Antimetabolites

Question 1

3 types of antimetabolites

Answer 1

Folate analogs
Pyrimidine analogs
Purine analogs

Question 2

Folate analogs [drug names]

Answer 2

Methotrexate
Pemetrexed
Pralatrexate

Question 3

Pyrimidine analogs [drug names]

Answer 3

Fluorouracil
Capecitabine
Cytarabine
Gemcitabine

Question 4

Purine analogs [drug names]

Answer 4

Thioguanine 
Mercaptopurine 
Fludarabine 
Cladribine 
Pentostatin

Question 5

What form of folate is essential in humans?

Answer 5

Tetrahydrofolate

Question 6

Folate analogs [MOA]

Answer 6

inhibition of dihydrofolate reductase (DHFR is enzyme that turns folic acid to dihydrofolate and then to tetrahydrofolate)
inhibition of thymidylate synthase

Question 7

Folate analogs [PK]

Answer 7

Lipophobic –> will not cross BBB

Renally eliminated

Question 8

Folate analogs [DDIs]

Answer 8

anything that reduces renal blood flow – NSAIDs, nephrotoxic drugs, cisplatin

Question 9

Folate analogs [ADEs]

Answer 9

methotrexate – mucositis and myelosuppresion

pregnancy category X

Question 10

Folate analogs [Treating ADEs]

Answer 10

Folinic Acid [Leucovorin]
Fully reduced folate coenzyme; will decrease MOA so avoid if possible
Reverses myelosuppression & mucositis caused by methotrexate because substitutes for 5,10-methylene-THF

Question 11

Folate analogs [Mechanisms of Resistance]

Answer 11

SLC19A1 mutations [brings methotrexate INTO cell]
DHFR mutations [alters binding affinity of drug and increased expression of DHFR]
Folylpolyglutamate synthetase mutations
Increased expression of efflux transporters (ABCs)
Enhanced expression of thymidylate synthase

Question 12

Folate analogs [PGx]

Answer 12

SLC19A1 allows entrance of methotrexate INTO cell

Amplification = more drug to cell

Question 13

How many times are folate metabolites used to transfer methyl groups in nucleic acid synthesis?

Answer 13

purines: 2
pyrimidines: 1

Question 14

What is the result of polyglutamylation of methotrexate?

Answer 14

More like to stay INSIDE cell

More likely to inhibit thymidylate synthase

Question 15

Why is leucovorin used to treat methotrexate toxicity?

Answer 15

ENHANCES thymidylate synthase activity –> substitutes cofactor

Question 16

Pyrimidine Analogs [subcategories]

Answer 16

Thymidylate Analogs

Fluoropyrimidine Analogs

Question 17

Thymidylate analogs [MOA]

Answer 17

dUMP —> dTMP

enzyme: Thymidylate Synthase
cofactor: 5,10-methyl THF

donate methyl group from 5,10-methyl THF to dUMP to get dTMP

Question 18

Thymidylate analogs [drug names]

Answer 18

Capecitabine
5-Fluorouracil [5-FU]

**Capecitabine is a prodrug that is converted to 5-FU

Question 19

Fluoropyrimidine analogs [MOA]

Answer 19

Inhibition of thymidylate synthase
Inhibition of RNA processing
Incorporation into DNA (rare but still happens)

Question 20

Fluoropyrimidine analogs [PK]

Answer 20

give IV because these drugs are orally unpredictable

Question 21

Fluoropyrimidine analogs [Metabolism]

Answer 21

Metabolized by LIVER
Mediated by DPD (dihydropyrimidine dehydrogenase)
**MORE clearance = LESS adverse effects; inactive DPD–> MORE risk of adverse effects

Question 22

Fluoropyrimidine analogs [ADEs]

Answer 22

Capecitabine and 5-FU: myelosuppression, mucositis, hand & foot syndrome (swelling/pain)

5-FU only: diarrhea

Question 23

Fluoropyrimidine analogs [Mechanisms of Resistance]

Answer 23

Mutations in activating enzymes (b/c PRODRUGS)
Mutations in thymidylate synthase
Insufficient 5,10-methylenetetrahydrofolate (cofactor–> cannot form inhibitory complex; can add leucovorin to enhance 5-FU efficacy)

Question 24

Leucovorin

Answer 24

Folinic Acid
Will REVERSE methotrexate toxicity
Will ENHANCE fluoropyrimidine analog activity

Question 25

How does leucovorin enhance 5-FU activity?

Answer 25

Can substitute as 5,10-methylene-THF and act as a cofactor to form inhibitory complex if insufficient amount available

Question 26

Cytidine Analogs [drugs]

Answer 26

Cytarabine | Gemcitabine

Question 27

Cytarabine [MOA]

Answer 27

due to trans -OH substituted for cis form, competes with dCTP for incorporation and causes DNA polymerase to be unable to synthesize more DNA enters cell via hENT1 (nucleoside transporter) converted Ara-C to Ara-CMP by enzyme deoxycytidine kinase (CdK)

Question 28

Gemcitabine [MOA]

Answer 28

gemcitabine --> FdCMP via CdK FdCDP inhibits ribonucleotide reductase (RNR) FdCTP competes with dCTP for incorporation and stop DNA polymerase

Question 29

Cytidine analogs [PK]

Answer 29

GIVE IV --> cytidine deaminase is high in GI tract; this enzyme degrades the drug; will not work as well

Question 30

Cytidine analogs [ADEs]

Answer 30

Cytarabine and Gemcitabine: myelosuppression Cytarabine ONLY: mucositis, hand & foot syndrome, visual disturbances

Question 31

Cytidine analogs [Mechanisms of Resistance]

Answer 31

Loss of function deoxycytidine kinase (CdK) Increased expression of cytidine deaminase or dCMP deaminase (metabolizes to non-toxic metabolites/degrades drug) Mutations in hENT1 (helps drug enter cell )

Question 32

Which folate metabolite is responsible for transfer of methyl group resulting in dUMP ---> dTMP

Answer 32

5,10-methylene THF

Question 33

Purine analogs [drug names]

Answer 33

Thioguanine Mercaptopurine Fludarabine Cladribine

Question 34

Thioguanine [MOA]

Answer 34

thioguanine --> 6-thioGMP via hypoxanthine guanine phosphoribosyl transferase (HGPRT) which inhibits IMP dehydrogenase, which is the RLS of GTP synthesis--> loss of GTP pools, causing DNA damage

Question 35

Mercaptopurine [MOA]

Answer 35

marcaptopurine --> 6-thioIMP via HGPRT, which inhibits PRPP glutamyl amidotransferase de novo purine synthesis; deplete ALL purine pools

Question 36

Thiopurine methyltransferase (TPMT) and thiopurines

Answer 36

TPMT is the inactivating enzyme -- low [TPMT] = high [drug] = increased ADE

Question 37

6-thiopurines [Mechanisms of Resistance]

Answer 37

Loss of HGPRT function Decreased drug uptake or increased efflux Impaired recognition of DNA breaks Impaired mismatch repair machinery

Question 38

Adenine analogs [drug names]

Answer 38

Cladribine | Fludarabine

Question 39

Fludarabine [MOA]

Answer 39

needs to be dephosphorylated to get INTO cell and then phosphorylated again once inside inhibit DNA polymerase, DNA primase, DNA ligase and RNR

Question 40

Cladribine [MOA]

Answer 40

inhibition of RNR | incorporation into DNA --> strand breaks

Question 41

Adenosine Deaminase

Answer 41

Fludarabine and Cladribine are resistant to adenosine deaminase metabolism due to Cl and F groups on purine ring