Cancer Part 4- 4 slide left but I gave up Flashcards
what is cisplatin?
Anticancer drug that is made up of platinum and chlorine ions.
What is the moa of cisplatin?
> Is a planar molecule that contains 2 chlorine atoms.
> These chlorine atoms are easily hydrated and leave the cisplatin molecule.
> The cisplatin then binds to the DNA base guanine at the n7 and o6 position.
How does the cisplatin interact with the DNA?
Cisplatin acts as an adduct on the DNA chain allowing the HMG domain to wrap around the chain bending it out of shape.
What are some of the uses of cisplatin?
V. effective-vs-certain rare tumours with poor alternative treatment options
Sometimes cures - often increased survival
Testicular - v. effective vs lung mets from testicular
Effective vs a broad range of cancers - Prostate, ovarian, cervical, bladder, thyroid, head/neck/ oesophageal cancers, breast cancer
Often in combo with vinblastine & bleomycin
What happens to the DNA when cisplatin binds
Intra-strand Breaks
Inter-strand Breaks
How is the nephrotoxicity of Cisplatin mitigated
Fractionate the dose: 5X iv instead of IV bolus
Pre-treat to forced diuresis
Regular testing: Renal and Auditory
What s another new gen metal based cytotoxic compound
Carboplatin
Oxaplatin
Carboplatin vs Cisplatin
Carboplatin has improved toxicity profile
-Reduced nephrotoxicity ,
-No forced Diuresis
-Pt return home sooner
-Myelotoxicity is dose limiting
Are Antitumour antibodies cell cycle non specific or cell cycle specific
Cell cycle non specific
Name the drugs and Drug classes fall under Anti-tumour antibodies
Anthracyclines
Actinomycin-D
Bleomycin
Give examples of Anthracycline
Doxorubicin
Aclarubicin
Idarubicin
Epirubicin
mitozantrone
Daunorubicin
What is Doxorubicin used for
cancer drug for sarcomas, breast, lung, ALL and lymphomas
What is Aclarubicin and Idarubicin use to treat
Same as Doxorubicin
What are Epirubicin & mitozantrone used to treat
Breast cancer
What is Daunorubicin used to treat
ALL and AML
What are the 4 mechanisms of Anthracyclines
1) Bind to DNA causing adducts
2) Intercalation with DNA between adjacent base-pairs blocking TOPO 2
3) Binds to cell membrane protein leading to altered transport functions
4)Produces redox species- A structure on the drug has a hydroquinone property.
>Produces Semi-Qunine in presence of NADPH
How does the 4th mechanism of the Anthracycline lead to Cardiotoxicity
The low levels of superoxide dismutase (which turn the semiquinone to Doxorubicin) leads to free radical build up.
What are the 4 mechanisms of Anthracyclines
1) Bind to DNA causing adducts
2) Intercalation with DNA between adjacent base-pairs blocking TOPO 2
3) Binds to cell membrane protein leading to altered transport functions
4)Produces redox species- A structure on the drug has a hydroquinone property.
>Produces Semi-Quinone in presence of NADPH
> Leads to cell rupture
What are some of the adverse effect of Anthracycline
Dose dependant irreversible Cardiotoxicity
Extravasation
Severe Alopecia
Transient bone marrow suppression
GI disturbances
What is Bleomycin
A mixture of different Metal chelating glycopeptides
Copper based
What is Bleomycin used for
> Testicular cancer - almost 100% effective in combo with cisplatin and vinblastin/etoposide
> Squamous cell carcinomas
> Lymphomas
What is the MOA of Blromycin
> The copper elements reacts with Fe2+ and creates a complex
> Creates free radical
> Leading to Strand break via adducting
> Cytotoxicity blocked progression
Are antimetabolites Cell cycle specific or non specific
Cell cycle specific
Characteristic of Antimetabolites
They are analogues of Natural substrates (looks like competitive antagonist)
General MOA of Antimetabolites
Affect the production of nucleotides needed to synthesis new DNA molecules
How do TOP2B inhibitor lead to heart failure
double-stranded DNA breaks accrue,
leading to events such as the activation of p53 tumor-suppressor protein, mitochondrial dysfunction, and the generation of ROS that result in cardiac cell death
How does Antimetabolites affect the new DNA
It is incorporated into the metabolic pathway and forms defective products
It mimics a feedback inhibitory action of a normal regulatory metabolite`
What are natural products that Antimetabolites mimic
Folic acid
Flurouricil
What is the importance of Folic acid
It is the precursors of Tetrahydrofolate(THFA): cofactor which acts as a coenzyme for carbohydrate donation.
Used to make purine and pyrimidine used to make Nucleotides and DNA
What class of drugs are antimetabolites
Antifolates
Name some Antifolates
Methotrexate
Raltitrexed (Tomudex)
Pemetrexed
Name the properties of methotrexate
> Very polar
> They enter cells by active transport
> Is kept in cells by polyglutamylation
Which enzyme does methotrexate work on
Dihydrofolate reductase (DHFR)
How much more affinity does Methotrexate in comparison to folic acid have to DHFR
1000x more
How does methotrexate indirectly inhibit folate dependant enzymes (THYMIDYLATE SYNTHASE)
> Accumlation of MTX polyglutamates
Accumulation of dihydrofolate polyglutamate
What is polyglutamylation
when a molecule enter the cell a glutamyl cell which maintains the concentration gradient.
What does thymidylate synthases do
Turns dUMP (deoxy-uridine monophosphates) to dTMP(deoxythymidine monophosphate )
Mode of action of methotrexate
Binds to the active side of DHFR in the cells and prevents the reduction of folate
What is leucovorin
Folinic acid which is used to donate methy groups to prevent or prevent side effects of methotrexate.
How does TOMUDEX differ to methotrexate
More specific to TS than DHFR
Which cancer is TOMUDEX used to treat
Advanced Colon cancer
Which other drugs can TOMUDEX be used with
irinotecan (Topo Inhibitor)
Oxaliplatin (cytotoxic)
Which enzyme systems does Pemetrexed (ALIMTA) work on
DHFR
TS
GARFT (Glycinamide ribonucleotide formyl transferase )
What is GARFT and what does it do?
It affects and prevents the production of pyrimidines
(Adenine and Guanine)
What are the 2 pyrimidine analogues
Fluorouracil
Fluorodeoxyuridine
Cy
How does fluorouracil work
Can be incorporated into the RNA via FUTP
OR
into the DNA
How can florouracil block TS
Flourouracil is turned into FUdR then into FdUMP
5-0FdUMP is an inhibitor of TS which is competitive with dUMP.
How does fluorouracil damage the DNA
It is turned into FdUTP which is very similar to Thymidine and so is incorporated into the DNA instead
Due to the missing methyl group in FdUTP, the correct hydrogen bonding is prevented weaking the DNA
How does FdUMP sustatin it’s inhibition
TS, FdUMP and an active folate cofactor covalently bind to form a complex
What is the primary action of Fluorouracil
Inhibition of TS
What is fluorouracil used to treat and why?
Colorectal cancer
It is a prodrug that is only activated in cells that have the enzyme to turn it into 5-FdUMP
This is highly expressed in the GI tract
What iS the metabolic profile of Fluorouracil
80-90% of it degraded by DPD
(dihydropyrimidine dehydrogenase)
10-20% of it is active
Why are some patients prone to more side effects
Because DPD is polymorphic.
What is the name of the pro-drug of Fluorouracil that is use to avoid reduce the side effects in patients.
Capecitabine (Xeloda)
How is Xeloda (drug name?) administered
orally
What enzyme metabolises Xeloda
thymidine phosphorylase to 5-FU
Name adrug that is administered with uracil and why
Tegafur- Encourages break down of uracil
Uracil inhibits 5-FU breakdown – higher target tissue concentration than with 5-FU alone
Name a cytidine analogue
Cytosine arabinoside
How does Cytosine arabinoside MOA
Blocks strand elongation and repair mechanisms due to steric hinderance
Inhibits reduction of CDP to dCDP
Name a drug that is a cytidine analogue
Gemcitabine (GEMZAR)
What cancers is GEMZAR (Brand name?) used to teat
Breast
Lung
Ovarian
Pancreatic
Name some purine (Guanine) antimetabolites
6-Mercaptopurine
6-Thioguanine
Hypoxanthine
What is 6-mercatopurine
Prodrug which can be converted to thioguanine
How does Thioguanine damage DNA
Because it has an S group as opposed to the OH in guanine
What is 6-mercaptopurine used for
For haematological tumours (PO)
Used for long term maintenance of ALL
What is 6-mecaptopurine made form
Azathioprine
How doe 6-Thiguanine work
Inhibits onward phosphorylation of GMP to GDP
False feedback to purine biosynthesis
