Anti-Metabolites Lapinsky

Question 1

What type of drugs are the anti metabolites?

Answer 1

CCS drugs (S Phase)

Question 2

What is the rate limiting step in overall DNA synthesis?

Answer 2

Thymidylate Synthase

Question 3

What enzyme does methotrexate inhibit?

Answer 3

DHFR

Question 4

What is the active metabolite of 5-FU?

Answer 4

5F-dUMP

Question 5

What does 5F-dUMP function as?

Answer 5

Irreversible, covalent inhibitor of Thymidylate Synthase

Question 6

Why can’t cancer cells tell the difference between dUMP and 5-FdUMP?

Answer 6

The size of F and H are roughly the same

Question 7

The bond strength of C5-F is __C5-H

Answer 7

> >

Question 8

What does the natural mechanism of Thymidylate synthase involve?

Answer 8

Enzyme breaking the C5-H bond

Question 9

What bond can Thymidylate synthase (TS) not break?

Answer 9

C5-F

Question 10

When should you give leucovorin with 5-FU?

Answer 10

Give 60 mins before 5-FU

Question 11

What is the cofactor needed for TS to work?

Answer 11

Business folate (5,10-CH2THF)

Question 12

What is leucovorin a precursor of?

Answer 12

Business folate

Question 13

What is needed for TS and 5-FdUMP to work?

Answer 13

Business folate

Question 14

5-FU drug action= cancer cells are said to die a “__________”

Answer 14

Thymine-less death

Question 15

How is capecitabine taken?

Answer 15

Orally

Question 16

How is Floxuridine and 5-Fluorouracil taken?

Answer 16

By injection

Question 17

True or false: normal healthy cells have more thymidine phosphorylase than cancer cells

Answer 17

False

Question 18

What does capecitabine display better than floxuridine and 5-fluorouracil?

Answer 18

Selective toxicity

Question 19

What enzyme is responsible for carrying out the natural detoxifying metabolite of fluoro-pyrimidine?

Answer 19

DihydroPyrimidine Dehydrogenase (DPD)

Question 20

What gene codes for DPD?

Answer 20

DPYD

Question 21

What can patients experience if they don’t have the DPYD gene?

Answer 21

5-FdUMP mediated toxicity (myelosuppression)

Question 22

What does methotrexate antagonize or block the actions of?

Answer 22

Folic acid (folate)

Question 23

Folic acid derivatives are generally used in what kind of reactions?

Answer 23

One carbon transfer reactions

Question 24

What is folic acids primary function in the body?

Answer 24

Acts as a cofactor for enzymes that catalyze one carbon transfer reactions

Question 25

What 2 amino acids can act as anti-folates and inhibit protein and enzyme synthesis?

Answer 25

1. Serine 2. Methionine

Question 26

What 2 things can act as anti-folates and inhibit DNA and RNA synthesis and repair?

Answer 26

1. Thymidine 2. Purines (A,G)

Question 27

The anti folates work by targeting and inhibiting what enzyme?

Answer 27

DHFR (dihydrofolate reductase)

Question 28

Anti folates are cytotoxic during what phase?

Answer 28

S phase (DNA and RNA synthesis)

Question 29

What can leucovorin also be referred to as?

Answer 29

Folinic acid

Question 30

True or False: Leucovorin can go to a business folate only if DHFR is intact

Answer 30

False

Question 31

Methotrexate binds to DHFR _____ times stronger than the natural substrates folic acid and dihydrofolate

Answer 31

1,000

Question 32

What 3 things is DHFR involved in the synthesis of?

Answer 32

1. dTMP 2. Purines and pyrimidines 3. Select amino acids

Question 33

High dose methotrexate therapy is traditionally followed by what?

Answer 33

Leucovorin rescue

Question 34

What does leucovorin get directly converted to?

Answer 34

Tetrahydrofolate (THF)

Question 35

Methotrexate kills via what theory?

Answer 35

Rate theory

Question 36

True or false: leucovorin does not show selectivity in its “rescue” properties

Answer 36

True

Question 37

What cannot be used as rescue therapy after high dose methotrexate treatment?

Answer 37

Folic acid

Question 38

What can be used in accidental cases of methotrexate overdoses?

Answer 38

Leucovorin

Question 39

The more biologically active enantiomer of leucovorin

Answer 39

Levoleucovorin

Question 40

True or false: methotrexate doses used for treating cancer are much lower than those used for RA or psoriasis

Answer 40

False

Question 41

What is the frequency of MTX doses for treating RA or psoriasis given?

Answer 41

Weekly

Question 42

How is MTX given in order to treat cancer?

Answer 42

Intrathecally

Question 43

What formulation should you use when administering MTX?

Answer 43

Preservative free

Question 44

What are two ADRs for MTX?

Answer 44

1. Nephrotoxicity 2. Crystalluria

Question 45

Where are high dose anti folates generally cleared?

Answer 45

In the kidneys

Question 46

What 2 things must be given to patients that are on high dose MTX therapy?

Answer 46

1. Hydration 2. IV sodium bicarbonate

Question 47

The unionized form of MTX has a ___ H2O solubility

Answer 47

Decrease

Question 48

The unionized form of MTX has a ___ risk for MTX crystalluria

Answer 48

Increased

Question 49

The ionized form of MTX has a ___ H2O solubility

Answer 49

Increased

Question 50

The ionized form of MTX has a ___ risk for MTX crystalluria

Answer 50

Decreased

Question 51

What is the MTX antidote last resort?

Answer 51

Glucarpidase

Question 52

Glucarpidase

Answer 52

VORAXAZE

Question 53

How is Voraxaze cleared?

Answer 53

By the liver

Question 54

What is the disadvantage to VORAXAZE?

Answer 54

Expensive

Question 55

What are 5 drug interactions associated with high dose methotrexate?

Answer 55

1. High dose Salicylate NSAIDs 2. PPIs 3. Sulfonamides 4. Beta lactam antibiotics 5. Probenacid

Question 56

Organic acids can compete with MTX in the kidney for what?

Answer 56

Organic Acid Transporter Proteins (OATs)

Question 57

What can the organic acid drugs do to the clearance of MTX?

Answer 57

Decrease the renal clearance of MTX and increase MTX nephrotoxicity

Question 58

What drug is clinically indicated for the treatment of mesothelioma?

Answer 58

Pemetrexed

Question 59

What 3 enzymes does pemetrexed inhibit?

Answer 59

1. TS 2. DHFR 3. Garftase

Question 60

What 2 things should be supplemented with pemetrexed?

Answer 60

1. Vitamin b12 2. Folic acid

Question 61

What should be given in the day prior, the day of, and the day after the use of pemetrexed?

Answer 61

Dexamethasone

Question 62

Pemetrexed

Answer 62

Alimta

Question 63

What drug is traditionally the top selling anti-folate?

Answer 63

Pemetrexed