Cancer Part 4- 4 slide left but I gave up

Question 1

what is cisplatin?

Answer 1

Anticancer drug that is made up of platinum and chlorine ions.

Question 2

What is the moa of cisplatin?

Answer 2

> 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.

Question 3

How does the cisplatin interact with the DNA?

Answer 3

Cisplatin acts as an adduct on the DNA chain allowing the HMG domain to wrap around the chain bending it out of shape.

Question 4

What are some of the uses of cisplatin?

Answer 4

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

Question 5

What happens to the DNA when cisplatin binds

Answer 5

Intra-strand Breaks

Inter-strand Breaks

Question 6

How is the nephrotoxicity of Cisplatin mitigated

Answer 6

Fractionate the dose: 5X iv instead of IV bolus

Pre-treat to forced diuresis

Regular testing: Renal and Auditory

Question 7

What s another new gen metal based cytotoxic compound

Answer 7

Carboplatin

Oxaplatin

Question 8

Carboplatin vs Cisplatin

Answer 8

Carboplatin has improved toxicity profile
-Reduced nephrotoxicity ,
-No forced Diuresis
-Pt return home sooner
-Myelotoxicity is dose limiting

Question 9

Are Antitumour antibodies cell cycle non specific or cell cycle specific

Answer 9

Cell cycle non specific

Question 10

Name the drugs and Drug classes fall under Anti-tumour antibodies

Answer 10

Anthracyclines

Actinomycin-D

Bleomycin

Question 11

Give examples of Anthracycline

Answer 11

Doxorubicin

Aclarubicin

Idarubicin

Epirubicin

mitozantrone

Daunorubicin

Question 12

What is Doxorubicin used for

Answer 12

cancer drug for sarcomas, breast, lung, ALL and lymphomas

Question 13

What is Aclarubicin and Idarubicin use to treat

Answer 13

Same as Doxorubicin

Question 14

What are Epirubicin & mitozantrone used to treat

Answer 14

Breast cancer

Question 15

What is Daunorubicin used to treat

Answer 15

ALL and AML

Question 16

What are the 4 mechanisms of Anthracyclines

Answer 16

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

Question 17

How does the 4th mechanism of the Anthracycline lead to Cardiotoxicity

Answer 17

The low levels of superoxide dismutase (which turn the semiquinone to Doxorubicin) leads to free radical build up.

Question 18

What are the 4 mechanisms of Anthracyclines

Answer 18

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

Question 19

What are some of the adverse effect of Anthracycline

Answer 19

Dose dependant irreversible Cardiotoxicity

Extravasation

Severe Alopecia

Transient bone marrow suppression

GI disturbances

Question 20

What is Bleomycin

Answer 20

A mixture of different Metal chelating glycopeptides

Copper based

Question 21

What is Bleomycin used for

Answer 21

> Testicular cancer - almost 100% effective in combo with cisplatin and vinblastin/etoposide

> Squamous cell carcinomas

> Lymphomas

Question 22

What is the MOA of Blromycin

Answer 22

> The copper elements reacts with Fe2+ and creates a complex

> Creates free radical

> Leading to Strand break via adducting

> Cytotoxicity blocked progression

Question 23

Are antimetabolites Cell cycle specific or non specific

Answer 23

Cell cycle specific

Question 24

Characteristic of Antimetabolites

Answer 24

They are analogues of Natural substrates (looks like competitive antagonist)

Question 25

General MOA of Antimetabolites

Answer 25

Affect the production of nucleotides needed to synthesis new DNA molecules

Question 26

How do TOP2B inhibitor lead to heart failure

Answer 26

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

Question 26

How does Antimetabolites affect the new DNA

Answer 26

It is incorporated into the metabolic pathway and forms defective products It mimics a feedback inhibitory action of a normal regulatory metabolite`

Question 27

What are natural products that Antimetabolites mimic

Answer 27

Folic acid Flurouricil

Question 28

What is the importance of Folic acid

Answer 28

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

Question 29

What class of drugs are antimetabolites

Answer 29

Antifolates

Question 30

Name some Antifolates

Answer 30

Methotrexate Raltitrexed (Tomudex) Pemetrexed

Question 31

Name the properties of methotrexate

Answer 31

>Very polar >They enter cells by active transport >Is kept in cells by polyglutamylation

Question 32

Which enzyme does methotrexate work on

Answer 32

Dihydrofolate reductase (DHFR)

Question 33

How much more affinity does Methotrexate in comparison to folic acid have to DHFR

Answer 33

1000x more

Question 34

How does methotrexate indirectly inhibit folate dependant enzymes (THYMIDYLATE SYNTHASE)

Answer 34

> Accumlation of MTX polyglutamates >Accumulation of dihydrofolate polyglutamate

Question 35

What is polyglutamylation

Answer 35

when a molecule enter the cell a glutamyl cell which maintains the concentration gradient.

Question 36

What does thymidylate synthases do

Answer 36

Turns dUMP (deoxy-uridine monophosphates) to dTMP(deoxythymidine monophosphate )

Question 37

Mode of action of methotrexate

Answer 37

Binds to the active side of DHFR in the cells and prevents the reduction of folate

Question 38

What is leucovorin

Answer 38

Folinic acid which is used to donate methy groups to prevent or prevent side effects of methotrexate.

Question 39

How does TOMUDEX differ to methotrexate

Answer 39

More specific to TS than DHFR

Question 40

Which cancer is TOMUDEX used to treat

Answer 40

Advanced Colon cancer

Question 41

Which other drugs can TOMUDEX be used with

Answer 41

irinotecan (Topo Inhibitor) Oxaliplatin (cytotoxic)

Question 42

Which enzyme systems does Pemetrexed (ALIMTA) work on

Answer 42

DHFR TS GARFT (Glycinamide ribonucleotide formyl transferase )

Question 43

What is GARFT and what does it do?

Answer 43

It affects and prevents the production of pyrimidines (Adenine and Guanine)

Question 44

What are the 2 pyrimidine analogues

Answer 44

Fluorouracil Fluorodeoxyuridine Cy

Question 45

How does fluorouracil work

Answer 45

Can be incorporated into the RNA via FUTP OR into the DNA

Question 46

How can florouracil block TS

Answer 46

Flourouracil is turned into FUdR then into FdUMP 5-0FdUMP is an inhibitor of TS which is competitive with dUMP.

Question 47

How does fluorouracil damage the DNA

Answer 47

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

Question 48

How does FdUMP sustatin it's inhibition

Answer 48

TS, FdUMP and an active folate cofactor covalently bind to form a complex

Question 49

What is the primary action of Fluorouracil

Answer 49

Inhibition of TS

Question 50

What is fluorouracil used to treat and why?

Answer 50

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

Question 51

What iS the metabolic profile of Fluorouracil

Answer 51

80-90% of it degraded by DPD (dihydropyrimidine dehydrogenase) 10-20% of it is active

Question 52

Why are some patients prone to more side effects

Answer 52

Because DPD is polymorphic.

Question 53

What is the name of the pro-drug of Fluorouracil that is use to avoid reduce the side effects in patients.

Answer 53

Capecitabine (Xeloda)

Question 54

How is Xeloda (drug name?) administered

Answer 54

orally

Question 55

What enzyme metabolises Xeloda

Answer 55

thymidine phosphorylase to 5-FU

Question 56

Name adrug that is administered with uracil and why

Answer 56

Tegafur- Encourages break down of uracil Uracil inhibits 5-FU breakdown – higher target tissue concentration than with 5-FU alone

Question 57

Name a cytidine analogue

Answer 57

Cytosine arabinoside

Question 58

How does Cytosine arabinoside MOA

Answer 58

Blocks strand elongation and repair mechanisms due to steric hinderance Inhibits reduction of CDP to dCDP

Question 59

Name a drug that is a cytidine analogue

Answer 59

Gemcitabine (GEMZAR)

Question 60

What cancers is GEMZAR (Brand name?) used to teat

Answer 60

Breast Lung Ovarian Pancreatic

Question 61

Name some purine (Guanine) antimetabolites

Answer 61

6-Mercaptopurine 6-Thioguanine Hypoxanthine

Question 62

What is 6-mercatopurine

Answer 62

Prodrug which can be converted to thioguanine

Question 63

How does Thioguanine damage DNA

Answer 63

Because it has an S group as opposed to the OH in guanine

Question 64

What is 6-mercaptopurine used for

Answer 64

For haematological tumours (PO) Used for long term maintenance of ALL

Question 65

What is 6-mecaptopurine made form

Answer 65

Azathioprine

Question 66

How doe 6-Thiguanine work

Answer 66

Inhibits onward phosphorylation of GMP to GDP False feedback to purine biosynthesis