Fitzpatrick - Anti-Neoplastic Drugs

Question 1

5FU requires activation in what location for clinical effects?

Answer 1

Conversion to activated metabolites occurs INSIDE the tumor cell.

Question 2

What is the active metabolite of 5FU?

Answer 2

5FdUMP

Question 3

What four actions does 5FdUMP do?

Answer 3

1. Inhibits thymidylate synthase…
2. …blocking conversion of dUMP into dTMP. Eventual depletion of dTTP.
3. Accumulation of dUTP distorts “dNTP” pools…
4. …causing “Thymineless” Death bc dTTP is essential for DNA synthesis.

Question 4

Classify the specificity of 5FU

Answer 4

A cell cycle specific drug acting in S-phase

Question 5

What metabolite of 5FU incorporates into the tumor DNA and causes DNA damage, cell cycle arrest, and death?

Answer 5

FdUTP

Question 6

What metabolite of 5FU incorporates into RNA to cause RNA damage?

Answer 6

FUTP

Question 7

TS is associated with MoR to ___ in what way?

Answer 7

Tumors with higher levels of TS protein are more resistant to 5FU. TS gene amplification

Question 8

5FU clearance occurs how?

Answer 8

Metabolic inactivation of 5FU by the liver.

Question 9

Clinical efficacy and toxicity of 5FU is dependent upon rate of metabolic activation in the tumor or its metabolic inactivation in the liver?

Answer 9

its metabolic inactivation in the liver

Question 10

What is the inactive metabolite of 5FU? How does this occur?

Answer 10

• Inactive metabolite: DHFU

- Hepatic enzyme: Dihydropyrimidine dehydrogenase (DPD) eliminates up to 80% of 5FU.

Question 11

A person with AR DPD mutation/deficiency is at risk for what?

Answer 11

5FU toxicity

called familial pyrimidineamia or hereditary thymine-uraciluria

Question 12

Symptoms of 5FU toxicity

Answer 12

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

Question 13

Metabolic activation of capecitabine.

Answer 13

1. Oral.

2. Activation in the LIVER and TUMORS

Question 14

What is capecitabine?

Answer 14

A pro-drug of 5FU

Question 15

Name the two enzymes in liver activation of capecitabine.

Answer 15

capecitabine +(CARBOXYESTERASE) –> 5’-DFCR + (CYTIDINE DEAMINASE) –> 5’-DFUR

Question 16

Name the three enzymes in tumor activation of capecitabine.

Answer 16

capecitabine +(CARBOXYESTERASE) –> 5’-DFCR + (CYTIDINE DEAMINASE) –> 5’-DFUR + (T/U PHOSPHORYLASE) –> 5FU

Question 17

Capecitabine therapeutic uses (two).

Answer 17

1. Colorectal cancer

2. Metastatic brest cancer

Question 18

Capecitabine toxicities.

Answer 18

Hand-Foot Syndrome - a chronic dose limiting toxicity.

Question 19

What two pyrimidine anti-metabolie drugs are analgous pro-drugs?

Answer 19

Gemcitabine and Ara-C

Question 20

Activated form of Ara-C in tumors is called?

Answer 20

Ara-CTP

Question 21

What happens to Ara-CTP in tumor cells?

Answer 21

• It binds to DNA polymerase, inhibiting/stalling DNA synthesis.
• Incorporated into DNA and terminates DNA strand elongation.

Question 22

How does Ara-CTP terminate DNA strand elongation when incorporated into DNA?

Answer 22

Arabinose cannot form 3’-5’ phosphodiester bond

Question 23

Although Ara-C and gemcitabine are similar pro-drugs, what

cancer is Ara-C used for v. Cancer that gemcitabine is used for.

Answer 23

Ara-C = AML
Gemcitabine = pancreatic cancer

Question 24

What two organs contain high levels of cytidine deaminase (CDA), which deaminate/inactivate Ara-C - resulting in residual AML in these two organs.

Answer 24

Spleen and liver.

Question 25

Comparable aspects of gemcitabine and Ara-C

Answer 25

1. *Metabolic activation
2. *Metabolic inactivation
3. *MoR
4. inhibit DNA polymerase via chain termination
5. IV administration
6. Dose limiting toxicities

Question 26

Co-treat 5-FU with what atwo other drugs?

Answer 26

Leucovorin and MTX.

Question 27

ENT1 nucleoside transporter

Answer 27

Ara-C and Gemcitabine