alkylating agents Flashcards
size of detectable tumour
10^9 cells
1cm/1g
size of lethal tumour
10^12 cells
fractional cell kill hypothesis
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
parts of body where there is rapid proliferation
bone marrow
GI mucosa
ovary
testis
hair follicles
proliferative side effects of chemo
myelosuppression
immunosuppression
mucositis
GI disturbances
alopecia
gonadal damage
What are alkylating agents and how do they work?
- 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
what can alkylating agents bind to/form covalent bonds with? (nucleophiles)
- 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
Are alkylating agents cell cycle specific?
NO
purine bases
2 rings
adenine
guanine
pyrimidine bases
1 ring
cytosine
thymine
uracil
How are bases from 2 strands of DNA bonded?
H bonding
How many H bonds between A and T?
2
How many H bonds between C and G?
3
What type of bond does alkylating agent form with anything in body?
covalent bond
examples of nitrogen mustards used as chemo
cyclophosphamide
ifosfamide
change from N mustards to mustine
replacement of S with N-CH3
When are nitrogen mustards more cycotoxic? (cell cycle)
during replication phase of cell cycle
structure of nitrogen mustards
2 Cl on either side
N in middle
main target on DNA of nitrogen mustards/alkylating agents
N-7 of guanine
What does bi-functional mean?
they casue intRAstrand linking AND intERstrand linking
MOA of alkylating agents
- 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 - depurination
- G bond with the sugar isn’t as strong
= G breaks away
- break in genetic code
- blank in the sugar
-> apoptosis - miscode
- alkylated N7 of G doesn’t recognise C anymore
- recognises T
- alkylated G pairs to T
-> apoptosis
MAIN MOA of alkylating agents
inter-strand cross linking
metabolism of alkylating agents
hydrolysis - most common
monoalkylation - also possible
Chlorambucil compared to other nitrogen mustards
AROMATIC RING replaces methyl group
- slowest acting
- least toxic
- less reactive than mustine
- only reacts with strong nucleophiles
- prevents some s/e
What is Melphalan derived from?
phenylalanine
How is cyclophosphamide activated?
prodrug
- metabolised by the liver
- and activated by CYP450
active agent of cyclophosphamide
normustine
metabolite of cyclophosphamide that causes problems
acrolein
What can acrolein cause?
irreversible alkylation of cysteine residues (acrolein binds to cycteine residues)
potential for renal/bladder damage
haemorrhagic cystitis
What intermediate is formed with alkylating agents?
ziridinium ion
Tx for acrolein
increase fluid intake
N-acetylcysteine
or
MESNA
-> these contain a THIOL
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
What is estramustine a combination of?
estradiol and nitrogen mustard
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
How does the estradiol on estramustine help?
can efficiently cross biological membranes
What does the P in estramustine do?
inc water solubility (oral admin possible)
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
premedication for alkyl sulfonates (Busulfan)
phenytoin
- crosses BBB, induces seizures
alkyl sulfonates/busulfan difference from N mustards
has 2 S groups
better leaving groups than Cl in itrogen mustards
common nitrosourea used
Lomustine
Were do nirtosiureas crosslink DNA?
N7, O6 of guanine
N3 of cytosine
serious s/e of nitrosoureas
bone marrow depression
final species of nitrosoureas that interact with DNA
chloroethyl carboniumion
or
chloroethyl diazonium ion
What is streptozocin?
a nitrosourea
naturally occurring
proposed MOA of streptozocin
generation of free radicals
methyl diazonium ion
What do temozolomide/dearbazine porduce as their active species?
methyl diazonium ion
type of drug is cisplatin
platinating/metalating agent
interaction with cisplatin and admin
aluminum
can’t use needles containing aluminium for admin
structure of cisplatin
Pt surrounded by 2 Cl and 2 NC3
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
How can liposomes target tumours?
tumours don’t have the same level of seal between cells and are leaky
'’ehanced permeability and retention effect’’
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
size of liposomes that can enter tumours
< 400nm
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
