Pyrimidine Anti-Metabolite Drugs That Inhibit DNA Synthesis (Fitz)

Question 1

This drugs active metabolite (FdUMP) inhibits thymidylate synthase) by inhibiting dTMP synthesis

Answer 1

5-FU

FdUTP and FUTP damage DNA and RNA respectively

Question 2

This is an oral pro-drug of 5-FU

Answer 2

Capecitabine

Question 3

Kinases convert this drug to nucleotide analogs and inhibit DNA synthesis

Answer 3

Gemcitabine

Question 4

Kinases convert Cytarabine (Ara C) to ___ to inhibit DNA synthesis

Answer 4

AraCTP

Question 5

Therapeutic uses for 5-FU?

Answer 5

Solid tumors: Colorectal and other GI
Breast, ovarian carcinomas

Topical-Basal Cell carcinoma

Question 6

Therapeutic uses of Capecitabine?

Answer 6

Colorectal cancer

Metastatic breast cancer (resistant to paclitaxel/anthracycline)

Question 7

Therapeutic uses of Gemcitabine?

Answer 7

Pancreatic cancer

Question 8

Therapeutic uses of Cytarabine (Ara C)?

Answer 8

Acute myelogenous leukemia (w/6-thioguanine, daunorubicin)

Question 9

Dose-limiting toxicity of 5-FU?

Answer 9

Severe GI intolerance
Mucositis
Myelosuppression

Question 10

Dose-limiting toxicity of Capecitabine?

Answer 10

Similar to 5-FU

PLUS Hand-Foot syndrome

Question 11

Dose-limiting toxicity of Gemcitabine?

Answer 11

Myelosuppression-neutropenia

Question 12

Dose-limiting toxicity of Cytarabine (Ara C)?

Answer 12

Severe myelosuppression-granulocytopenia

Question 13

In addition to colorectal cancer and adjuvant therapy of early-stage colon cancer, 5-FU is also used for other solid tumors usually in combo with ___ antagonists, and other chemotherapy drugs

Answer 13

Folate

Question 14

How is 5-FU administered?

Answer 14

Parenterally

Question 15

MOA of 5-FU?

Answer 15

Tumor cells activate 5-FU –> the 5-FU metabolite FdUMP inhibits thymidylate synthase –> depletes dTMP (and dTTP downstream) –> distorts dNTP pools –> causes Thymineless death

Question 16

What cell cycle phase does 5-FU act on?

Answer 16

S

Question 17

How exactly is thymidylate synthase inhibited by 5-FU?

Answer 17

Ternary complex

5-FdUMP covalently complexes with thymidylate synthase and folic acid

This complex inhibits thymidylate synthase –> decrease dTMP –> decrease DNA synthesis

Question 18

The 5-FU metabolite __ incorporates into and causes DNA damage, cell cycle arrest, death

Answer 18

FdUTP

Question 19

The 5-FU metabolite __ incorporates into RNA and causes RNA damage

Answer 19

FUTP

Question 20

Co-tx with __ can increase the anti-cancer activity of 5-FU

Answer 20

Leucovorin and methotrexate

Question 21

Mechanisms of resistance to 5-FU?

Answer 21

Alterations in TS are most common mechanism of resistance to 5-FU

Cell lines and tumors with higher levels of TS are relatively more resistant to 5-FU. Increased TS protein content usually associated with TS gene amplification

Question 22

5-FU clearance? t1/2? Enzyme that metabolically inactivates 5-FU?

Answer 22

Metabolic inactivation by the liver

t1/2 ~ 10 mins

Metabolic inactivation by DPD in the liver which converts 5-FU to DHFU (inactive metabolite)

Question 23

Individuals with this liver enzyme deficiency (hereditary/familial) experience severe 5-FU toxicity d/t prolonged systemic exposure to 5-FU and slower clearance with a t1/2 of 159 mins

Answer 23

DYPD gene mutations –> DPD deficiency

Can lead to stomatitis, leukopenia, thrombocytopenia, hair loss, diarrhea, fever, cerebellar ataxia, NEUROLOGIC symptoms

Question 24

MOA of capecitabine? Route of administration?

Answer 24

Capecitabine activated in liver by Carboxyesterase 1A1 and 2 to 5’-DFCR –> Cytidine deaminase converts 5’-DFCR to 5’-DFUR –> tumors overexpress thymidine phosphorylase which converts 5’DUFR to 5-FU –> 5-FU in tumor active metabolites

PO adminstration –> intestinal absorption 80% bioavailable

Question 25

Hand-foot syndrome is a chronic dose-limiting toxicity of this drug, leading to significant morbidity in affected patientes

Answer 25

Capecitabine

Question 26

These drugs are chemical analogs of Cytidine

Answer 26

Ara-C and Gemcitabine

Question 27

MOA of Ara-C and Gemcitabine?

Answer 27

Ara-c goes through ENT1 nucleoside transporter –> Ara-C converted to Ara-CMP by dCK enzyme –> Ara-CMP converted to Ara-CDP by CMPK enzyme –> Ara-CDP converted to active species Ara-CTP by NDPK enzyme –> Ara-CTP COMPETES with CTP in DNA polymerase and Ara-CTP incorporated into DNA causes chain termination and tumor cell death

Gemcitabine is analagous

Question 28

How does Ara-CTP work inside a replicating tumor cell (AML)?

Answer 28

Ara-CTP binds to DNA polymerase and competitively inhibits DNA synthesis AND Ara-CTP actually incorporated into DNA “terminates” further DNA strand elongation, Arabinose cannot form a 3’-5’ phosphodiester bond

Question 29

Mechanisms of resistance to Ara-C?

Answer 29

• rate of activation by dCK versus rate of inactivation by PN and CDA in tumor cells (AML)
• liver and spleen contain very high levels of CDA and are a santuary for leukemic cells b/c liver and spleen deaminate Ara-C, dramatically lowering its level by converting it to an inactive Ara-U metabolite which has no leukemic activity

Question 30

List distinctions between Ara-C and Gemcitabine:

Answer 30

Gemcitabine: Gem-disphosphate inhibits ribonucleotide reductase (depletes cellular dNTPs); Tx of pancreatic cancer, non-small cell lung cancer; drug-induced fever and flu-like syndrome

Ara-C: Tx of acute myelogenous leukemia