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
What inhibits oxazaphosphorine metabolism
Fluconazole (azole antifungal)
The AUC of cyclophosphamide patients who developed _ was lower than patients that didn’t developed _.
cardiotoxicity
Tumour response durability was significantly longer is cyclophosphamide patients who _
had lower AUCs (had cardio toxicity)
How does pharmacogenetics effect cyclophosphamide
CYP2C19
2 decreased cyclophosphamide elimination
CYP2B6
2,9,4 decrease overall survival in breast cancer
What is Mitomycin C
Naturally synthesised antibiotic (usually in non-small cell lung and head/neck cancer)
Main clinical use is superficial bladder cancer
Prototype bio-reductive drug
What causes enzymatic reduction of MMC
NQO1 (NAD(P)H Qunone Oxidoreductase 1)
NQO2 (NAD(P)H Qunone Oxidoreductase 1)
Xanthine dehydrogenase
P450 reductase
Cytochome b5 reductase
Xanthine oxidase
high expression of MQO1 in tumour cells confer _
tumour specificity novel drugs
What is E09 (alkylating agents)
Mitomycin C analogues - substrate for NQO1 which produces interstrand cross links
- Caused tumour regression in high NQO1 expressing xenograft models following IP administration.
- Phase II trials showed compund was ineffective following IV admin
- DLT was renal toxicity
What is RH1 (alkylating agent)
NQO1 substrate
Dose-limiting toxicity = hematotoxicity
No efficacy
NO correlation between NQO1 expression and DNA damage
Give some examples of monofunctional alkylators and what do they do
Temozolomide
Dacarbazine
- both add methyl groups to DNA = mismatched bases
Give an outline of temozolomide use
Clinical use:
- Oral administration – high bioavailability
- 200 mg/m2/day for 5 days, every 4 weeks
- Good penetration of blood brain barrier
- Glioma, astrocytoma
Modest activity in melanoma
- 10-15% response rate
- Comparable to dacarbazine (but more expensive)
what is the mechanism of action of temozolomide
- Spontaneous activation reaction
- Methylates O6 or N7 of guanine and N3 of adenine
- Augmented by low expression of MGMT
Explain the link between MGMT expression and survival in paediatric brain tumours
O6-methylguanine-DNA methyltransferase over expression had been linked to decreased probability of overall survival
How does MGMT methylation effect survival in glioblastomas and why?
Unmethylation decreases cumulative survival why methylation did cause a decrease in survival however later on
Methylation of gene promoter silences expression
How are alkyltransferase inhibited
Lomeguatrib inhibits MGMT
pre-clinical studies + phase I clinical trials
what occurs in lomeguatrib phase II trials
disappointing
- No difference in response
Alkylating agents are superseded by _
BRAF inhibitors
(in 50% melonama)
