Alkylating agents Flashcards

1
Q

What are alkylating agents

A
  • add alkyl group to acceptor molecules
    -small molecule drug which covalent bond with bio-molecules (DNA)
  • Kill cancer cells (cure/palliation)
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2
Q

How does alkylating agents effect DNA

A

Forms DNA adducts N7/O6 guanine and N3 adenine
- monofunctional /bifunctional
- Cross link (BF) interstrand, intrastrand and DNA-Protein
== Stops transcription and replication

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3
Q

what are archetypal alkylating agents

A

Typical of nitrogen mustard related compounds
- Initial reaction = activation
- Further reaction = inactivation monoadduct

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4
Q

What is the mechanism of cell death linked to alkylating agent

A

Inhibition of replication
Lethal repair (Mismatch repair)
Induction of apoptotic pathways (P53)

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5
Q

How do tumour cells become resistance to alkylating agents

A
  • Decreased Transport
  • Inactivation (Glutathione conjugates, Role of GST ?)
  • Repair of adducts (MMR Deficiency, MGMT)
  • Downstream events (P53 mutation +Deficient apoptotic pathway)
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6
Q

What are the adverse effects of alkylating agents

A
  • Drug specific organ toxicities = Bladder toxicity associated with cyclophosphamide and ifosfamide
  • Common toxicities = Hematopoietic and immuno supression, Nausea & vomiting, Alopecia, Infertility, Teratogenesis and Carcinogenesis
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7
Q

Give an example of oxazaphosphorines

A
  • Prodrugs
    Ifosfamide & cyclophosphamide
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8
Q

What are the clinical indications for ifosfamide

A

sarcoma, metastatic BC, lung cancer and paediatric tumours [sarcoma]

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9
Q

What are the clinical indications for cyclophosphamide

A

adjuvant breast, leukaemia/lymphomas and paediatric tumours

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10
Q

what are the regimens of oxazaphosphorines

A
  • Intravenous, short or prolonged infusion (100-600 mg/m2)
  • Cyclophosphamide also oral (Ifosfamide neurotoxic orally)
  • High dose cyclophosphamide (up to 9 g/m2)
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11
Q

What are the toxicities surrounding oxazaphosphorines use

A
  • Myelosuppression
  • Haemorrhagic cystitis (MESNA)
  • Secondary malignancy (AML)
  • Cardiotoxicity (high-dose cyclo)
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12
Q

Cyclophosphamide are activated by _
to _

A

CYP2B6,2C9,2C19,3A4,2A5
4-Hydroxycyclophosphamide

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13
Q

4-Hydroxycyclophosphamide can be activated further by _

A

Reversibly to Aldophosphamide
-> phosphoramide mustard + acrolein

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14
Q

How are cyclophosphamide and its activated product inactivated

A
  • 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)
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15
Q

How is oxazaphosphorine metabolism induced

A
  • Anticonvulsants (carbamazepine, phenytoin)
  • Steroids (prolonged treatment with dexamethasone = 80% increase in CP clearance)
  • Autoinduction
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16
Q

What inhibits oxazaphosphorine metabolism

A

Fluconazole (azole antifungal)

17
Q

The AUC of cyclophosphamide patients who developed _ was lower than patients that didn’t developed _.

A

cardiotoxicity

18
Q

Tumour response durability was significantly longer is cyclophosphamide patients who _

A

had lower AUCs (had cardio toxicity)

19
Q

How does pharmacogenetics effect cyclophosphamide

A

CYP2C19
2 decreased cyclophosphamide elimination
CYP2B6
2,9,
4 decrease overall survival in breast cancer

20
Q

What is Mitomycin C

A

Naturally synthesised antibiotic (usually in non-small cell lung and head/neck cancer)
Main clinical use is superficial bladder cancer
Prototype bio-reductive drug

21
Q

What causes enzymatic reduction of MMC

A

NQO1 (NAD(P)H Qunone Oxidoreductase 1)
NQO2 (NAD(P)H Qunone Oxidoreductase 1)
Xanthine dehydrogenase
P450 reductase
Cytochome b5 reductase
Xanthine oxidase

22
Q

high expression of MQO1 in tumour cells confer _

A

tumour specificity novel drugs

23
Q

What is E09 (alkylating agents)

A

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

24
Q

What is RH1 (alkylating agent)

A

NQO1 substrate
Dose-limiting toxicity = hematotoxicity
No efficacy
NO correlation between NQO1 expression and DNA damage

25
Q

Give some examples of monofunctional alkylators and what do they do

A

Temozolomide
Dacarbazine
- both add methyl groups to DNA = mismatched bases

26
Q

Give an outline of temozolomide use

A

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)

27
Q

what is the mechanism of action of temozolomide

A
  • Spontaneous activation reaction
  • Methylates O6 or N7 of guanine and N3 of adenine
  • Augmented by low expression of MGMT
28
Q

Explain the link between MGMT expression and survival in paediatric brain tumours

A

O6-methylguanine-DNA methyltransferase over expression had been linked to decreased probability of overall survival

29
Q

How does MGMT methylation effect survival in glioblastomas and why?

A

Unmethylation decreases cumulative survival why methylation did cause a decrease in survival however later on
Methylation of gene promoter silences expression

30
Q

How are alkyltransferase inhibited

A

Lomeguatrib inhibits MGMT
pre-clinical studies + phase I clinical trials

31
Q

what occurs in lomeguatrib phase II trials

A

disappointing
- No difference in response

32
Q

Alkylating agents are superseded by _

A

BRAF inhibitors
(in 50% melonama)