Alkylating Agents

Question 1

What are 3 examples of alkylating agents?

Answer 1

1. Cyclophosphamide
2. Ifosfamide
3. Temozolamide

Question 2

What is the mechanism of action of cyclophosphamide?

Answer 2

NOT SPECIFIC TO ANY POINT IN CELL CYCLE

1. Enters body in inactive form
2. Metabolised by P450 enzymes in liver
3. Becomes 4-hydroxy-cyclophos
4. Becomes aldophosphamide
5. Becomes phosphoramide mustard and acrolein
6. This causes inter and intra strand DNA cross linking
7. Inhibits DNA synthesis

Question 3

What is the bioavailability of cyclophosphamide (Absorption)?

Answer 3

PO >75%

Question 4

What is the distribution of cyclophosphamide?

Answer 4

65% plasma binding
Vd 0.56L/kg

Question 5

How is cyclophosphamide metabolised?

Answer 5

CYP450 particularly CYP2B6

Question 6

How is cyclophosphamide excreted?

Answer 6

Urine
Half life 3-12h

Question 7

What is the mechanism of drug resistance of cyclophosphamide?

Answer 7

1. Reduced cellular uptake
2. Reduced expression of P450 enzymes that would activate the drug
3. Increased expression of enzymes that detoxify metabolites
4. Increased activity of DNA repair enzymes

Question 8

What are the toxicities associated with Cyclophosphamide?

Answer 8

1. Myelosuppression
2. Haemorrhagic cystitis ( caused by acrolein metabolite) - use Mesna and irrigate
3. SIADH
4. Alopecia
5. Cardiotoxicity
6. Highly ematogenic ~1500mg/m2
7. Lung fibrosis
8. Wasabi nose
9. Radiation recall reactions

Question 9

What does cyclophosphamide interact with?

Answer 9

1. Metabolised by CYP450 so inhibitors and inducers
2. Warfarin (increases INR)

Question 10

What is the MOA of Ifosfamide?

Answer 10

NOT SPECIFIC TO ANY PHASE IN CELL CYCLE
Same as cyclophos except highlighted in bold:
1. Metabolised by P450 enzymes in liver
2. 4 hydroxyl-ifosfamide
3. Aldophosphamide
4. Isophosphamide mustard and acrolein
7. This causes inter and intra strand DNA cross linking
8. Inhibits DNA synthesis

Question 11

What are the mechanisms of drug resistance of Ifosfamdie?

Answer 11

Same as cyclophosphamide

Also increased expression of aldehyde dehydrogenase leads to increased activation of drug

Question 12

What toxicities are associated with Ifosfamide?

Answer 12

1. Haemoarrhagic cystitis (acrolein metabolite)
2. Myelosuppression
3. Neurotoxicity (chloracetylaldehyde metabolite) (?methylene blue)
4. Faconi syndrome - proximal tubule dysfunction
5. Nausea/vomiting
6. Deranged LFTs
7. Bladder cancer
8. SIADH

Question 13

What does Ifosfamide interact with?

Answer 13

1. Metabolised by CYP450 so inhibitors and inducers
2. Warfarin (increases INR)
3. Allopurinol

Question 14

What is the absorption of Ifosamide?

Answer 14

100% oral but high neurotox so has to be IV

Question 15

What is the distribution Ifosfamide?

Answer 15

Negligible plasma prtoen binding
Vd 6-49L
Crosses BBB but at subtherapuetic

Question 16

How is Ifosfamide metabolised?

Answer 16

Liver CYP450

Question 17

How is Ifosfamide excreted?

Answer 17

Urine
Half life 7 hours

Question 18

How can haemorrhagic cystitis be managed?

Answer 18

Mesna - binds acrolein

Question 19

What is the mechanism of action of Temozolomide?

Answer 19

G2/M phase

1. MTIC is the active form
2. Methylates DNA at O-6 or N-7 of guanine
3. DNA strand breaks
4. Apoptosis

Question 20

What are the mechanisms of drug resistance of Temozolomide?

Answer 20

1. Increased DNA repair
2. MMR deficient
3. MGMT proficient