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name 3 drugs in the platinum complexes class of DNA interactive drugs
cisplatin
carboplatin
oxaliplatin
how was cisplatin discovered?
serendipity
was found that passing an electric current through platinum electrodes led to arrest of cell division without killing E. coli cells
cytostatic effect :. growth without division led to elongated cells with spindle-like appearance
what type of DNA interactive anticancer agent are platinum complexes?
intrastrand cross linkers in major groove
where does cisplatin produce intrastrand cross links?
guanine N7 - guanine N7
guanine N7 - adenine N7
^ bases next to each other
guanine N7 - X - guanine N7
^ one base “X” in between the alkylated guanines
comment on the activity of transplatin vs cisplatin
transplatin has less antitumour activity because its interaction with DNA is less efficient
what happens when cisplatin forms intrastrand cross links?
kinks DNA at adduct sites
what is the likely mechanism of action for cisplatin?
cells have limited ability to repair cisplatin adducts compared to healthy cells
what are the disadvantages of cisplatin?
IV administration
general anticancer drug side effect profile: bone marrow suppression, nausea, vomiting, GI disturbances, hair loss
side effects specific to cisplatin: peripheral neuropathy and ototoxicity
what is carboplatin?
analogue of cisplatin that incorporates a cyclobutyl-substituted dilactone ring
compare the tolerability of cisplatin vs carboplatin
carboplatin is generally better tolerated in terms of side effects, but myelosuppression is more pronounced
describe the structure of intercalating agents
flat in shape
consists of 3 or 4 fused aromatic rings
side hcains often rich in hydrogen bonding functionalities
describe the mechanism of action of intercalating agents
insertion between the base pairs of DNA → perpendicular to the axis of the helix
once in position, the drug is held in place by interactions like H bonds and vdW
side chains are positioned in either major or minor grooves
what is a threading agent?
an intercalator with a range of functional groups at either end of the molecule which protrude into both the minor and major grooves after insertion
what is the effect of intercalators on DNA?
blocks transcription and interferes with DNA processing enzymes
what are the 3 main types of intercalating agents?
anthracyclines
anthracenes
phenoxazines
describe the structure of anthracyclines
4 fused aromatic rings
describe the structure of anthracenes
3 aromatic rings
describe the structure of phenoxazines
3 fused 6-membered rings with the central ring containing oxygen and nitrogen heteroatoms
what are the possible mechanisms of action of anthracyclines?
planar ring inserts between DNA base pairs perpendicular to the long axis of the double helix → hydrogen bonds stabilise drug
form complexes with topoisomerase enzymes and DNA causing strand breaks → if you can’t unwind DNA, pressure can accumulate which can break the strands
binding to cell membranes :. altering fluidity and ion transport
generation of free radicals causing DNA damage
give 2 examples of anthracyclines
doxorubicin
idarubicin
why is doxorubicin one of the most widely used and successful anticancer drugs?
broad spectrum of activity
how is doxorubicin administered? what should you be careful of?
injection into a fast running infusion
3 week intervals
should take care to avoid local extravasation which can cause severe tissue necrosis
when should the dose of doxorubicin be reduced? why?
elevated bilirubin level s
drug is largely excreted by biliary tract
which toxicity is higher cumulative doses of doxorubicin associated with?
cardiotoxicity
how can you limit cardiotoxicity when taking doxorubicin?
cardiac monitoring
liposomal formulations are available which are though to reduce incidence of cardiotoxicity and local necrosis
what is the benefit of idarubicin over other anthracyclines?
only anthracycline that can be given orally as well as intravenously
give an example of an anthracene
mitoxantrone
describe the structure of mitoxantrone
rich in oxygen and nitrogen substituents and side chains :. extensive stabilisation via H bonding
preference for binding to GC rich sequences
how is mitoxantrone administered? what are its major side effects?
IV
myelosuppression and cardiotoxicity
give an example of a phenoxazine
dactinomycin
describe the structure of dactinomycin
contains 2 cyclic peptide side chains which stabilise drug by inercalating in the minor groove
how is dactinomycin administered?
IV
why is resistance to dactinomycin common?
reduced uptake of the drug into the tumour cells
increased active transport of drug out of tumour cells
cardiac toxicity is present in all intercalating agent classes. compare the toxicity in anthracyclines vs anthracenes vs phenoxazines
anthracyclines have the highest cardiac toxicity risk, followed by anthracenes then phenoxazines
what is the significance of the topoisomerase enzyme?
DNA is highly packed in the nucleus → it is coiled around histones :. needs to be unwound to be read in transcripiton → toposiomerase enzyme unwinds DNA
where in the cell cycle to topoisomerase inhibitors work best?
DNA is unwound in S phase of cell cycle :. here is where topoisomerase levels are highest :. cytotoxicity is highest in S phase
what are the 2 types of topoisomerase enzymes?
type I and type II
describe how toposisomerase I enzymes unwind DNA
break only one strand of DNA and attach the free phosphate residue of the broken strand to a tyrosine residue on the enzyme
second strand is passed through the break in the first strand
the 2 ends are then resealed
:. able to unwind without leaving damaging nicks
describe how toposisomerase II enzymes unwind DNA
cleave both strands of DNA simultaneously :. passing complete duplex strand though the cut
followed by resealing of both strands
describe how topoisomerase I inhibitors work
inhibitor binds to enzyme
replication fork cannot advance since DNA is not being unwound
DNA single strand breaks
cell death is induced
how do toposiomerase I inhibitors get their selectivity?
cells that grow and reproduce at a faster rate are more vulnerable to inhibition
give an example of a topoisomerase I inhibitor
camptothecin
why was the use of camptothecin limited? what was introduced to help with this?
serious side effects and poorly soluble :. topotecan introduced with hydrophilic substituents to aid solubility
what are the 2 isoforms of topoisomerase II
topoisomerase IIalpha and topoisomerase IIbeta
give an example of a topoisomerase II inhibitor. how does it work?
etoposide
inhibits resealing ability of toposiomerase IIalpha and topoisomerase IIbeta :. reversible double strand breaks are convered to lethal breaks
how can etoposide be administered?
orally or by slow IV infusion
how do DNA cleaving agents work?
binds to DNA helix (usually sequence selective) and generates free radicals which then cleaves the double stranded helix
give an example of DNA cleaving agents
bleomycin
how is bleomycin administered?
IV or IM
describe the side effect profile of bleomycin
only slightly myelosuppressive
toxicity is confined to skin, mucosa and lungs
dermatological toxicity is common → increased pigmentation
what are the 2 types of DNA repair? describe them
homologous base recombination: use the other existing copy of a gene as a template to repair damage :. ERROR FREE
non-homologous end joining: occurs when you cannot use a template :. if double strand break, you just bring 2 pieces’ ends together → if there’s multiple breaks, this is a problem because you don’t know which ends go together :. ERROR PRONE
which type of repair is mediated by BRCA 1 and 2? what happens in one of the genes were to be mutated?
they mediate homologous repair
if mutated, the cell loses the ability to do error free DNA repair :. relies on error prone repair :. predisposed to cancer due to higher rates of mutation
what is the concept of synthetic lethality?
if cells have lost function of one gene, they become sensitive to inhibition of second gene
if you inhibit one gene nothing happens but if you inhibit both genes then you kill the cell :. look for mutations that have already mutated 1 gene already then inhibit the 2nd gene using drug
normal cells will have functioning of both genes :. suppressing 1 using the drug won’t have any effect
give an example of a treatment using the synthetic lethality concept
PARP inhibitors
cells that carry a BRCA 1 or 2 mutation rely on PARP enzymes to aid DNA repair
:. using PARP inhibitors will effectively kill cell because both genes are inhibited simultaneously
define epigenetic control
a mechanism which regulates gene expression independent of any changes to the DNA sequence
genome contains 2 types of information: genetic (DNA sequence) and epigenetic (chemical modifications to individual DNA bases)
what are the 2 epigenetic modifications that can occue?
methylation in DNA
acetylation in histones
why are epigenetic changes significant?
information in epigenome is transmissible :. can inherit epigenetic information
hypermethylation in the promoter of a tumour suppressor gene can silence expression :. gives cell growth advantage
hypomethylation on the promoter of an oncogene may lead to over-expression :. tumourigenesis
other than genetics, what else can epigenome be affected by?
environment e.g. diet
how are RNA interference (RNAi) drugs useful as anticancer therapeutics?
RNA is made before proteins are synthesised → can develop an inhibitor for mutant protein which will kill cancer cell
some genes are difficult to make drugs for :. can destroy mRNA which encodes mutant protein :. prevents translation :. prevents gene expression
what are the challenges of using RNA interference (RNAi)?
RNA is prone to chemical and enzymatic cleavage upon storage and use
how can you overcome the challenges surrounding RNA interference (RNAi)?
nanoparticle approach
encapsulating drug in liposomal coat to avoid degradation in bloodstream
