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PHAM02 > alkylating agents > Flashcards

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
Q

What is Melphalan derived from?

A

phenylalanine

26
Q

How is cyclophosphamide activated?

A

prodrug
- metabolised by the liver

  • and activated by CYP450
27
Q

active agent of cyclophosphamide

A

normustine

28
Q

metabolite of cyclophosphamide that causes problems

A

acrolein

29
Q

What can acrolein cause?

A

irreversible alkylation of cysteine residues (acrolein binds to cycteine residues)

potential for renal/bladder damage

haemorrhagic cystitis

30
Q

What intermediate is formed with alkylating agents?

A

ziridinium ion

31
Q

Tx for acrolein

A

increase fluid intake

N-acetylcysteine
or
MESNA

-> these contain a THIOL

32
Q

How can resistance to drugs occur?

A
  • 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
Q

What is estramustine a combination of?

A

estradiol and nitrogen mustard

34
Q

differences with ifosfamide

A
  • 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
Q

How does the estradiol on estramustine help?

A

can efficiently cross biological membranes

36
Q

What does the P in estramustine do?

A

inc water solubility (oral admin possible)

37
Q

cancer Thiotepa is used in

A

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
Q

premedication for alkyl sulfonates (Busulfan)

A

phenytoin

  • crosses BBB, induces seizures
39
Q

alkyl sulfonates/busulfan difference from N mustards

A

has 2 S groups

better leaving groups than Cl in itrogen mustards

40
Q

common nitrosourea used

A

Lomustine

41
Q

Were do nirtosiureas crosslink DNA?

A

N7, O6 of guanine

N3 of cytosine

42
Q

serious s/e of nitrosoureas

A

bone marrow depression

43
Q

final species of nitrosoureas that interact with DNA

A

chloroethyl carboniumion
or
chloroethyl diazonium ion

44
Q

What is streptozocin?

A

a nitrosourea

naturally occurring

45
Q

proposed MOA of streptozocin

A

generation of free radicals

methyl diazonium ion

46
Q

What do temozolomide/dearbazine porduce as their active species?

A

methyl diazonium ion

47
Q

type of drug is cisplatin

A

platinating/metalating agent

48
Q

interaction with cisplatin and admin

A

aluminum
can’t use needles containing aluminium for admin

49
Q

structure of cisplatin

A

Pt surrounded by 2 Cl and 2 NC3

50
Q

MOA of cisplatin

A
  • 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
Q

How can liposomes target tumours?

A

tumours don’t have the same level of seal between cells and are leaky

'’ehanced permeability and retention effect’’

52
Q

What is the ‘‘enhaced permeability and retention effect’’?

A

tumours are leaky

permeability - liposomes can enter tumour cells

retention - liposomes can’t leave, adhere to cell surface

53
Q

size of liposomes that can enter tumours

A

< 400nm

54
Q

What is lipoplatin?

A
  • 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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