Alkylating agents Flashcards
What are alkylating agents
- add alkyl group to acceptor molecules
-small molecule drug which covalent bond with bio-molecules (DNA) - Kill cancer cells (cure/palliation)
How does alkylating agents effect DNA
Forms DNA adducts N7/O6 guanine and N3 adenine
- monofunctional /bifunctional
- Cross link (BF) interstrand, intrastrand and DNA-Protein
== Stops transcription and replication
what are archetypal alkylating agents
Typical of nitrogen mustard related compounds
- Initial reaction = activation
- Further reaction = inactivation monoadduct
What is the mechanism of cell death linked to alkylating agent
Inhibition of replication
Lethal repair (Mismatch repair)
Induction of apoptotic pathways (P53)
How do tumour cells become resistance to alkylating agents
- Decreased Transport
- Inactivation (Glutathione conjugates, Role of GST ?)
- Repair of adducts (MMR Deficiency, MGMT)
- Downstream events (P53 mutation +Deficient apoptotic pathway)
What are the adverse effects of alkylating agents
- Drug specific organ toxicities = Bladder toxicity associated with cyclophosphamide and ifosfamide
- Common toxicities = Hematopoietic and immuno supression, Nausea & vomiting, Alopecia, Infertility, Teratogenesis and Carcinogenesis
Give an example of oxazaphosphorines
- Prodrugs
Ifosfamide & cyclophosphamide
What are the clinical indications for ifosfamide
sarcoma, metastatic BC, lung cancer and paediatric tumours [sarcoma]
What are the clinical indications for cyclophosphamide
adjuvant breast, leukaemia/lymphomas and paediatric tumours
what are the regimens of oxazaphosphorines
- Intravenous, short or prolonged infusion (100-600 mg/m2)
- Cyclophosphamide also oral (Ifosfamide neurotoxic orally)
- High dose cyclophosphamide (up to 9 g/m2)
What are the toxicities surrounding oxazaphosphorines use
- Myelosuppression
- Haemorrhagic cystitis (MESNA)
- Secondary malignancy (AML)
- Cardiotoxicity (high-dose cyclo)
Cyclophosphamide are activated by _
to _
CYP2B6,2C9,2C19,3A4,2A5
4-Hydroxycyclophosphamide
4-Hydroxycyclophosphamide can be activated further by _
Reversibly to Aldophosphamide
-> phosphoramide mustard + acrolein
How are cyclophosphamide and its activated product inactivated
- Cyclophosphamide - 2-Dechloroethylcyclophosphamide + chloroacetaldehyde (via CYP3A4/3A5)
- 4-Hydroxycyclophosphamide into 4-glutathionylcyclophosphamide (via GSTA1/P1) and 4-Ketocyclophosphamide
- phosphoramide mustard into Diglutathionylphosphoramide mustard via (GSTA1)
How is oxazaphosphorine metabolism induced
- Anticonvulsants (carbamazepine, phenytoin)
- Steroids (prolonged treatment with dexamethasone = 80% increase in CP clearance)
- Autoinduction