Antimetabolites

Question 1

What antimetabolites work as folic acid analogs?

Answer 1

Methotrexate

Question 2

What antimetabolites work as pyrimidine analogs?

Answer 2

Flurouracil (5-FU)
Capecitabine
Cytarabine (cytosine arabinoside)
Gemcitabine

Question 3

What antimetabolites work as Purine Analogs?

Answer 3

6-Mercaptopurine (6-MP)
Thioguanine
Fludarabine

Question 4

Methotrexate

• Intake, Retention?
• MOA

Answer 4

Taken in via ABC transporters and POLYGUTAMATED causing it to get trapped inside the cell (*this version is still effective)

• Dihyrdofolate Reductase Inhibitor (DHFR)

Pyrimidine Synthesis Block:
- Thymidylate Synthase Inhibition (TS)

Purine Synthesis Block:
- Glycinamide Ribonucleotide Transformylase (GARFT) and ribonucleotide transformylase (AICARFT)

Question 5

At Higher than usual doses what is the major adverse effect of methotrexate?

• how do we combat this effect?
• explain this processes

Answer 5

Bone Marrow Toxicity is High doses

Combat Effect by:
- LEUCOVORIN RESCUE

Leucovorin:
- aka Folinic Acid - does not need DHFR for conversion so purine and pyrimidine synthesis can resume

Question 6

Why don’t other drugs that inhibit DHFR like Trimetoprim and Pyrimethamine get used for cancer?

Answer 6

They are target specifically for non-human DHFRs making them inaffective against cancer

Question 7

How is Methotrexate Resistance conferred?

• What are some other toxic effects of MTX besides bone marrow toxicity?
• Elimination?
• Drug -Drug interactions?

Answer 7

Resistance:

• Less uptake by ABC trasporters
• Less Polyglutamation
• More DHFR production

Toxicity:

• GI toxicity, N/V, abdominal pain
• Pulmonary Infiltrates and Fibrosis

Elimination:
- Renal via GF and Tubules NSAIDs may inhibit Tubular secretion leading to Increased MTX toxicity

Question 8

5-Fluorouracil; 5-FU [adrucil]
Method of Administration
MOAs

Answer 8

Delivered IV only

DNA synthesis Inhibition
- Inhibits Thymidine Synthase

Incorporation into DNA:
- Inhibits DNA synthesis

Translation inhibitor:
- Interferes with mRNA translation

Question 9

What 3 antimetabolites cause hand and foot syndrome?

Answer 9

• 5-Fluorouracil (IV)
• Capecitabine (PO)
• Cytarabine

Question 10

5-Flurouracil

• Resistance mechanisms
• Toxicity

Answer 10

Resistance:

• Thymidine Synthase Upregulation or Mutations
• Decreased Activation of 5-FU

Toxicity:

• Acute Chest pain
• Other usual (myelosupp., GI, anemia, etc.)
• HAND-FOOT SYNDROME

***Note: Hand and foot more common with acute drug infusions

Question 11

What is hand and foot syndrome?

- cause?

Answer 11

Symptoms:

• Redness of Hands and Feet
• Tingling Sensations
• Swelling
• Blisters

Cause:
- Drug escapes from capillaries and irritates the skin in these areas of the body

Question 12

Why would you use Levocovorin with 5-FU?

Answer 12

• Drives Inhermediary Metabolism into Incorporating 5-FU (IV) in to Thymidine Synthase

**Remember Levocovorin is also used in Bone Marrow Rescue with Methotrexate

Question 13

What is the oral version of 5-FU?

- differences in side effects?

Answer 13

Capecitabine [xeloda]
**essentially just a 5-FU pro-drug

• Hand and Foot Syndrome occurs more frequently with this drug

Question 14

What is the most specific of the Anti-metabolites for the S-phase of the cycle?

Answer 14

Cytarabine; ARA-c [cytosar]

Question 15

Cytarabine; ARA-C [cytosar]
MOA
administration method?

Answer 15

MOA:

• ARA-CTP (triphosphate)
• Gets incorporated into growing chain and creates STERIC hinderance with 2’-hydroxyl

Administered:

• IV
• SC
• ITH (intrahecally)

Question 16

How is resistance to Cytarabine ARA-C conferred?

- Toxicity?

Answer 16

• Decreased Cellular Uptake
• Decreased Phosphorylation to make ARA-CTP
• Increased ARA-C —> ARA-UMP (inactive)

Toxicity:

• Usual (Myelosupp., G.I. effects, thrombocytopenia)
• STOMATITIS
• Hepatic Enzyme Elevations

Question 17

Gemcitabine [gemzar]
MOA
Toxicity

Answer 17

MOA:

• Must be TriPhosphorylated (like ARA-C)
• 1 additional base pair added making repair more difficult
• Better Penetration/Retention

Toxicity:

• Same as all others
• Pneumonitis

Question 18

Mercaptopurine [purinethol]
MOA
- Administration method?
- Reasons to Dose adjust?

Answer 18

MOA:

• 6 Mecraptopurine (6-MP) gets converted to 6-thioinosine monophosphate by HGPRT
• Ultimately because 6-thioguanine Monophosphate and inhibits DNA synthesis

Administration:
Oral

• **Dose adustment:
  1) ALLOPURINOL - blocks 6-thiouric acid (side pdt) formation leading to Toxicity of 6-MP (reduce to 25% of original 6-MP dose)

2) TPMT - converts 6-MP to 6-methyl-MP, Activity of this enzyme is determined by SINGLE NUCLEOTIDE polymorphisms (3 levels of activity)

Question 19

Mechanisms of Resistance to Mercaptopurine (PO)?

- Toxicity?

Answer 19

Resistance:

• Lowered of HGPRT
• Less drug uptake, more efflux
• Recognition of DNA breaks

Toxicity:

• Bone marrow depression (like always) - DOSE LIMITING
• Jaundice and Hepatic Enzymes may Increase

Question 20

How do you know how much Mercaptopurine to give someone?

Answer 20

***Do Genetic tests to see which version of TMPT they have (polymorphic gene with 3 different possible levels of activity)

(remember HGPRT is involved in Lesch-Nyhan syndrome)

Question 21

Thioguanine; 6-TG [tabloid]

• MOA
• resistance
• Toxicity

Answer 21

MOA:
- Same as 6-MP EXCEPT NO 6-thiouric acid conversion so NO conflicts with Allopurinol

Resistance (same as 6-MP)

• Lowered of HGPRT
• Less drug uptake, more efflux
• Recognition of DNA breaks

Toxicity:

• Bone Marrow Suppression - DOSE LIMITING
• Hepatic/Jaundice

Question 22

Hydroxyurea [hydrea]

• MOA
• resitance?
• Toxicity

Answer 22

MOA:
- Free Radical Scavenger that grabs a free radical needed in the conversion of ribonucleotides to DEOXYribonucleotides (RATE LIMITING step)

Resistance:
- Upregulation of Ribonucleotide Reductase

Toxicity:

• Bone Marrow Depressino
• RASHES, ERYTHEMA, ULCERATIONS, SKIN CANCER, SKIN DARKENING

Question 23

What is the difference between Hydroxyurea and Antimetabolites?

Answer 23

Hydroxyurea doesn’t pretend to be a nucleotide or nucleotide intermediate it just inhibits the RATE LIMITING step in nucleotide synthesis

Question 24

Which of the drugs have resistance conferred against them by decreasing their activation?

Answer 24

• Mercptopurine and Thioguanine (HGPRT and pathway)
• Gemicitabine and Cytarabine ARA-C (triphos. activation)
• 5-FU

Question 25

Which of the metabolites are resisted by inactivation?

Answer 25

Most Purine and Pyrimidine Antimetabolites

Question 26

How accumulation of drug within the cell prevented with the antimetabolites, MTX?

Answer 26

P-gp
- can efflux just about any drug out

MTX- polyglutamation is needed to keep it in the cell, if this doesn’t happen MTX is no longer effective

Question 27

What reproductive effects do most anti-cancer drugs have?

Answer 27

• Most drugs are TERATOGENS

- Most also cause INFERTILITY

Question 28

What are some cancer drugs that may cause Red urine. Explain the difference in each.

Answer 28

Cyclophosphamide:
- causes hemorrhagic cystitis leading to RBCs in the urine

Doxyrubicin:
- causes red urine because its metabolites are red not because its causing disease

Question 29

T or F: the Platinum drugs are considered alkylating agents.

Answer 29

False, they are platininating agents, not alkylating agents

Question 30

T or F: in some cases cancer cells can just upregulate DNA excision repair mechanisms to remove antimetabolites and keep moving on.

Answer 30

True.