Antimetabolites

Question 1

5-FU

Answer 1

uridine analogs–> inhibit thymidine synthesis from uracil

MOA: In the presence of tetrahydrofolate, FdUMP binds to the active site of thymidylate synthase and cannot be completed trapping thymidylate synthase in the ternary complex irreversible inhibiting–>TMP is not produced resulting in the inhibition of DNA synthesis

Cannot exchange fluorine for a methyl group

Question 2

Cytarabine (Ara-C)

Answer 2

cytosine analog–> inhibit DNA synthesis

MOA: converted to Ara-CTP intracellularly that competitively inhibits DNA polymerase

Ara-CTP is also incorporated into DNA furthering inhibiting DNA synthesis

Question 3

Overall effects of 5-FU

Answer 3

Cannot produce thymidine for DNA synthesis

Interferes with RNA processing and function

Interferes with polyadenylation of mRNA (affects RNA stability)

Question 4

Drug rescue for 5-FU

Answer 4

Thymidine

Question 5

Drug synergy for 5-FU

Answer 5

leucoverate

Leucoverate is a stable folate cofactor that is converted to tetrahydrofolate in cells

Higher tetrahydrofolate levels increases the efficacy of 5-FU by increasing the amount of the covalent ternary complex

Question 6

Resistance of 5-FU

Answer 6

Downregulation of activating enzymes that converts 5-FU to FdUMP

Upregulation of thymidylate synthase

Question 7

Toxicity of 5-FU

Answer 7

5% of the population has gene polymorphisms that result in the deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) that breaks down 5-FU

Question 8

Another uracil analog

Answer 8

Capecitabine is an oral active prodrug of 5-FU

Question 9

Pearl of Cytarabine

Answer 9

Cytidine deaminase converts cytarabine to a non-toxic uracil arabinoside

Decreased levels of cytidine deaminase in the CNS makes Ara-C high toxic in meningeal leukemia/lymphoma

Question 10

Drug synergy for Cytarabine

Answer 10

Tetrahydrouridine

Tetrahydrouridine is a cytidine deaminase inhibitor to increase levels of cytarabine to increase efficacy and decrease resistance

Question 11

Resistance of Cytarabine

Answer 11

Downregulation of activating enzymes

Upregulation of cytidine deaminase

Downregulation of transport to move drug into cells

Question 12

Gemcitabine

Answer 12

more potent than cytarabine

Question 13

6-MP

Answer 13

Purine analog–>inhibit purine biosynthesis

MOA: inhibits multiple enzymes in the purine biosynthesis pathway

Question 14

Resistance of 6-MP

Answer 14

Loss of HGPRT (activating enzyme)

Question 15

Drug interactions/metabolism of 6-MP

Answer 15

6-MP is inactivated by TPMT

TMPT polymorphisms occur in 10% of children

Heterozygotes: 65% of standard dose
Homozygotes: 10% of standard dose

Allopurinol:
Xanthine oxidase is the enzyme that breaks down 6-MP
Allopurinol is a xanthine oxidase inhibitor to prevent gout

Question 16

6-Thioguanine

Answer 16

does not have drug interaction by allopurinol

Question 17

Methotrexate

Answer 17

Antifolate–> folate is an essential vitamin for enzymatic reactions–> Vitamin B9

MOA: inhibits dihydrofolate reductase (DHFR) to inhibit TMP synthesis

Inhibits RNA and purine synthesis
Inhibits purine and pyrimidine base synthesis

Question 18

Drug rescue for Methotrexate

Answer 18

leucovorin

Leucovorate is a stable folate cofactor that is converted to tetrahydrofolate in cells

increases intracellular pool of tetrahydrofolate and reverses toxic effects of DHFR inhibition

Leucovorin competes with methotrexate for transport into cells

Question 19

Resistance of methotrexate

Answer 19

Upregulation of DHFR gene

Mutation of DHFR to resist the actions of methotrexate

Decreased polyglutamation results in decrease intracellular methotrexate accumulation

Polyglutamation of intracellular methotrexate helps retain methotrexate inside the cell