Ph anti neoplastics continued

Question 1

List conventional antineoplastic chemotherapy:

Answer 1

Chemo

1. Alkylators
2. Vinca-alkaloids
3. Anti tumour antibiotics
4. Platinating agents
5. Antimetabolites

Question 2

Platinating agents MOA

Answer 2

o Platinum binds both within and between strands
 Similar to alkylating agents, except adding platinum group
• Transcription and replication are inhibited
• Cells die if lesion not repaired

Question 3

Where are platinating agents excreted and side effects

Answer 3

o Excreted unchanged by the kidney

o Possible side effects

1. Myelosuppression
   
   • Can be marked (especially cats with renal disease)
     - Sometimes late nadir or prolonged suppression (up to 21 d)
2. Occasional GI toxicity
3. Rare kidney toxicity - But adverse effects worse in kidney failure

Question 4

Antimetabolites MOA

Answer 4

o Interact with DNA production pathways, but differing mechanisms
o Cell cycle specific to S phase
 Often given as slow infusions for this reason

Question 5

Side effects antimetabolites

Answer 5

 Myelosuppression
 GI side effects
• Particularly if given over a number of days
 Transient hepatic dysfunction - cytosine
o Recommended to be given by slow dosing

Question 6

What is biotherapy?

Answer 6

is treatment that uses living substances to treat disease. The substance may be a natural part of the body

Or it may be made in a lab, rather than by nature. For example, DNA or an antibody could be used in biotherapy

Question 7

Biotherapy examples of anti - neoplastics

Answer 7

• L’asparaginase
• Glucocorticoids
• NSAIDs

Question 8

L’asparaginase MOA

Answer 8

o Enzyme – L-asparagine  L-aspartic acid
 Malignant lymphocytes dependent upon asparagine therefore L-asparaginase  lymphocyte death
 In dogs asparagine levels are low for several weeks
 In cats protein metabolism faster therefore drugs is less effective

Question 9

Effect of L’asparaginase

When used?

Produced by what?

Side effects?

Answer 9

o Effect penetrates blood brain barrier
o Used in lymphoma/leukaemia
o L’asparaginase usually produced from E.Coli

Possible side effects

1. Anaphylaxis – rare
2. Pancreatic inflammation
3. Transient alterations in liver function

Question 10

Glucocorticoids

MOA

Answer 10

 Bind to cytosolic receptors  Transport to the nucleus  acts as a transciption factor increasing anti-inflammatory protein expression
 Stays in the cytosol reducing inflammatory protein production

Question 11

Which glucocorticoids are commonly used? and possible side effects

Answer 11

o	Commonly used:
	Prednisolone and Dexamethasone
o	Possible side effects
	Increased appetite/ thirst
	Lethargy / panting
	GI bleeding and ulcers (usually low grade)

Question 12

• NSAIDs e.g and MOA

Answer 12

Meloxicam, Piroxicam
o Inhibit COX (1 and 2)  reduced prostaglandins and thromboxanes and thus inflammation.
 Reduce pain, pyrexia and inflammation
 Some cancers thought to be driven by COX-2 activation

Question 13

o Possible side effects NSAIDS

Answer 13

 GI bleeding, ulcer and in worst case perforation
• Worse in combination with steroids (contraindicated)
 Renal / hepatic damage
 COX-1 inhibition considered significant for side effects therefore move toward selectivity

Question 14

What is the function of receptor Tyrosine kinase?

Answer 14

1. Proliferation and cell growth
2. Cell survival
3. Chemotherapy and radiation resistance
4. Depending upon the receptor in question additional functions include
   • New blood vessel formation
   • Some aspects of immune function

Question 15

Tyrosine kinase overactivity

Answer 15

 Excess growth factor or receptor can lead to excess signaling
 Mutations can lead to constant activation of the receptor without growth factor
 Leading to excess growth and tumours
• Various types in humans and pets

Question 16

Receptor tyrosine kinase inhibition

Answer 16

 Drugs are competitive inhibitors
• Sit in ATP binding pocket block phosphate transfer
• Not dependent upon presence of a mutation
• BUT mutations = constitutive activation meaning lower threshold for inhibition as proportionally more signal blocked
• i.e. mutation =100% activation whereas signaling never 100%

Question 17

What are mast cell tumours

Waht is growth controlled by?

Answer 17

the most common canine skin tumour
• Growth of normal mast cell tumours controlled by KIT gene Tyrosine kinase receptor
Mutation = tumour, prognosis poor

Question 18

Potential adverse affects to receptor tyrosine kinase inhibition drugs

Answer 18

 Drugs not entirely specific for a particular receptor
 Receptors are not entirely specific to a particular cell types
 Therefore side effects are not always predictable
 The drugs work as competitive inhibitors
• Therefore side effects usually occur after a period of treatment
• Are usually reversible upon stopping treatment
• Some dogs benefit from occasional drug holidays or altered dosing frequency
 Diarrhoea, vomiting and anorexia
 Bone marrow suppression

Question 19

What is metronomic chemotherapy?

Answer 19

• Low doses of chemotherapy given often – daily/every other day
• Reduce angiogenesis

Question 20

MOA of metronomic chemo

Answer 20

o Kills chemotherapy sensitive cycling cancer cell
o Reduces cancer supporting new blood vessels
o Improves anti-cancer immune response

Generally well tolerated

Question 21

What is immunotherapy?

Answer 21

Two broad approaches, active and passive:

1. Active Immunotherapy
   Aim is to stimulate the immune system against the tumour
   The usual goal is to invoke a cytotoxic T lymphocytes response
2. Passive immunotherapy
   Use monoclonal antibodies to target an immune response against a tumour

These approaches need more time for immune response to develop vs chemo

Question 22

What are anti cancer therapeutic vaccinations?

Answer 22

o	Oncept melanoma
o	DNA plasmid vaccine
o	Coding human tyrosinase
o	Induces a response against tyrosinase
o	Licensed for oral melanoma

o vaccine triggers the dog’s immune system to mount an immune response against the human tyrosinase protein
o tyrosinase protein expressed at high levels in the dog’s melanoma tumor cells. This is thought to trigger an immune response against the dog’s tumor.