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Cancer > Cancer Part 4- 4 slide left but I gave up > Flashcards

Cancer Part 4- 4 slide left but I gave up Flashcards

1
Q

what is cisplatin?

A

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

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2
Q

What is the moa of cisplatin?

A

> 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.

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3
Q

How does the cisplatin interact with the DNA?

A

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

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4
Q

What are some of the uses of cisplatin?

A

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

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5
Q

What happens to the DNA when cisplatin binds

A

Intra-strand Breaks

Inter-strand Breaks

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6
Q

How is the nephrotoxicity of Cisplatin mitigated

A

Fractionate the dose: 5X iv instead of IV bolus

Pre-treat to forced diuresis

Regular testing: Renal and Auditory

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7
Q

What s another new gen metal based cytotoxic compound

A

Carboplatin

Oxaplatin

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8
Q

Carboplatin vs Cisplatin

A

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

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9
Q

Are Antitumour antibodies cell cycle non specific or cell cycle specific

A

Cell cycle non specific

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10
Q

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

A

Anthracyclines

Actinomycin-D

Bleomycin

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11
Q

Give examples of Anthracycline

A

Doxorubicin

Aclarubicin

Idarubicin

Epirubicin

mitozantrone

Daunorubicin

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12
Q

What is Doxorubicin used for

A

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

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13
Q

What is Aclarubicin and Idarubicin use to treat

A

Same as Doxorubicin

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14
Q

What are Epirubicin & mitozantrone used to treat

A

Breast cancer

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15
Q

What is Daunorubicin used to treat

A

ALL and AML

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16
Q

What are the 4 mechanisms of Anthracyclines

A

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

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17
Q

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

A

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

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18
Q

What are the 4 mechanisms of Anthracyclines

A

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

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19
Q

What are some of the adverse effect of Anthracycline

A

Dose dependant irreversible Cardiotoxicity

Extravasation

Severe Alopecia

Transient bone marrow suppression

GI disturbances

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20
Q

What is Bleomycin

A

A mixture of different Metal chelating glycopeptides

Copper based

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21
Q

What is Bleomycin used for

A

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

> Squamous cell carcinomas

> Lymphomas

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22
Q

What is the MOA of Blromycin

A

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

> Creates free radical

> Leading to Strand break via adducting

> Cytotoxicity blocked progression

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23
Q

Are antimetabolites Cell cycle specific or non specific

A

Cell cycle specific

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24
Q

Characteristic of Antimetabolites

A

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

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25
Q

General MOA of Antimetabolites

A

Affect the production of nucleotides needed to synthesis new DNA molecules

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26
Q

How do TOP2B inhibitor lead to heart failure

A

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

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26
Q

How does Antimetabolites affect the new DNA

A

It is incorporated into the metabolic pathway and forms defective products

It mimics a feedback inhibitory action of a normal regulatory metabolite`

27
Q

What are natural products that Antimetabolites mimic

A

Folic acid
Flurouricil

28
Q

What is the importance of Folic acid

A

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

29
Q

What class of drugs are antimetabolites

A

Antifolates

30
Q

Name some Antifolates

A

Methotrexate

Raltitrexed (Tomudex)

Pemetrexed

31
Q

Name the properties of methotrexate

A

> Very polar

> They enter cells by active transport

> Is kept in cells by polyglutamylation

32
Q

Which enzyme does methotrexate work on

A

Dihydrofolate reductase (DHFR)

33
Q

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

A

1000x more

34
Q

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

A

> Accumlation of MTX polyglutamates
Accumulation of dihydrofolate polyglutamate

35
Q

What is polyglutamylation

A

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

36
Q

What does thymidylate synthases do

A

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

37
Q

Mode of action of methotrexate

A

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

38
Q

What is leucovorin

A

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

39
Q

How does TOMUDEX differ to methotrexate

A

More specific to TS than DHFR

40
Q

Which cancer is TOMUDEX used to treat

A

Advanced Colon cancer

41
Q

Which other drugs can TOMUDEX be used with

A

irinotecan (Topo Inhibitor)

Oxaliplatin (cytotoxic)

42
Q

Which enzyme systems does Pemetrexed (ALIMTA) work on

A

DHFR

TS

GARFT (Glycinamide ribonucleotide formyl transferase )

43
Q

What is GARFT and what does it do?

A

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

44
Q

What are the 2 pyrimidine analogues

A

Fluorouracil

Fluorodeoxyuridine

Cy

45
Q

How does fluorouracil work

A

Can be incorporated into the RNA via FUTP

OR

into the DNA

46
Q

How can florouracil block TS

A

Flourouracil is turned into FUdR then into FdUMP

5-0FdUMP is an inhibitor of TS which is competitive with dUMP.

47
Q

How does fluorouracil damage the DNA

A

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

48
Q

How does FdUMP sustatin it’s inhibition

A

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

49
Q

What is the primary action of Fluorouracil

A

Inhibition of TS

50
Q

What is fluorouracil used to treat and why?

A

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

51
Q

What iS the metabolic profile of Fluorouracil

A

80-90% of it degraded by DPD
(dihydropyrimidine dehydrogenase)

10-20% of it is active

52
Q

Why are some patients prone to more side effects

A

Because DPD is polymorphic.

53
Q

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

A

Capecitabine (Xeloda)

54
Q

How is Xeloda (drug name?) administered

A

orally

55
Q

What enzyme metabolises Xeloda

A

thymidine phosphorylase to 5-FU

56
Q

Name adrug that is administered with uracil and why

A

Tegafur- Encourages break down of uracil

Uracil inhibits 5-FU breakdown – higher target tissue concentration than with 5-FU alone

57
Q

Name a cytidine analogue

A

Cytosine arabinoside

58
Q

How does Cytosine arabinoside MOA

A

Blocks strand elongation and repair mechanisms due to steric hinderance

Inhibits reduction of CDP to dCDP

59
Q

Name a drug that is a cytidine analogue

A

Gemcitabine (GEMZAR)

60
Q

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

A

Breast

Lung

Ovarian

Pancreatic

61
Q

Name some purine (Guanine) antimetabolites

A

6-Mercaptopurine

6-Thioguanine

Hypoxanthine

62
Q

What is 6-mercatopurine

A

Prodrug which can be converted to thioguanine

63
Q

How does Thioguanine damage DNA

A

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

64
Q

What is 6-mercaptopurine used for

A

For haematological tumours (PO)

Used for long term maintenance of ALL

65
Q

What is 6-mecaptopurine made form

A

Azathioprine

66
Q

How doe 6-Thiguanine work

A

Inhibits onward phosphorylation of GMP to GDP

False feedback to purine biosynthesis

Cancer (18 decks)

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