Lecture 4 Antimetabolites

Question 1

pyrimidines

Answer 1

cytosine
thymine
uracil

Question 2

purines

Answer 2

adenine

guanine

Question 3

nucleosides

Answer 3

ribose = RNA
deoxyribose = DNA
purines change to -osine: adenosine, guanosine
pyrimidines change to - idine: uridine, thymidine, and cytidine

Question 4

AMP

Answer 4

adenosine monophosphate

Question 5

CDP

Answer 5

cytidine diphosphate

Question 6

dGTP

Answer 6

deoxy-guanosine triphosphate

Question 7

dTTP

Answer 7

deoxy-thymidine triphosphate

Question 8

cAMP

Answer 8

3-5 cyclic adenosine monophosphate

Question 9

nucleotides

Answer 9

adding one or more phosphates to the sugar portion of a nucleoside results in a nucleotide

Question 10

antimetabolite

Answer 10

similar in structure to native molecules required for normal biochemical rxns, yet slightly different to interfere with normal function of cells

Question 11

antimetabolites are analogues of

Answer 11

vitamins –> coenzymes

nitrogenous bases, nucleosides, adn nucleotides

Question 12

antimetabolite general MOA

Answer 12

1. interfere with production of nucleic acids by:
   - inhibiting key enzymes for nucleotide synthesis
   - substituting normal purines or pyrimidines
2. antimetabolites inhibit DNA and RNA synthesis
3. antimetabolites inhibit cell growth and proliferation
   - usually cell-cycle S phase dependent

Question 13

antimetabolite examples

Answer 13

folate antagonists
pyrimidine antagonists
purine antagonists

Question 14

Folate antagonists

Answer 14

antifolate
methotrexate (MTX, Trexall)
pemetrexed (Alimta)

Question 15

Folic acid

Answer 15

B9

essential for cell growth and fetal development -> low folic acid can lead to neural tube defects

Question 16

What is folic acid reduced to

Answer 16

tetrahydrofolate (FH4 active) by
dihydrofolate reductase (DHFR)

Question 17

What is FH4

Answer 17

coenzyme for the biosynthesis of purines and in the conversion od dUMP to dTMP

Question 18

Methotrexate

Answer 18

MTX, analogue of folic acid
most widely used antifolate in cancer chemotx
activity against wide range of malignancies, including solid tumors and hematologic

Question 19

What does MTX inhibit

Answer 19

dihydrofolate reductase (DHFR) -> prevents synthesis of FH4 -> crucial enzyme required for DNA synthesis and therefore exerts its effect on the S phase of the cell cycle.

Question 20

What reverses methotrexate

Answer 20

leucovorin (reduced folate)

cells during S phase most sensitive

Question 21

MOA of 5-fluorouracil (5-FU)

Answer 21

1. 5-FU is ribosylated and phosphorylated -> nucleotide analogs
2. 5-FUTP (instead of UTP) is incorportated into RNA -> inhibition of RNA processing
3. 5-FdUMP inhibits irreversibly thymidylated syntase -> decrease dTMP -> decrease DNA synthesis

Question 22

Combo leucovorin with 5-FU

Answer 22

• FH4 acts as a coenzyme for TS. In the presence of the fake substrate, it won’t work
• when given with 5-FU or capecitabine, it allows 5-FU to form a more stable bond to TS
• inhibition of TS in enhanced
  cytotoxic effects of 5-FU are enhanced
• Leucovorin allows TS To bind more tightly so when the TS binds 5-FU active metabolite, it allows the 5-FU to be more strongly inhibitory

Question 23

What is TS

Answer 23

Thymidylate synthetase

Question 24

MOA of 5-FU

Answer 24

LEUCOVORIN IS COENZYME TO TS -> BINDS AND ENHANCES BINDING TO 5-FU -> 5-FU WE WANT TO BIND TO MAKE TS STOP MAKING DNA SYNTHESIS (BLOCKS ENZYME LONGER) -> NO LONGER MAKING dTMP, SO NO DNA SYNTHESIS

Question 25

MOA of capecitabine/Xeloda

Answer 25

can be taken orally unlike 5-FU taken as 5-FU + X + Y metabolized to 5-FU-X in liver, then metabolized in tumor tissue to 5-FU highly selective analog

Question 26

Cytarabine

Answer 26

analog of cytidine or deoxycytidine (nucleoside analogues)

Question 27

Structure of cytarabine

Answer 27

``` AraC (cytarabine arabinoside) difference in sugar only for leukemias and lymphomas effective when combined with idareubicin cell cycle S phase specific ```

Question 28

Cytarabine MOA

Answer 28

active metabolite at triphosphate stage --> AraCTP 1. AraCTP is incorporated into DNA and RNA -> inhibits chain elongation and ligation 2. AraCTP is a competitive inhibitor of DNA polymerase -> reduce DNA synthesis

Question 29

Gemcitabine

Answer 29

analog of cytidine or deoxycytidine | Nucleoside analog

Question 30

Gemcitabine application

Answer 30

- structurally similar to cytarabine - Wider anti-tumor activity - S and G1/S cell cycle phase specific

Question 31

Gemcitabine MOA

Answer 31

- Gemcitabine is phosphorylated to gemcitbine di (dDdCPD) and tri (dFdCTP) phosphate 1. dFdCDP inhibits the ribonucleotide reductase -> decreases dCTP pool -> reduces DNA synthesis 2. dFdCTP inhibits DNA polymerase -> decrease DNA synthesis and induces apoptosis 3. dFdCTP is incorporated into DNA -> inhibits chain elongation and ligation

Question 32

substrates of ribonucleotide reductase

Answer 32

diphosphate forms: ADP, GDP, UDP, and CDP

Question 33

Toxicity of pyrimidine antagonist

Answer 33

5-FU: N/V, oral and GI ulceration, bone marrow depression capecitabine: myelosupression, N/V (less than 5_FU) Cytarabine: N/V, bone marrow depression, megaloblastosis, leukopenia thrombocytopenia Gemcitabine

Question 34

Purine Antagonists

Answer 34

6-thioguanine 6-mercaptopurine fludarabine phosphate

Question 35

MOA purine analogs

Answer 35

After ribosylation and phosphorylation  DNA incorporation. DNA incorporation  inhibition of DNA synthesis.

Question 36

MOA 6-TG and 6-MP

Answer 36

6-Thioguanine and 6-Mercaptopurine are analogs of Guanine (=O  -SH). For childhood acute leukemias. Triphosphate nucleotides formed from 6-MP and 6-TG  DNA incorporation  inhibition of DNA synthesis.

Question 37

Fludarabine phosphate

Answer 37

nucleotide analog

Question 38

MOA fludarabine

Answer 38

- Fludarabine phosphate is first dephosphorylated (extracellular). - The intermediate is then phosphorylated (intracelluarly). - The triphosphate metabolite inhibits DNA polymerase; incorporated into DNA and RNA; diphosphate metabolite inhibits ribonucleotide reductase -> reduces DNA synthesis. For chronic lymphocytic leukemia (CLL)

Question 39

Purine Antagonist Toxicity

Answer 39

Thioguanin and Mercaptopurine: well tolerated, bone marrow suppresion at high doses and TPMT deficient pt Fludarabine: myelosupression, neurotoxicity at high doses