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alkylating agents Flashcards

1
Q

size of detectable tumour

A

10^9 cells
1cm/1g

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2
Q

size of lethal tumour

A

10^12 cells

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3
Q

fractional cell kill hypothesis

A

each time chemotherapy dose is repeated, same proportion of cells, not same number, is killed

3 log kill, 1 log growth

  • 10^3 are killed, 10^1 grow back
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4
Q

parts of body where there is rapid proliferation

A

bone marrow
GI mucosa
ovary
testis
hair follicles

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5
Q

proliferative side effects of chemo

A

myelosuppression
immunosuppression
mucositis
GI disturbances
alopecia
gonadal damage

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6
Q

What are alkylating agents and how do they work?

A
  • highly reactive
  • electrophilic
  • form covalent bonds (SN1 and SN2 mechanisms)
  • NOT cell cycle specific
  • cross linking of DNA
    -> miscoding through abnormal base pairing with thymine (T-G not C-G)
  • block DNA synthesis
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7
Q

what can alkylating agents bind to/form covalent bonds with? (nucleophiles)

A
  • O in phosphate groups of DNA/RNA
  • O of purines/pyrimidines
  • amino groups of purines
  • primary/secondary amino groups of proteins
  • sulfur of methionine
  • thiol of cysteine
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8
Q

Are alkylating agents cell cycle specific?

A

NO

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9
Q

purine bases

A

2 rings

adenine
guanine

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10
Q

pyrimidine bases

A

1 ring

cytosine
thymine
uracil

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11
Q

How are bases from 2 strands of DNA bonded?

A

H bonding

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12
Q

How many H bonds between A and T?

A

2

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13
Q

How many H bonds between C and G?

A

3

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14
Q

What type of bond does alkylating agent form with anything in body?

A

covalent bond

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15
Q

examples of nitrogen mustards used as chemo

A

cyclophosphamide

ifosfamide

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16
Q

change from N mustards to mustine

A

replacement of S with N-CH3

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17
Q

When are nitrogen mustards more cycotoxic? (cell cycle)

A

during replication phase of cell cycle

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18
Q

structure of nitrogen mustards

A

2 Cl on either side

N in middle

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19
Q

main target on DNA of nitrogen mustards/alkylating agents

A

N-7 of guanine

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20
Q

What does bi-functional mean?

A

they casue intRAstrand linking AND intERstrand linking

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21
Q

MOA of alkylating agents

A
  1. cross link
    - N7 of G is exposed nucleophile in DNA helix
    - DNA major groove alkylation
    - inter strand cross linking with another N7
    - DNA can’t separate during transcription
    - can’t enter replication process
    - can’t unwind
    -> apoptosis
  2. depurination
    - G bond with the sugar isn’t as strong
    = G breaks away
    - break in genetic code
    - blank in the sugar
    -> apoptosis
  3. miscode
    - alkylated N7 of G doesn’t recognise C anymore
    - recognises T
    - alkylated G pairs to T
    -> apoptosis
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22
Q

MAIN MOA of alkylating agents

A

inter-strand cross linking

23
Q

metabolism of alkylating agents

A

hydrolysis - most common

monoalkylation - also possible

24
Q

Chlorambucil compared to other nitrogen mustards

A

AROMATIC RING replaces methyl group
- slowest acting
- least toxic
- less reactive than mustine
- only reacts with strong nucleophiles
- prevents some s/e

25
What is Melphalan derived from?
phenylalanine
26
How is cyclophosphamide activated?
prodrug - metabolised by the liver - and activated by CYP450
27
active agent of cyclophosphamide
normustine
28
metabolite of cyclophosphamide that causes problems
acrolein
29
What can acrolein cause?
irreversible alkylation of cysteine residues (acrolein binds to cycteine residues) potential for renal/bladder damage haemorrhagic cystitis
30
What intermediate is formed with alkylating agents?
ziridinium ion
31
Tx for acrolein
increase fluid intake N-acetylcysteine or MESNA -> these contain a THIOL
32
How can resistance to drugs occur?
- decreased prodrug activation by key enzymes (CYP3A4, CYP2B6) - inc metabolism (deactivation) - dec entry into tumour cells - inc efflux from tumour cells - inc cellular thiol levels - inc DNA repair capacity - deficient apoptotic response to DNA damage
33
What is estramustine a combination of?
estradiol and nitrogen mustard
34
differences with ifosfamide
- related to cyclophosphomade, similar structure - linkage between DNA different: 7 ATOM LINKAGE (not 5) - can tolerate slightly less guanine rich region to undergo alkylation
35
How does the estradiol on estramustine help?
can efficiently cross biological membranes
36
What does the P in estramustine do?
inc water solubility (oral admin possible)
37
cancer Thiotepa is used in
bladder cancer most commonly - admin directly into bladder by catheter - dehydrate patient for 8-12hrs - retain for 2hrs - once per week for 4 weeks
38
premedication for alkyl sulfonates (Busulfan)
phenytoin - crosses BBB, induces seizures
39
alkyl sulfonates/busulfan difference from N mustards
has 2 S groups better leaving groups than Cl in itrogen mustards
40
common nitrosourea used
Lomustine
41
Were do nirtosiureas crosslink DNA?
N7, O6 of guanine N3 of cytosine
42
serious s/e of nitrosoureas
bone marrow depression
43
final species of nitrosoureas that interact with DNA
chloroethyl carboniumion or chloroethyl diazonium ion
44
What is streptozocin?
a nitrosourea naturally occurring
45
proposed MOA of streptozocin
generation of free radicals methyl diazonium ion
46
What do temozolomide/dearbazine porduce as their active species?
methyl diazonium ion
47
type of drug is cisplatin
platinating/metalating agent
48
interaction with cisplatin and admin
aluminum can't use needles containing aluminium for admin
49
structure of cisplatin
Pt surrounded by 2 Cl and 2 NC3
50
MOA of cisplatin
- binds to DNA as bifunctional alkylating agent - intrastrans platination - N7 of G on major groove favoured site - alters structure of DNA - prevents replication - proteins bind to minor groove preventing replication - involves water, water reaplces Cl, then binds to N atom on DNA
51
How can liposomes target tumours?
tumours don't have the same level of seal between cells and are leaky ''ehanced permeability and retention effect''
52
What is the ''enhaced permeability and retention effect''?
tumours are leaky permeability - liposomes can enter tumour cells retention - liposomes can't leave, adhere to cell surface
53
size of liposomes that can enter tumours
< 400nm
54
What is lipoplatin?
- liposome product - reverse micells between cisplatin and DPPG - they're converted into micelles from interaction with PEG - min toxic exposure to normal tissues - max uptake and penetration into tumour - small size: passive extravasation into tumours - PEG coating: prolonges circulation time

PHAM02 (32 decks)

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