerosolized material
* Also wrap gauze around ampules before they are opened to catch particulate matter.
PPE for handling chemo drugs
Double glove:
– Surgical latex gloves are less permeable to cytotoxic drugs and should always be used unless the manufacturer of the compound stipulates that another type be used.
– Only powder-free latex gloves should be used
* Protective disposable gown:
– Closed front, long-sleeves, and elastic or knit-closed cuffs must be worn.
– Cuffs tucked into under gloves.
* These should not be transferred between the mixing and administration areas; separate sets of PPE should be available in both areas.
* If biosafety cabinet is not available, then the use of an appropriate respirator and face shield/splash goggles
you are going to dispense chemotherapy drugs to the owner of buddy as they can be given orally at home. what do you do for the owners?
Provide them with latex surgical gloves for administration and provide a cytotoxic drug-waste disposal bag for the gloves that can be returned to the clinic for proper disposal.
– Discourage owners from disposing of gloves in trash!
– Inform owners that pills should never be crushed or broken to reduce the potential for drug aerosolization and exposure
Then, review the information with the client to make sure there is a clear understanding of the hazards and precautions.
* Explain to each client that excretions from their pet receiving chemotherapy may be hazardous
