Antimetabolites (MC) - Block 4

Question 1

What is the general MOA of antimetabolites?

Answer 1

Stop de novo synthesis of DNA by inhibiting formation of nucleotides:
1. Inhibit enzymes or promote incorporation of false nucleotides into DNA strands

Question 2

What are false substrates?

Answer 2

Looks like endogenous substrates
* If cell can’t synthesize nucleotides -> DNA synthesis and tumor growth is stopped

Question 3

What phase of mitosis do antimetabolites target?

Answer 3

S phase

Question 4

What is the natural ligand targeted by pyrimidine antagonist?

Answer 4

dUMP: drug blocks formation of dTMP

Question 5

Describe the MOA of dTMP synthesis?

Answer 5

dUMP is attacked by thymidylate synthase
* Cofactor (THF) removes hydrogen from 5th position

Question 6

Describe the activity of fluorouracil?

Answer 6

5-Fluorinated dUMP (replaced H with F) -> 5-F-dUMP
* C6 postion more electrophilic (F is EWG) -> Cys195 attacks very fast -> C5-H can’t be removed because it is absent
* THF and drug are permanently bound together (irreversible inhibitor)

Question 7

How is fluorouracil inactivated?

Answer 7

DPD (deficiency leads to toxicity)

Question 8

Describe the formulation/PK of fluorouracil?

Answer 8

Prodrug that gets activated by the addition of a sugar and phosphate (5-F-dUMP)

Question 9

Describe the mechanism and metabolism of capecitabine?

Answer 9

Carbamylated cytidine analog but also a 5-F-dUMP prodrug:
* Metabolized to fluorouracil than 5-F-dUMP
* Thymidine phophorylase is more active in tumors -> tumor selective generation of fluorouracil -> less side effect (hand foot syndrome and diarrhea)

7 steps to get activated

Question 10

Formulation of capecitabine?

Answer 10

PO

Question 11

Metabolism/DDI s of capecitabine?

Answer 11

InhibitionCYP2C0 and competes for albumin binding
* DDI with warfarin and pheyntoin

Question 12

What are the methods of inactivating dTMP?

Answer 12

1. Pyrimidine analogs
2. Antifolates

Question 13

MOA of methotrexate?

Answer 13

Completes witth 7,8-DHF for DHFR:
* Amine at N4 -> N1 is more basic -> misorients in proteins -> pseudoirrevesibly bound
* Inhibits THF from forming dTMP

Question 14

What makes methotrexate tumor selective?

Answer 14

Gets polyglutamated by FPGS which traps it at site of action (because of negative charges) -> more efficient in tumor cells due to the entrappment of glutamates

Question 15

ADRs of methotrexate? How is toxicity treated?

Answer 15

Lung disease and fatal skin reactions:
* Can give leucovorin to replace folates

Question 16

Describe the imporvements of pemetrexed compared to methotrexate?

Answer 16

Targeting higher affintiy for FPGS -> more polyglutamed drug gets generated and trapped
* mono and polyglutamed can all inhibti enzyme

Question 17

COunseling when administering pemetrexed?

Answer 17

• Take foic acid and vitamin B12 to reduce bone marrow suppression
• Pretreat with corticosteroids (rash) and antiemetics

Question 18

Describe the MOA purine antagonist?

Answer 18

Inhibit de novo biosynthesis of AMP and GMP through inactivation of amidophosphoribosyl transferase

Question 19

Describe the activation of purine antagonist?

Answer 19

Prodrugs that need to be converted to nucleotides through the addition of a phosphate and sugar

Question 20

What are complications associated with purine antagonists?

Answer 20

Thiopurines are inactivated by TPMT:
* TPMT forms more active metabolite from active thiopurine ribonucleotide (more for mercaptopurine than thioguanine)
* Poor TPMT metabolizers -> no inactivation of prodrug -> more active drug (dose must be decreased)
* Extensive TMPT metabolizers for mercaptopurine will have more highly active metabolite -> drug sensitivity

Question 21

How is the unique structure of mercaptopurine?

Answer 21

6-thio analog of purine

Question 22

What are the major use-limiting toxicity of mercaptopurine?

Answer 22

Bone marrow suppression
Hepatotox in high doses

Question 23

What is the structure and main structure of thioguanine?

Answer 23

6-thio analog of guanine
MOA: incorporation of di and triphosphate deoxy and ribonucleotides into DNA and RNA -> stops further elongation

Question 24

What is the major use-limiting side effect of DNA Polymerase/DNA Chain Elongation Inhibitors?

Answer 24

Myelosuppression

Question 25

Describe the structural similarities of DNA Polymerase/DNA Chain Elongation Inhibitors?

Answer 25

Halogenated and/or ribose-modified DNA nucleoside analogs/prodrugs that gets converted into triphosphate nucleotides
* Drugs based off DNA/RNA bases need to be nucleotides to be active otherwise they are prodrugs

Question 27

What is the nucliec acid base of cytarabine and gemcitabine?

Answer 27

Cytidine (pyrimidine)

Question 28

Elimination properties of gemcitabine?

Answer 28

Sex-dependent
* Women have greater risk for tox due to lower renal clearance

Question 29

General structure of Cytarabine and Gemcitabine?

Answer 29

Missing triphosphate

Question 30

What is the nucleic acid base of fludarabine?

Answer 30

Adenosine (Purine)
* Contains a phosphate group

Question 31

What structure prevents some metabolism of fludarabine?

Answer 31

2-halogen

Question 32

Why is fludarabine a monophosphate nucleotide?

Answer 32

Enhanced water solubility for IV but rapidly cleaved in bloodstream -> uses normal transport proteins

Question 33

ADRs of fludarabine?

Answer 33

1. Hemolytic anemia
2. High doses -> CNS tox
3. Potent immunosuppressant -> opportunisitc infection (for PCP prophylaxisis: Bactrim for 1 yr)

Question 34

What is the MOA of pentostatin?

Answer 34

Ring-expanded purine ribonucleoside -> inhibits adenosine deaminase by elevating deoxyadenosine triphosphate levels -> inhibiting ribonucleotide reductase -> halting DNA synthesis

Question 35

What is the MOA of hydroxyurea?

Answer 35

Blocks DNA synthesis by trapping tyrosyl free radicals at catalytic site of ribonucleotide reductase

Question 36

Benefits and ADRs of hydroxyurea?

Answer 36

Increases effectiveness of radiation therapy (selective tox to cells in radiation-resistant S phase and stalls G1 stage, not achieved by radiation)

ADR: mild toxicities indefinitely