Antimetabolites

Question 1

What is the way that Antimetabolites work within the body to affect cancer?

Answer 1

• Block the production of one or more of these building block [nucleotides] = DECREASE in DNA replication and transcription

Question 2

What is the main part of the cell cycle that Antimetabolites affect?

Answer 2

• S Phase = Inhibit Synthesis

Question 3

What are the Pyridine Analongs?

Answer 3

• 5-FU, Capecitabine [nucleotide production]
• Ara-C, Gemcitabine [DNA polymerase]

Question 4

What is the mechanism of action for 5-Fluorouracil [5-FU]?

Answer 4

• Will INHIBIT thymidine synthesis for dUMP to TMP = inhibition of DNA synthesis

Question 5

What is the way that 5-FU stops the production of TMP & the DNA replication?

Answer 5

• 5-FU makes fdUMP [mimincs dUMP]
• Tetrahydofolate binds to fdUMP locking [F- group] it in Ternary Complex = thymineless death
• Tymidylate Synthase can’t break the FdUMP

Question 6

What is the importance of Thymidylate Synthase?

Answer 6

• Makes TMP from dUMP = DNA proliferation

Question 7

How does 5-FU interfere with RNA produce?

Answer 7

• 5-FU makes FdUTP [mimics UTP] causing RNA death

Question 8

What are some of the ways that 5-FU is resisted in the body?

Answer 8

• By dowregulation of enzymes [NO 5-FU to FdUMP]
• Upregulation of Thymidylate Synthease [increase TMP production]

Question 9

How would toxicites arise in patients taking 5-FU for cancer treatment?

Answer 9

• Polymorphism: deficiency of dihydropyrimidine dehydrogenase [DPD] which breaks down 5-FU; decrease DPD = increase 5-FU = more toxicities

Question 10

What is one way that Thymidine will help with 5-FU?

Answer 10

• Thymidine THEN 5-FU: more thymidine affecting thymidine synthesis = increased efficacy for 5-FU
• 5-FU THEN Thymidine: Helps with Overdose

Question 11

What is Leucovorate and how does Leucovorate help 5-FU?

Answer 11

• Leucovorate is basically folate
• It helps by over saturating the folate site and make more tetrahydrofolate = increase efficacy of 5-FU

Question 12

What is the mechanism of action for Capecitabine?

Answer 12

• Will INHIBIT thymidine synthesis [same and 5-FU]

Question 13

What is important to know about Capecitabine?:

Answer 13

• Orally active prodrug = improves selectivity to tumors while decreasing toxicities

Question 14

What is the mechanism of action for Cytarabine?

Answer 14

• Inihibit DNA polymerase = Decreasing DNA replication

Question 15

In what way does Cytarabine inhibit DNA polymerase?

Answer 15

• Its converted to Ara-C causing the inhibition

Question 16

What is the way that Cytarabine can be toxic and where does it affect?

Answer 16

• Cytidine Deaminase converts cytarabine to Ara-C
• DECREASE cytidine Deaminase will make Cytidine VERY toxic in CNS = leukemia and lymphoma

Question 17

What are some of the ways that Cytarabine has resistance?

Answer 17

• Downregulation of enzyme [NO Ara-C made]
• Upregulation of Cytidine Deaminase [lower Ara-C]
• Downregulation of transporters [NO drug in cell]

Question 18

What is the mechanism of action for gemcitabine?

Answer 18

• Inhibit DNA polymerase [same as Cytarabine]

Question 19

What is important to know about the potency of Gemcitabine?

Answer 19

• Has greater potency than Cytarabine

Question 20

What is the way that Terahydrouridine is used to help Cytarabine?

Answer 20

• Cytidine Deaminase Inhibitor = INCREASED levels of Ara-C [may increase Toxicity]

Question 21

What are the Purine Analogs?

Answer 21

• 6-Mercaptopurine, 6-Thioguanine

Question 22

What is the mechanism of action for 6-Mercaptopurine?

Answer 22

• Inhibits purine nucleotide production [MULTIPLE enzymes]
• Converted to TIMP via HGPRT [active]

Question 23

What is one way that 6-MP could become toxic within the body?

Answer 23

• Polymorphism: TPMT inactivates 6-MP
• Decrease in TMPT will increase hematologic toxicities [lower bone marrow and blood cells]; drugs isnt metabolized quickly

Question 24

What is the way that Allopurinol affects 6-MP?

Answer 24

• Allopurinol is a Xanthine Oxidase inhibitor; Xanthine Oxidase breaks down 6-MP; Allopurinol will increase 6-MP toxicities

Question 25

What is the mechanism of action for 6-Thioguanine?

Answer 25

- Inhibit purine nucleotide production [same as 6-mercapopurine]

Question 26

What is important to know about 6-thioguanine and allopurinol?

Answer 26

- DOES NOT break down 6-TG

Question 27

What is folate?

Answer 27

- **B9** - Needed for **Metabolism of Amino Acids and nucleic acids** - **FH2 to FH4** - **Methly donor for MTHF**

Question 28

Brief explain the Folic Acid Cycle?

Answer 28

- Folate enters as **Dihydrofolate [FH2]** - **FH2 reduce to** Tetrahydrofolate [**FH4**] by dihydrofolate reductase [**DHFR**] - **MTHF converted to FH2** where it helps **make TMP from dUMP**

Question 29

What happen when Dihydrofolate Reductase [DHFR] become inhibited?

Answer 29

- Cause an **increase in FH2** [inactive] causing an **INHIBITION in Thymidine Synthesis** = **decrease TMP**

Question 30

What is the mechanism of action for Methotrexate?

Answer 30

- Inhibits DHFR = lower THF levels causing a decrease in DNA synthesis

Question 31

What would be a way that there is resistance for Methotrexate?

Answer 31

- **Amplification of DHFR** - **Mutation of DHFR** to resistant the enzyme

Question 32

What is Leucovorin and how does it help against overdose?

Answer 32

- **Basically folate** - Used to **reverse overdose of MTX toxicity** by **INCREASING tetrahydrofolate and REVERSE toxic effects of DHFR inhibition**

Question 33

How does Lecovorin compare to Lecovorate?

Answer 33

- Lecovorin helps with MTX = DECREASE efficacy - Lecovorate helps with 5-FU = INCREASE efficacy

Question 34

What rescues a 5-FU overdose?

Answer 34

- Thymidine

Question 35

Which antifolate inhibits multiple enzymes, which results in decreased resistance?

Answer 35

- Pemetrexed

Question 36

Which antimetabolite should not be given to patents being treated for gout?

Answer 36

- 6-MP