Antimetabolites

Question 1

Methotrexate

Answer 1

1. MOA: inhibits dihydrofolate reductase, blocks conversion of folic acid to THF, blocks DNA/RNA/protein synthesis. Leucovorin bypasses metabolic block by methotrexate (reduces toxicity). Resistance develops thru decreased uptake by tumor and increased target enzyme concentration.
2. SE: renal toxicity (hydrate), N/V/D, BM suppression, hepatotoxicity, pulmonary, teratogen
3. Use: leukemia, choriocarcinoma, burkitts/non-hodgkins, head/neck squamous cell, osteosarcoma, immunosuppression

Question 2

Pemetrexed

Answer 2

1. MOA: inhibits thymidylate synthase
2. SE: myelosuppression, rash, diarrhea, fatigue, hand-foot syndrome
3. Excreted in urine
4. Used w/cisplatin for mesothelioma and non-small cell lung cancer

Question 3

6-Mercaptopurine

Answer 3

1. MOA: inhibits purine synthesis/metabolism, must be activated by HGPRT (resistance by dec HGPRT)
2. Kinetics: metabolized by xanthine oxidase (breakdown blocked by allopurinol, reduce dose if allopurinol is used)
3. SE: Anorexia/N/V/D, gradual BM suppression, cholestatic jaundice, hyperuricemia
4. Use: Leukemia and immunosuppression

Question 4

Thioguanine

Answer 4

1. MOA: similar to 6-mercaptopurine, becomes incorporated into DNA/RNA inhibiting further syn.
2. Kinetics: not metabolized by xanthine oxidase, unaffected by allopurinol
3. SE: nause, myelosuppression w/leukopenia and thrombocytopenia
4. Use: part of combined therapy for AML

Question 5

5-Fluorouracil

Answer 5

1. MOA: pyrimidine analogue, enzymatically converted to nucleotide 5-FUMP which is active compound, binds to thymidylate synthase and locks it in an inhibited state.
2. Kinetics: Cell cycle specific-toxic to cells in G1 and S. Resistance occurs by decreased activation of drug and increased breakdown, requires folic acid-leucovorin increases response by providing folate
3. SE: Oral/GI ulceration, BM depression, anorexia and nausea, stomatitis, diarrhea
4. Use: solid tumors, topical cream for premalignant keratosis of skin and basal cell carcinomas, combined w/leucovorin for colorectal cancer.

Question 6

Capecitabine

Answer 6

1. MOA: oral prodrug that generates 5-FU selectively in tumor cells, activated by thymidine phosphorylase which is in higher concentration in tumor cells
2. SE: does not produce alopecia, myelosuppression is not common
3. Use: metastatic breast carcinoma resistant to paclitaxel, colorectal cancer

Question 7

Cytarbine

Answer 7

1. MOA: analogue of cytidine; activated in the cell to the triphosphate, tumor cells activate more rapidly than normal cells, inhibits DNA pol by competing w/deoxycytidine tri-P
2. Kinetics: cell cycle specific for S phase, IV admin by continuous infusion or every 8-12 hrs for 5-7 days.
3. SE: N/V, BM depression, severe leukopenia, thrombocytopenia and megaloblastic anemia.
   Use: intrathecal for meningeal leukemia, induces remission in AML and ALL

Question 8

Gemcitabine

Answer 8

1. MOA: deoxycytidine analogue, decreases ribonucleotides for DNA syn –> causes chain term, inhibits DNA pol
2. SE: N/V, flu like symp, BM depression
3. Use: advanced pancreatic cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, soft tissue sarcoma, non-hodgkins lymphoma

Question 9

Hydroxyurea

Answer 9

1. MOA: interferes w/conversion of ribonucleotide to deoxyribonucleotide (rate limiting step in DNA syn)
2. Kinetics: S phase specific, oral admin
3. SE: GI upset, BM suppression, alopecia, hyperpigmentation
4. Use: Chronic granulocytic leukemia, melanoma, ovary carcinoma