cancer Flashcards
outline the MoA of tamoxifen
competes w oestrogen receptors (ER) at AF2 (= binding site for co-activation transcription factors)
this reduces tumour growth
outline the MoA of bleomycin
binds to DNA and removes the C4 hydrogen atom
this introduces single and double DNA strand breaks
this inhibits DNA polymerase and DNA replication = cell death
outline the mechanism of action of gleevec/imatinib (Bcr-Abl TKI)
Bcr-Abl promotes downstream pathways which stimulates cell growth in the nucleus
gleevec acts on the ATP binding site of the Bcr-Abl kinase which locks it in a closed configuration
inhibition of Bcr-Abl inhibits the downstream pathways and prevents phosphorylation = cell death
outline the MoA of MTX
normally DHFR (dihydrofolate reductase) enzymes converts into THR (tetrahydrofolate) (= needed for purine + pyrimidine synthesis)
MTX inhibits DHFR enzymes = reduced THR
THR deficiency causes decreased thymidylate synthesis
this disrupts DNA and RNA synthesis during S phase of mitosis = cell death
outline the MoA of paclitaxel
paclitaxel binds to beta-tubulin MT subunits
MTs are stabilised which locks them in a rigid state
stabilisation means the mitotic spindle cannot disassemble and depolymerise
cells cannot undergo anaphase = cell death
outline MoA of alkylating agents (i.e., cyclophosphamide)
main anti tumour activity is due to formation of interstrand crosslinks (90%) = formation of cross-links between 2 guanine bases on different DNA strands
intrastrand crosslinks can also occur (10%) = formation of cross-links between 2 adjacent guanine bases on the same DNA strand
after intrastrand crosslinks are formed, the drug binds to the N7 nucleophilic site on the guanine base
this inhibits transcription as the DNA cannot separate
DNA cannot replicate = cell death
outline the MoA of capecitabine (5-FU)
caepecitabine is a prodrug of 5-FU and is converted through a series of enzymatic reactions
5-FU converts into its active form –> FdUMP
FdUMP forms stable complex with thymidylate synthase
this stops the conversion of dUMP –> dTMP (DNA building block)
reduced dTMP inhibits DNA synthesis and repair = cell death
outline the MoA of cisplatin
cisplatin enters cell
aquation occurs due to lower intracellular conc of Cl- ions which replaces these ions w H2O molecules
the aqua ligand makes the platinum more susceptible to bind to guanine bases
this forms intrastrand crosslinks –> inhibits DNA strand separation
this inhibits DNA replication + transcription –> impairs DNA mechanisms (so DNA cannot repair itself) –> cell death
outline the MoA of vincristine (vinca alkaloids)
usually MTs undergo polymerisation (growth) & depolymerisation (shrinkage) during mitosis
vincristine binds to alpha and beta tubulin heterodimers & MT ends
this disrupts polymerisation & depolymerisation of MTs which in turn disrupts the formation of the mitotic spindle
this blocks the formation of MTs
this causes mitotic arrest = cell death
outline three MoAs of anthracyclines (doxorubicin, etoposide)
- topoisomerase II inhibitors - topo II normally helps to recleave (cut + rejoin) DNA
anthracyclines inhibit these enzymes which prevents DNA recleaving & introduces double stranded DNA breaks.
accumulation of strand breaks = cell programmed cell death - DNA intercalation - anthracyclines have planar aromatic structure which allows for the drug to insert into DNA
this causes changes in the structure + function of DNA = cells cannot replicate = cell death - formation of reactive oxygen species - anthracyclines have quinine scaffold which allows molecules to transfer electrons to make oxygen free radicals
radicals react w/ O2 to make O2- (superoxide) and H2O2 (hydrogen peroxide)
reactive oxygen species can cause membrane + DNA damage = cell death
outline the two main MoAs of trastuzumab
- HER2 receptor blockade - binds to domain IV on extracellular part of HER2 receptor
this disrupts dimerisation = reduced cell growth + survival & cell cycle arrest - antibody-dependent cellular cytotoxicity (ADCC) -
Fc region of trastuzumab draws immune cells to the tumour sites which overexpresses HER2 –> kills HER2 cells
what is the primary MoA of 5-FU?
inhibition of thymidylate (dTMP) synthesis
what is the primary MoA of imatinib (Gleevec)?
inhibition of Bcr-Abl protein kinase
what is the antidote for cyclophosphamide (or ifosfamide) induced haemorrhagic cystitis? how does it work?
mesna
binds to acrolein which is what cyclophosphamide breaks down into (acrolein irritates bladder lining causing it to shed)
why are hemastix offered to patients taking cyclophosphamide?
these detect blood in urine
+ve test can indicate haemorrhagic cystitis
what is extravasation? what does it cause?
accidental leakage of fluids from vein into SC tissue causing tissue damage, i.e., necrosis
DNA binding more toxic than non-DNA binding since hangs around for longer
what s/e is associated w anthracyclines (doxorubicin)?
how do you manage it?
plantar-palmar erythema –> red/tender hands/feet, peeling, numbness, difficulty using hands/feet
limit hot water use on hands/feet
cool them
avoid heat sources inc sauna or sitting in sun
gently apply skin creams
wear loose fitted clothes
try not to walk barefoot
what are long term s/e associated w tamoxifen?
increased risk of endometrial cancer and thromboembolism (DVT, PE)
what four cancer drug classes are associated w alopecia?
taxanes - paclitaxel
antimetabolites - MTX and capecitabine
vinca alkaloids - vincristine
anthracyclines - doxorubicin, etoposide
what four cancer therapies have a higher risk of causing diarrhoea?
capecitabine
irinotecan
TKIs (i.e., Gleevec)
immunotherapy
what are the three main methods of tumour reduction and when are they used?
surgery - localised disease, non vital organs
radiotherapy - localised disease cure for palliation of disseminated disease
chemo - localised or disseminated disease
what three classes of cancer drugs are most associated w peripheral neuropathy?
vinca alkaloids - vincristine
platinum agents - cisplatin
capecitabine (but not MTX)
what types of cancer agents are most likely to cause extravasation?
vesicants - DNA & non DNA binding (DNA: doxorubicin, epirubicin – WORST one, non: paclitaxel, vincristine)
irritants - etoposide, 5-FU, ifosfamide, MTX, melphalan, trastuzumab
acidic or alkaline agents
how does Tx differ for extravasation for DNA binding and non-DNA binding vesicants?
DNA binding - body cannot flush out, causes BAD tissue damage, cold pack to = vasoconstriction - reduces blood flow to prevent drug spread in system
non-DNA binding - quickly metabolised, can be more easily removed, hot pack to = vasodilation - increases blood flow to allow drug metabolism + excretion
