Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PHAM02 > Wk 12: Alkylating + platinating agents (nitrogen mustards) > Flashcards

Wk 12: Alkylating + platinating agents (nitrogen mustards) Flashcards

1
Q

What is the size of a clinical detectable tumour?

A

10^9 cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the size of a lethal tumour?

A

10^12 cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the doubling time of hodgkin’s disease + testicular teratoma?

A

3-6 days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the doubling time of breast, prostate, lung and colon cancer?

A

80-100 days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the 3 log, 1 log regrowth principle?

A
  • In tumour w/ 10^11 cells, cycle of chemo = 10^3 cells dying
  • Regrowing by 10^1 btw each cycle
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Which tissues have the most rapid proliferation?

A
  • Bone marrow
  • GI mucosa
  • Ovary
  • Testis
  • Hair follicles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Which tissues have slow proliferation?

A
  • Liver
  • Lung
  • Kidney
  • Endocrine glands
  • Vascular endothelium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Which tissues have no proliferation?

A
  • Muscle
  • Bone
  • Cartilage
  • Nerve
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the proliferation side effects of anti-cancer agents?

A
  • Myelosuppression
  • Immunosuppression
  • Mucositis
  • GI disturbance
  • Alopecia
  • Gondal damage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are alkylating agents?

A

Highly reactive electrophilic compounds that form covalent bonds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the mode of action of alkylating agents?

A
  • React w/ nucleophilic group on DNA (N-7 of guanine bc on major groove)
  • Covalent bond forms btw DNA + agent, removing CI
  • Bifunctional: causes intrastrand cross linking - stops strand unzipping
  • Causes: Enzymes not to work, missing DNA base (depurination), mispairing of G-T
  • Leads to apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How many H bonds do complementary base pairs form?

A
  • AT = 2
  • CG = 3
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the groups of alkylating agents?

A
  • Nitrogen mustards
  • Nitrosoureas
  • Platinum compounds
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

In which part of the phase are alkylating agents most effective?

A
  • G1 + M phase
  • Most base pairs not hydrogen bonded tf more susceptible to alkylation
  • Impairs progression from G1 + S phase to M
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is bis-(2-chloroethyl)sulfide?

A
  • Chemical warfare agent
  • Destroys WBC + depresses bone marrow prod of WBC
  • Toxic in rapidly dividing cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What was the first anti-cancer drug?

A

Mustine:

  • Replace sulfur by N-CH3
  • Treated: lymphomas + hodgkin disease
  • Administered as hydrochloride salt
17
Q

What were the changes made to bis(2-chloroethyl)sulfide to make into the nitrogen mustards used for chemotherapy today?

A
  • N = less nucleophilic + basic
  • Less reactive, less toxic + better therapeutic agent
18
Q

What is the mode of action of nitrogen mustards?

A

DNA strand cross linked tf can’t unwind

Interfered w/ transcription + replication

Inhibits cell division:

  • Removal of guanine bases
  • Alkylated guanine paired w/ Thymine

Ineffective repair (frameshift mutation)

19
Q

Outline the signalling pathway once nitrogen alkylating groups have caused damage to the DNA

A
  • Induces p53 + DNA damage-induced apoptotic pathway
  • Converge on caspase by cytochrome C from mitochondrial inter-membrane
  • Mitochondrial apoptotic pathway activation
  • Upregulation of pro apoptotic genes (TRAIL) + tumour suppressor gene
20
Q

What are the 2 most used nitrogen mustards?

A

Cyclophosphamide + ifosfamide

21
Q

Give examples of nitrogen mustards

A
  • Cyclophosphamide
  • Ifosfamide
  • Chlorambucil
  • Melphalan
  • Cyclophosphamide
22
Q

What is chlorambucil?

A

Leukeran

  • 2mg tabs (oral)
  • Aromatic nitrogen mustard
  • Slow acting + least toxic
  • Less basic + toxic than mustine
  • Less reactive: intermediate aziridinium ion less easily formed + only reacts with strong nucleophiles
23
Q

Why is chlorambucil less reactive in terms of its structure?

A

N lp of aromatic amine = less nucleophilic than aliphatic amine due to resonance (weaker base = poorer nucleophile)

24
Q

What is melphalan?

A

Alkeran

  • Oral 5mg tabs
  • Mostly: IV 50 mg anhydrous melphalan hydrochloride w/ 10ml solvent
  • Derivative: L-phenylalanine
  • Absorbed by AT (stereospecific)
  • Plasma levels higher than other mustards
25
Q

What is cyclophosphamide?

A

Nitrogen mustard prodrug (endoxan)

  • Oral 50mg tabs
  • IV/IM: powder reconstituted w/ sterile water
  • Activated by liver metabolism (CYP450)
  • Active agent: normustine (bifunctional)
26
Q

Outline the activation of cyclophosphamide

A
  • Bioactivation by CYP450
  • Hydrolysis causes ring to open
  • Further hydrolysis = releasing acrolein
  • Hydrolysis = releasing normustine
27
Q

What is acrolein + how does it cause hemorrhagic cystitis?

A
  • Cyclophosphamide is a prodrug
  • Activated by oxidisation by CYP450 which produces acrolein
  • In glomerular filtration = water is reabsorbed, tf comparison of acrolein in blood compared to urine is concentrated
  • Tf damage of acrolein in kidney tubules is much worse than when in blood
  • Causes irreversible alkylation of cysteine residue -> significant renal + bladder damage -> hemorrhagic cystitis
28
Q

How is the damage from acrolein resolved?

A
  • Inc fluid intake
  • Administer MESNA at 0, 4, 8 hrs of treatment (minimal cell penetration + no interference w/ cytotoxic effect)
29
Q

What has a similar mode of action as cyclophosphamide?

A

Ifosfamide (mitoxana)

30
Q

What is estramustine?

A

Estracyt:

  • Caps w/ estramustine phosphate 140mg
  • Combine estradiol + nitrogen mustard
31
Q

What are the advantages of the combination of estradiol + nitrogen mustard in estramustine?

A
  • Carbamate lowers N nucleophilicity
  • Phosphate inc water sol
  • Estradiol crosses membrane
  • Targets cells w/ estrogenic receptor
  • Alkylate as intact drug/cleavage by plasma/carbamase enzyme
32
Q

What are the possible resistance pathways?

A
  • Dec prodrug activation by CYP3A4 + CYP2B6
  • Inc metabolism
  • Dec entry into tumour cells
  • Inc efflux from tumour cells
  • Inc cellular thiol
  • Inc DNA repair
  • Deficient apoptotic response

PHAM02 (35 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions