Pyrimidine and Purine Analogs

Question 1

All Pyrimidine Analogs

Answer 1

Fluoruracil (5-FU)
Fluxuridine
Capecitabine
Cytarbine
Gemcitabine

Question 2

5-FU Use

Answer 2

• GI, pancreas, head & neck, colon, rectum, breast, and ovarian cancer

Question 3

5-FU MOA

Answer 3

• Phosphorylated to 5-FUTP and 5-FdUMP (tight-binding inhibitor of thymidylate synthase)
• Fluororibonucleotides are incorporated into RNA and perturb RNA processing (splicing, transport, translation)
• Fluorodeoxyuridines are incorporated into DNA → strand breaks

Question 4

5-FU Cytotoxic MOA

Answer 4

5-FU is converted to 5-FdUMP which competes with dUMP for the enzymes thymidylate synthetase
o Normally TS + N5N10 use dUMP to make dTMP but this is blocked by 5-FU
o The N5N10 is then converted to dihydrofolate at the loss of the methyl group to dUMP

Question 5

FdUMP MOA

Answer 5

o Enzymes tries to use FdUMP making it unable to transfer the methyl group and you end up with a dead end complex because they just get stuck together

Question 6

5-FU + Leucovorin

Answer 6

• More inihibition of TS → more anticancer effect

* Called “biochemical modulation”

Question 7

5-FU Side effects

Answer 7

• Bone marrow suppression
• Stomatitis and mucotitis
• N/V
• Cardiac
• Hand & Foot syndrome (lots of rashes on hands and sole of feet)*****

Question 8

Cytarabine Use

Answer 8

Acute leukemias

Question 9

Cytarabine Drug Class

Answer 9

Analog of CTP - only difference is the sugar used (arabinose)

Question 10

Cytarabine MOA

Answer 10

Incorporated into DNA and inhibits chain synthesis via a lack of OH preventing phosphodiester bonds → DNA fragmentation; inhibits DNA polymerase alpha
MOST SPECIFIC FOR S PHASE!!!***

Question 11

Cytarabine SE

Answer 11

• Severe myelosuppression
• Stomatitis
• Hand & Foot syndrome

Question 12

Capecitabine Use and MOA

Answer 12

 Use: Breast Cancer

 MOA: prodrug of 5-FU

Question 13

Gemcitabine Use

Answer 13

Metastatic pancreatic cancer

Question 14

Gemcitabine MOA

Answer 14

Phosphorylated to monophosphate then to di and triphosphate
• Triphosphate inhibits DNA polymerases (terminates elongation)
• Diphosphate inhibits ribonucleotide reductase

Question 15

All PURINE analogs

Answer 15

Fludarabine
Mercaptopurine
Thioguanine

Question 16

Fludarabine Use

Answer 16

CLL (leukemia)

Question 17

Fludarabine MOA

Answer 17

• Phosphorylated inhibition of DNA polymerases

* Incorporation into the DNA strand to leads to chain termination

Question 18

Fludarabine SE

Answer 18

Myelosuppression
Neurotoxicity
Pulmonary toxicity

Question 19

6-MP MOA

Answer 19

Inhibits the first step in purine biosynthesis

Question 20

Thioguanine (6-TG) MOA

Answer 20

Incorporated into DNA/RNA and causes fragmentation

Question 21

6-MP and 6-TG Activation

Answer 21

Activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism

Question 22

6-MP + Allopurinol MOA

Answer 22

 6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted
 Allopurinol is used frequently to treat/prevent hyperuricemia cause by many anticancer drugs

Question 23

6-MP + Allopurinol Dosing

Answer 23

If allopurinol is used with 6-MP then the dose of 6-MP has to be reduced by more than 75% to prevent 6-MP induced myelosuppression, hepatotoxicity, mucosititis and hematotoxicity

Question 24

Fibonucleotide Reductase MOA

Answer 24

Catalyzes conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates
Activated prior to DNA synthesis and controlled by feedback inhibition

Question 25

Hydroxyurea Use and MOA

Answer 25

o Use: leukemia, sickle cell anemia
o MOA: inhibits ribonucleotide reducatase
 Inhibits DNA synthesis without affecting RNA synthesis or other nucleotide pools

Question 26

Downside to hydroxyurea?

Answer 26

Cleared rapidly so not used often