Antimetabolites

Question 1

Classes of antimetabolites

Answer 1

1. Folic acid analogs
2. Pyrimidine analogs
3. Purine analogs

Question 2

Drug in folic acid analog class

Answer 2

Methotrexate –> dihydrofolate reductase inhibitor

Question 3

Methotrexate mechanisms

Answer 3

Dihydrofolate reductase inhibition –> no THF for DNA/RNA synthesis
Polyglutamation traps drug inside cell

Question 4

Rescue drug given with methotrexate

Answer 4

Leucovorin –> folinic acid, acts as a folate cofactor, allows for some purine/pyrimidine synthesis
Prevents bone-marrow toxicity

Question 5

Unique mechanism of methotrexate resistance

Answer 5

Decrease in polyglutamation so drug is excreted through ABC transporters

Question 6

Unique toxicities of methotrexate

Answer 6

GI toxicity and renal precipitation

Question 7

Drugs that cannot be administered with methotrexate

Answer 7

NSAIDs and probenecid –> reduce renal clearance and increase toxicity

Question 8

Drugs in pyrimidine analogs class

Answer 8

1. 5-fluorouracil (5-FU)
2. Capecitabine
3. Gemcitabine
4. Cytarabine

Question 9

Mechanism of 5-FU

Answer 9

Inhibits thymidylate synthase –> cells die from lack of thymidine
***Requires metabolic activation to 5-FdUMP to inhibit

Question 10

Unique toxicities of 5-FU

Answer 10

Hand-foot syndrome

Question 11

Action of leucovorin given with 5-FU

Answer 11

Leucovorin drives thymidylate synthase to incorporate 5-FU into DNA (acts to enhance activity of 5-FU against thymidylate synthase)

Question 12

Capecitabine

Answer 12

Oral pro-drug of 5-FU

Hand-foot syndrome appears more frequently

Question 13

Mechanism of cytarabine

Answer 13

Converted to arabinose-CTP –> Resistance
Inhibits chain elongation
S phase specificity

Question 14

Unique toxicities of cytarabine

Answer 14

Severe myelosuppression, Stomatitis, elevated hepatic enzymes, pulmonary edema

Question 15

Gemcitabine mechanism

Answer 15

Deoxycytidine analog converted to triphosphate intracellularly
Results in chain termination

Question 16

Unique toxicities of gemcitibine

Answer 16

Interstitial pneumonitis –> treat with steroids

Question 17

Drugs in purine analogs class

Answer 17

1. 6-mercaptopurine
2. Thioguanine
3. Fludarabine

Question 18

6-mercaptopurine and thioguanine mechanism

Answer 18

Activated by HGPRTase to toxic nucleotides that inhibit enzymes in purine metabolism

Question 19

What should be done before giving 6-mercaptopurine and thioguanine?

Answer 19

Genotyping for SNPs in TPMT to prevent extreme toxicity due to variable metabolism

Question 20

Unique mechanism of resistance to mercaptopurine and thioguanine

Answer 20

Decrease or complete lack of HGPRT enzyme to prevent metabolic activation

Question 21

Dose-limiting toxicity of mercaptopurine or thioguanine

Answer 21

Bone marrow suppression

Question 22

Hydroxyurea mechanism

Answer 22

Free radical scavenger in catalytic center of ribonucleotide reductase –> prevents formation of deoxyribonucleotides

Question 23

Unique toxicities for hydroxyurea

Answer 23

Desquamative interstitial pneumonitis, skin toxicities (darkening of the skin)

Question 24

How does Hand Foot Syndrome occur? What are the symptoms?

Answer 24

Anticancer drugs escape from the capillaries in the hands and feet; erythema, swelling, and pain to the effected areas

Question 25

Capecitabine indications?

Answer 25

Metastatic Breast and Colorectal

Question 26

5-FU indication?

Answer 26

Colorectal (IV)

Question 27

Which drug of the antimetabolites is the most specific for S-phase of the cell cycle?

Answer 27

Cytarabine

Question 28

What drug should not be given with 6-Mercaptopurine? Why??

Answer 28

Allopurinol; because it inhibits a side pathway to an inactive metabolite and increases drug toxicity

Question 29

Overarching theme of most anticancer drugs concerning patient’s future reproductive potential??

Answer 29

They’re teratogenic, many cause infertility in both men and women