Cancer Chemotherapy III: Specific Drugs and Safety

Question 1

L-asparaginase drugs act by doing what? how is this effective against tumors?

Answer 1

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!

Question 2

what are L-asparaginase drugs derived from

Answer 2

purified enzyme from E. coli is used

Question 3

administering L-asparaginase

Answer 3

• IM, IP, SQ
• half life in blood is long
• hypersensitivity reactions can occur though, leading to decreased half-life from increased clearance

Question 4

toxicities of L-asparginase

Answer 4

• anaphylaxis, pancreatitis, DIC are big ones
• minimally myelosuppressive

Question 5

platinum agents drugs

Answer 5

cisplatin, carboplatin

Question 6

similarities between cisplatin and carboplatin

Answer 6

• both IV dosed
• eliminated primarily renally, carboplatin clearance correlates with GFR
• carboplatin is preferred to cisplatin because of decreased renal toxicity!

Question 7

cisplatin is contraindicated in what species

Answer 7

cats!! cisplatin splats cats!!

Question 8

what were platinum agents primarily used for

Answer 8

testicular cancer

Question 9

cisplatin

Answer 9

• intra/interstrand DNA cross links
• IV delivery thru polymer delivery systems

Question 10

cisplatin toxicities

Answer 10

• BAG acutely, neurotoxicity, ototoxicity, nephrotoxicity
• FATAL pulmonary edema in cats!

Question 11

what is cisplatin used to treat

Answer 11

osteosarcoma, transitional cell carcinoma, nasal, squamous cell carcinoma, testicular, ovarian
primarily osteosarc and TCC

Question 12

carboplatin

Answer 12

• intra/interstrand DNA cross-links
• IV or intracavitary
  INCLUDE GFR FOR DOSING DETERMINATION !! CLEARANCE IS CORRELATED FOR RENAL FX

Question 13

what toxicities can be observed with carboplatin?

Answer 13

BAG, nephrotoxicity is rare, neurotoxicity
preferred over cisplatin

Question 14

what is carboplatin used to treat

Answer 14

OSA, TCC, carcinomas

Question 15

topoisomerase inhibitors

Answer 15

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

Question 16

how are the topoisomerase inhibitors similar to the taxanes?

Answer 16

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

Question 17

hydroxyurea

Answer 17

• 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

Question 18

what is the only FDA approved chemo drug for dogs?

Answer 18

tanovea

Question 19

tanovea

Answer 19

• 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

Question 20

PMEG

Answer 20

known proliferative effects but severe DLTs when given systematically
- drug tanovea is a prodrug of PMEG; leads to accumulation of PMEG in lymphoid cells

Question 21

toxicities of tanovea

Answer 21

• manageable (BAD) and relatively minor
• unique toxicities: dermatopathy and pulmonary fibrosis
• skin toxicities include erythema, alopecia, pruritis of ears, dorsum, axillae, inguinal area

Question 22

molecularly targeted agents

Answer 22

new in vetmed: targeted to block pathways considered to be more cancer specific: block signaling molecules involved in tumor cell proliferation and survival

Question 23

a vast majority of molecular target agents are targeted towards what type of reactions?

Answer 23

kinase reactions! used in cellular signaling. a lot of oncogenes are tyrosine kinases!

Question 24

dysregulation of RTKs in cancer

Answer 24

• overexpression
• activating mutations
• oncogenic fusions
• ligand dysregulation

Question 25

first targeted TKI based chemotherapy

Answer 25

imatinib (Gleevec)
- fusion protein BCR/ABL causes chronic myelogenous leukemia: this protein is a tyrosine kinase! the chemotherapy blocks the TK of BCR/ABL

Question 26

TKI in vetmed cancer therapy

Answer 26

• not super effective because such a specific target; unsure if those are present in K9 tumors

Question 27

TKIs in vetmed

Answer 27

• 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

Question 28

what is toceranib used to treat?

Answer 28

mast cell tumors

Question 29

how does toceranib work

Answer 29

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

Question 30

tumor biopsies from dogs treated with toceranib leads to decreased activation of what

Answer 30

MAPK proteins

Question 31

toxicities associated with toceranib

Answer 31

GI toxicity and neutropenia

Question 32

how are TKs being worked on in veterinary oncology?

Answer 32

1. ID appropriate targets: cell line work
2. apply drugs that hit the target: in Vivo studies
3. review responders and non-responders (clinical studies and trials)

Question 33

future of cancer therapy in veterinary medicine

Answer 33

1. TKI utilization as more come off patent and become cheaper
2. optimization and introduction of novel combo therapies
3. precision therapy
4. immunotherapies

Question 34

2 essential elements about chemotherapy safety

Answer 34

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.

Question 36

handling of chemo drugs

Answer 36

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.

Question 37

PPE for handling chemo drugs

Answer 37

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

Question 38

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?

Answer 38

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