Pharmacology of anti-neoplatics

Question 1

What is anti neoplastic pharmacology?

Answer 1

Drugs used to treat cancer, also called:
anticancer, chemotherapy,
cytotoxic, or hazardous drugs

Question 2

When is medical therapy indicated for cancer?

Answer 2

• Neoadjuvant therapy
• Eradication of micro-metastasis
• Medical treatment sensitive tumour
• Palliation

Question 3

What is Neoadjuvant therapy:

Answer 3

o Admin of therapeutic agents before a main treatment.

Examples of neoadjuvant therapy include chemo, radiation therapy and hormone therapy BEFORE main surgery

Question 4

What are:
Micrometastasis?
And what is Palliationtherapy?

Answer 4

EMM= refers to presence of clinically undetectable tumour cells at diagnosis or cells that remain present after treatment to eradicate the primary tumour

Palliation = Making patient feel more comfortable, not curing disease

Question 5

When does chemo work best?

What are the responses in large tumours typically?

Answer 5

When tumour/metastasis is small

Responses in large tumours typically limited and transient

Generally a bigger tumour = higher chance of resistant cells within:(

Question 6

What do we need to consider before chemotherapy?

Answer 6

o Tumour growth kinetics
o Naturally resistant populations (tumour heterogeneity)
o Factors influencing drug penetration of tumour
o Patient factors (signalment, pharmacogenetics)

Question 7

What are ways in which we can overcome resistance in tumours?

Answer 7

o Reduce tumour burden before medical therapy
o Multidrug chemotherapy
o High dose intensity

Question 8

Why use multidrug chemotherapy?

Answer 8

1. Broaden range of tumour cells which are sensitive to treatment
2. Slow development of resistant population
3. Maintain acceptable toxicity and allows increase dose intensity

Question 9

What is dose intensity?

What does a high dose intensity mean?

Answer 9

Intensity = drug dose per unit time

Keeping high dose intensity reduces the number of resistant cells

Question 10

How can we achieve a high dose intensity?

Answer 10

1. Use drugs known to have single agent efficacy
2. Avoid drug combination with overlapping toxicities
3. Administer drugs as close to maximum tolerated dose as possible

Question 11

What are the factors affecting response and side effects chemo?

Answer 11

EDAM

1. Administration
2. Distribution
3. Metabolism
4. Excretion

Question 12

Talk about Administration and Distribution in factors affecting response and side effects of chemo

Answer 12

Administration: Dose, ability to get into blood stream if oral (can be quite variable)

Distribution:

1. Ability of molecule to get to target site
   - Size of drug, vasculature, necrosis, environment
   - Blood barriers e.g. blood brain barrier
2. Cellular uptake / efflux pumps e.g ABCB1

Question 13

Talk about Metabolism and Excretion in factors affecting response and side effects of chemo

Answer 13

Metabolism

1. Drug activation / deactivation e.g. CYP450, glutathione s-transferase
2. (Anti-apoptotic mechanism, DNA damage repair)
3. Cell cycle

Excretion

1. Clearance – hepatobiliary system, kidney, (lung)
2. For kidney excreted GFR correlates with adverse effects of some drugs

Question 14

How does chemotherapy work?

Answer 14

There are 2 broad categories:

1. damages DNA
2. Inhibits DNA replication

Question 15

What is a problem with chemo untargeted therapy

Answer 15

1. will affect all tissues, especially rapidly dividing tissue
2. General side effects:
   o Bone marrow – lowest white count typically 7 – 10 days
   o Alopecia – uncommon in dogs /cats except a few breeds
   o Gastrointestinal – usually lasts longer than the first 4 days

Question 16

Which agents come under “conventional chemotherapy”

Answer 16

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

Question 17

MOA alkylators

Answer 17

MOA: add an alkyl group to the guanine base of the DNA molecule, preventing the strands of the double helix from linking as they should. This causes breakage of the DNA strands, affecting the ability of the cancer cell to multiply.
o Bind DNA, insert an alkyl group leading to a change in structure.
Transcription and replication are thus inhibited.
If the lesion is not repaired the cell undergoes apoptosis

Question 18

How are alkylators metabolised and excreted?

Answer 18

o Metabolism to active forms in the liver

o Excretion via the kidney

Question 19

Side effects alkylators

Answer 19

1. Myelosuppression (low white blood cells) > GI problems
2. Cyclophosphamide – sterile haemorrhagic cystitis
   • Caused by metabolite acrolein
   • To protect: Monitor urine for blood, increase water intake and urination frequency, take Diuretics - furosemide
3. Lomustine – hepatic toxicity

Question 20

• Vinca-alkaloids MOA

Answer 20

o Either binds to or inhibits formation of microtubules thus preventing the formation mitotic spindle.
o Cell cycle specific (cells die in M phase but most sensitive in S phase)

Question 21

Where are Vinca-alkaloids metabolised and excreted?

Answer 21

o Metabolism in the liver

o Excretion in bile

Question 22

Side effects Vinca-alkaloids

Answer 22

 GI – vincristine > vinblastine
 Myelosuppression – vinblastine > vincristine
 Perivascular irritation if drug extravasation

Question 23

Antitumour antibiotics OA

Answer 23

1. Topoisomerase inhibition  DNA strand breaks
2. Intercalation with DNA  Prevents transcription
3. Free radical formation  DNA damage

Greatest effect in S phase, but not specific to cell cycle

Question 24

Whereare anti-tumour antibiotics excreted and metabolsied?

Answer 24

o Metabolised by hydrolysis in the liver

o Excreted in bile

Question 25

Side effects anti-tumour antibiotics

Answer 25

 GI
 Myelosuppression
 Severe perivascular irritation in case of extravasation
 Cumulative cardiotoxicity (systolic dysfunction) (dogs)
 Arrhythmia if administered too quickly (VPCs)
 Anaphylaxis (skin in dogs/lung in cats)
 Kidney damage (cats)