Cancer Pharm: Antimetabolites

Question 1

What is the MOA of Methotrexate?

Answer 1

• Inhibits synthesis of THF
• Interferes w/ formation of DNA, RNA, and key cellular proteins

Question 2

Which enzyme is responsible for activating and increasing the selectivity of the antifolates: methotrexate, pemetrexed, and pralatrexate?

Answer 2

Folyl polyglutamate synthase (FPGS) catalyzes formation of intracellular metabolites which are selectively retained in cancer cells

Question 3

What are 4 mechanisms by which resistance to Methotrexate may develop?↓

Answer 3

• ↓ drug transport via the reduced folate carrier or folate receptor protein
• ↓ formation of cytotoxic methotrexate polyglutamines
• ↑ levels of the target enzyme DHFR thru gene amplification, etc.
• Altered DHFR protein with reduced affinity for methotrexate

Question 4

What are 4 drug-drug interactions that you must be aware of when giving Methotrexate?

Answer 4

Aspirin, NSAIDs, penicillin, and cephalosporinsallinhibititsrenal excretion—> ↑toxicity

Question 5

Which drug is sometimes used in combo with high-dose methotrexate therapy to rescue normal cells from undue toxicity?

Answer 5

Reduced folate leucovorin; reverses action of methotrexate

Question 6

Which antifolate drug has activity during the S-phase?

Answer 6

Pemetrexed

Question 7

What is the MOA of the antifolate, Pemetrexed?

Answer 7

• Inhibition of thymidylate synthase (TS)
• Targets and inhibits DHFR and enzymes involved in de novo purine nucleotide biosynthesis

Question 8

What are some AE’s associated with the antifolate, Pemetrexed; which is unique to this drug?

Answer 8

• Hand-foot syndrome* = painful erythema and swelling of hands and feet
• Myelosuppression
• Skin rash + Mucositis
• Diarrhea + Fatigue

Question 9

Vitamin supplementation with what can significantly reduce toxicities associated with Pemetrexed and Pralatrexate?

Answer 9

Folic acid and Vitamin B12

Question 10

What are the 3 MOA’s of the antifolate, Pralatrexate?

Answer 10

• Inhibits DHFR
• Inhibits enzymes involved in de novo purine nucleotide biosynthesis
• Inhibits thymidylate synthase (TS)

Question 11

The antifolate, Pralatrexate has been approved for the tx of what?

Answer 11

Relapsed or refractory peripheral T-cell lymphoma

Question 12

What are the 3 active metabolites of 5-FU and what is the MOA of each?

Answer 12

• FdUMP —> inhibition of DNA synthesis thru “thymineless death”
• FUTP –> incorporated in RNA; interferes w/ RNA processing and mRNA translation
• FdUTP –> incorporated into DNA resulting in inhibition of DNA synthesis

Question 13

What are 4 AE’s of the antimetabolite, 5-FU; which is unique?

Answer 13

• GI toxicity (diarrhea/mucositis) = unique
• Myelosuppression
• Skin toxicity (hand-foot syndrome) = unique
• Neurotoxicity

Question 14

5-FU is the most widely used drug in the tx of which cancer?

Answer 14

Colorectal cancer

Question 15

What is special about the antimetaboite, Capecitabine?

Answer 15

A prodrug that is metabolized to 5-FU by thymidine phosphorylase (which has higher expression in some solid tumors - breast and colorectal)

Question 16

2 main AE’s of the antimetabolite, Capecitabine?

Answer 16

Main = diarrhea, hand-foot syndrome

Question 17

Capecitabine used in conjunction with what drug is the first-line tx for metastatic colorectal cancer?

Answer 17

Capecitabine + oxaliplatin = XELOX regimen

Question 18

What are the 2 components of the antimetabolite, TAS-102 and how does each work?

Answer 18

• Trifluridine = metabolized to monophosphate form (inhibits TS) or metabolized to triphosphate form (inhibits DNA synthesis and function)
• Tipiracil = a TP inhibitor, the key enzyme that degrades trifluridine

Question 19

TAS-102 is useful in which type of colorectal cancer?

Answer 19

• Wild-type and mutant RAS colorectal cancer
• Used in progressive, refractory colorectal cancer

Question 20

Which phase of the cell cycle is Cytarabine specific for?

Answer 20

S phase

Question 21

The antimetabolite, Cytarabine is converted into what; describe the 3 MOA of this metabolite.

Answer 21

• Converted to ara-CMP —> ara-CTP
• Inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)
• Incorporated into DNA –> interferes w/ chain elongation and causes defective ligation of new DNA fragments
• Incorporated into RNA

Question 22

What are 4 AE’s of Cytarabine?

Answer 22

• Myelosuppression
• Mucositis
• N/V
• Neurotoxicity (at high doses)

Question 23

2 clinical uses for Cytarabine?

Answer 23

AML and NHL’s; only has activity against hematologic malignancies

Question 24

The anti-metabolite Gemcitabine is phosphorylated to a diphosphate and triphosphate form, what is the MOA of each form?

Answer 24

• Diphosphate = inhibits ribonucleotide reductase; ↓ level of deoxyribonucleotide triphosphates needed for DNA synthesis
• Triphosphate = inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)

Question 25

What is the dose limiting toxicity of Gemcitabine and which AE is most common?

Answer 25

- **Dose limiting** = myelosuppression in form of **neutropenia** - **Nausea** and **vomiting** (70% of patients) + **flu-like syndrome**

Question 26

Although both deoxycytidine analogs, how does the clinical use of Cytarabine differ from Gemcitabine?

Answer 26

- **Cytarabine** only effective against **hematologic** malignancies - **Gemcitabine** can be used for **both** solid and hematologic malignancies

Question 27

Gemcitabine was initally approved for use in what type of cancer?

Answer 27

Advanced **pancreatic** cancer

Question 28

Which enzyme is responsible for metabolizing the 6-thiopurines; which toxic effects may be seen with loss of this enzyem?

Answer 28

- Metabolized by **thiopurine methyltransferase (TPMT)** - Loss of this enzyme can lead to: **myelosuppression** and **GI toxicity** (mucositis and diarrhea)

Question 29

6-mercaptopurine (6-MP) is inactive in parent form and becomes active when metabolized to what?

Answer 29

Metabolized by **HGPRT** --\> **monophosphate nucleotide 6-thioinosinic acid**

Question 30

What is the MOA of the active metabolite of 6-MP, mono- and triphosphate nucleotide 6-thioinosinic acid?

Answer 30

- **Monophosphate** acts to **inhibit** several enzymes of de novo **purine nucleotide synthesis** - **Triphosphate** form incorporated into both **DNA** and **RNA**

Question 31

How is the active form of 6-mercaptopurine (6-MP) inactivated and what clinical implication does this have?

Answer 31

- Converted to **inactive** metabolite by **xanthine oxidase** - **Allopurinol** (xanthine oxidase **inhibitor**) is commonly used in tx of **acute leukemia** for prevention of **hyperuricemia** - If **allopurinol** is used w/ **6-MP**, would result in ↑ levels of 6-MP and **excessive toxicity**

Question 32

6-mercaptopurine is used in the tx of what?

Answer 32

**Childhood acute leukemia**

Question 33

List the 5 MOA of 6-thioguanine?

Answer 33

- **Inhibits** several enzymes in de novo **purine nucleotide** synthesis - **Inhibition** of **purine nucleotide** interconversion - ↓ IC levels of **guanine nucleotides** --\> **inhibits glycoprotein** synthesis - **Interferes** w/ formation of **DNA** and **RNA** - **Incorporation** of **thiopurine** nucleotides in **DNA** and **RNA**

Question 34

6-thioguanine synergizes with what drug in the tx of adult acute leukemia?

Answer 34

Cytarabine

Question 35

What is the MOA of the triphosphate and diphosphate form of Fludarabine (purine antagonist)?

Answer 35

- **Triphosphate**: inhibits **DNA polymerase-α** and **β** (interferes w/ **DNA synthesis** and **repair**) - **Diphosphate**: inhibits **ribonucleotide reductase** leading to inhibition of production of deoxyribonucleotide triphosphates - Also **induces apoptosis** in **susceptible cells**

Question 36

What is an AE you must consider when using the purine antagonist, Fludarabine; how can this AE be managed?

Answer 36

- ↑ risk for **opportunistic infections** i.e., ***P. jiroveci* pneumonia (PCP)** - **PCP prophylaxis** w/ **TMP-SMX** at least **3x/week** during tx and for one week after

Question 37

2 clinical uses for the purine antagonist, Fludarabine?

Answer 37

- **Low-grade NHL's** - **Chronic lymphocytic leukemia**

Question 38

The purine antagonist, Cladribine, has a high specificity for what cells?

Answer 38

**Lymphoid cells**

Question 39

What is the MOA of the purine antagonist, Cladribine, when in active triphosphate form?

Answer 39

- **Incorporated** into **DNA**, causing **inhibition** of synthesis and function - **Inhibition** of **DNA polymerase-α** and **β** (interferes w/ **synthesis** and **repair**)

Question 40

What AE must you keep in mind when using the purine antagonist, Cladribine?

Answer 40

- **Main effect** = myelosuppression - ↓ in **CD4** and **CD8 T cells** can last **1+ year**

Question 41

2 main clinical applications of the purine antagonist, Cladribine?

Answer 41

- **Hairy cell leukemia** - **Low-grade lymphoid malignancies**: CLL and low-grade NHL's