Chemo Lecture 1: Pyrimidine Antimetabolites - Fitzpatrick

Question 1

what are the pyridimine antimetabolites

Answer 1

• 5FU
• Capecitabine
• Gemcitabine
• Cytarabine (Ara C)

Question 2

What are the active metabolites of 5FU

Answer 2

1. FdUMP (Fluorodeoxyuridine monophosphate) - inhibits thymidylate synthase thus inhibits dTMP synthesis
2. FdUTP and FUTP - damange DNA and RNA respectively

Question 3

What is the main clinical use of 5FU?

Answer 3

Used for solid tumors: colorectal and other GI; breast, ovarian carcinomas.
Topical use: basal cell carcinoma

Question 4

What is the main clinical use of Capecitabine?

Answer 4

Colorectal cancer; metastatic breast cancer that are resistant to paclitaxel and anthrocycline –> slows progression

Question 5

What is the main clinical use of Gemcitabine?

Answer 5

Pancreatic Cancer

Question 6

What is the main clinical use of Cytarabine?

Answer 6

AML

Question 7

Main dose-limited Tox of 5FU

Answer 7

Severe GI intolerance, mucositis, myelosuppression

Question 8

main dose limited tox of capecitabine

Answer 8

similar to 5FU (severe GI intolerance, mucositis, myelosuppression) PLUS hand-foot syndrome

Question 9

main dose limited tox of gemcitabine

Answer 9

Myelosuppression - Neutropenia

Question 10

Main dose liited tox of Cytarabine (araC)

Answer 10

Severe myelosuppression- granulocytopenia

Question 11

What is the MOA of 5FU?

Answer 11

Tumor cells activate 5FU (thymidine phosphorylase turns 5FU into 5FUdR), then thymidine kinase turns 5FUdR into 5FdUMP which is the active metabolite.
- FdUMP then inhibits thymidylate synthease and depletes dTMP (and dTTP downstream); distorst ‘dNTP’ pools and causes thymeless death

Question 12

5FU is a cell cycle specific drug that acts during which phase?

Answer 12

S phase

Question 13

why is folinic acid (Folfox) commonly given with 5FU

Answer 13

The active metabolite of 5FU, 5FdUMP binds to the complex of thymidylate synthease irreversibly. Folinic Acid (folfox) enhances this irreversibility and depletes the enzyme from the cell

Question 14

Differentiate how the three active metabolites of 5FU work as antineoplastic

Answer 14

1. FdUMP - inhibits thymidylate synthase which blocks conversion of dUMP into dTMP and thus deletes dTTP and accumulates dUTP –> Thymineless death. This is the MAIN mechanism for this this drug is administered
2. FdUTP incorporates into and causes DNA damage and cell cycle arrest and death
3. FUTP incorporates into RNA and causes RNA damage

Question 15

What two other drugs are said to increase the anticancer activity of 5FU when co-treated?

Answer 15

Leucovorin and methotrexate

Question 16

what is the most common mechanism of resistance to 5FU?

Answer 16

Alterations in thymidylate synthelase (TS). Cells and tumors with higher levels of TS are relatively more resistant to 5FU. Increased TS proteins content is usually associated with TS gene amplification

(Question stems usually ask which enzyme determines 5FU efficacy)

Question 17

what determines the efficacy and toxicity of 5FU?

Answer 17

Relative rates of its metabolic activation in tumor cells versus its metabolic (enzymatic) inactivation by liver and other cells. Toxicity: 5FU systemic exposure. Efficacy: 5FU delivered to tumors to make FdUMP, FdUTP, FUTP

Question 18

How is 5FU cleared?

Answer 18

Metabolic inactivation of 5FU is by dihydropyrimidine dehydrogenase (DPD) in the liver. Half life is about 10 mins. DHFU is the inactive metabolite

Question 19

What can aggravate 5FU systemic toxicity?

Answer 19

allelic variation in the DpDP gene (DPYD) which can slow 5FU clearance and thus have longer systemic exposure (up to 160mins vs 10min normally) of 5FU

Question 20

Inherited DPD deficiency can cause severe 5FU toxicity such as

Answer 20

• stomatitis
• leukpenia
• thrombocytopenia
• hair loss
• diarrhea
• fever
• cerebellar ataxia
• neurologic symptoms

Question 21

Capecitabine is an analog of _ and is given via what route?

Answer 21

Fluropyrimidine

- given orally

Question 22

How is capecitabine activated?

Answer 22

In the liver, carboxyesterase 1A1 and 2 converts it to 5’-dyoxy-5-fluorocytidine. Then cytidine deminase converts that to 5’-deoxy-5-fluorouridine (5’-DFCR). Finally, tumors overexpress thymidine phosphorylase which converts 5’DUFR to 5FU

Question 23

Both Ara-C and Gemcitabine are chemical analogs of _

Answer 23

cytidine

Question 24

what is the MOA of Ara C and Gemcitabine?

Answer 24

Ara C enters tumor cells via equilibrative neulcoside transporter 1 (hENT1) and is phosphorylated to Ara-CMP and to Ara-CDP and finally to Ara-CTP which is the active metabolite.

• Ara-CTP gets incorporated into DNA and cause chain termination and tumor cell death cuz arabinose CANNOT form a 3’-5’ phosphodiester bond. In addition: Ara-CTP binds to DNA pol and competitively inhibits DNA synthesis
• Gemcitabine is a analogous

Question 25

Mechanism of resistance of ARA-C and gemcitabine

Answer 25

Resistance of ARA- C depends on rate of activation by deoxycytidine kinase versus it’s rate of inactivation by pyrimidine nucleotidase (PN) and cytidine demainse (CDA) in tumor cells. Commonly increased rate of CDA conversion to it’s inactive form is the main cause of ARA-C resistance.
- Other mechanism: deficient drug uptake via ENT transporter; deficient kinase activity

Resistance of gemcitabine is comparable

Question 26

what is ARA-C and gemcitabine used for?

Answer 26

Ara-C = ALM
Gemcitabine = pancreatic cancer and other