anticancer alkylating agents Flashcards
what do they contain and do to nucleophilic substances in cells
contains chemical groups which form covalent bonds
what do alkylating agents do
formation of a carbonium ions
highly reactive
reacts instantaniously with electron donor
what do most alkylating agents contain
2 alkylating groups
bifunctional
what is the main target
N at position 6 of guanine
which is strongly nucleophilic
what does the reaction cause
causes intra and inter chain cross-linking
interferes with transcription and replication
what can alkylating guanine do
can pair with thymine
whats the main impact
during S phase
as there are zones of DNA that are unpaired
what are the side effects of alkylating agents
depress bone marrow
GI disturbances
increased risk of acute non-lymphocytic leukaemia
prolonged use gives what
depression of gametogenesis
nitrogen mustards
what happens to the side chains
each 2-chloroethyl undergoes an intramolecular crystalisation with the release of a Cl-
with nucleophilic centres
what interacts with the DNA
highly reactive ethylene immonium derivative
what do nitrogen mustards cause
cross linking of DNA strands
1 reaction with 1 strand and the other with the other
what does the cross linking do in nitrogen mustards
dna cannot replicate
recognised as damaged
induces apoptosis
what resistance forms
up regulation of repair system
mono-alkylators are not anticancer but are
mutagenic
what is another alkylating agent
cyclophosphamide
cyclophosphamide
how is it activated
metabolised by p450
producing phosphoramide mustard
and acrolein
cyclophosphamide
what does acrolein cause
dose limiting
has bladder toxicity
cyclophosphamide
how to over come acrolein
combo with MESNA
which is a small molecule to react with acrolein
cyclophosphamide
what does it affect
lymphocytes
used in immunosuppression
cyclophosphamide
what are the toxic effects
nausea
vomiting
bone marrow depression
haemorrhagic cystitis
nitrosoureas examples
lomustine and carmustine
what do nitrosoureas do that nitrogen mustards cant
lipid soluble
crosses bbb
disadvantages of nitrosoureas
severe cumulative depressive effects on bone marrow
stands 3- 6 weeks after
other alkylating agents
Busulfan
Busulfan what is it selective for
bone marrow
Busulfan in low dosages have
depressing formation of granulocytes and platelet
where is Busulfan used
chronic granulocytic leukaemia
