B-33. Cancer Chemotherapy - antimetabolites

Question 1

Antifolate Drugs

Answer 1

Inhibit the synthesis of thymidine (pyrimidine deoxynucleotide) catalyzed by thymidylate synthetase (methylation of dUMP → dTMP) using a methylated H4-folate (methylene-THF becomes DHF).
THF is re-formed from DHF by DHF reductase which is then re-methylated and used again.

1. Methotrexate (MTX)
2. Pemetrexed

Question 2

Methotrexate (MTX) (MOA, kinetics, indications, SE)

Answer 2

1. MOA: acts as a folate analog → uses membrane transporters to enter cell → form MTX-polyglutamates which irreversibly inhibit DHF reductase + thus folate/dTMP synthesis (→ DHF builds up in cell).
   * MTX-polyGlu also inhibits thymidylate synthesis and AICAR transformylase (↓ chemotaxis) and synthesis of some purines / AAs.
2. Kinetics: oral or parenteral; given IV if high conc. desired systemically; intrathecally for CNS effects
   NSAIDs, penicillins + cephalosporins inhibit MTX renal elimination
3. Indications:
   a. Solid tumors - breast cc. (combo with CP + 5-FU); head + neck, lung cc.
   b. Lymphoma - NHL (including w/ CNS involvement)
   c. Autoimmune conditions - RA, psoriasis, IBD, SLE (lower doses)
   d. Childhood Tumors - Wilms’, choriocarcinoma (as monotherapy), etc.
   e. (Abortion / Early Ectopic Pregnancy - in combo with misoprostol; inhibits trophoblast division)
4. Side Effects:
   a. Folate Deficiency - in normal cells as well, leading to megaloblastic anemia + pancytopenia
   * “Leucovorin rescue” - leucovorin = folinic acid; treats folate deficit in normal cells, but some tumor cells can’t take it up → MTX still effective
   b. Hepatotoxicity - ↑ LFTs common; fibrosis/cirrhosis more rare)
   c. Pulmonary Fibrosis - restrictive lung disease

Question 3

Pemetrexed (indications

Answer 3

mechanism is similar to MTX.

indications: NSCLC, mesothelioma, solid tumors (combo w/ cisplatin).

Question 4

Pyrimidine Antagonists

Answer 4

• inhibit de novo synthesis
• Drugs-
  
  1. 5-Fluorouracil (5-FU).
  2. Capecitabine.
  3. Hydroxyurea.

Question 5

5-Fluorouracil (5-FU) (MOA, kinetics, SE, indications)

Answer 5

1. MOA: a pyrimidine analog that complexes with THF and inhibits thymidylate synthase; forms false nucleotides (5-F-dUMP) that incorporate into DNA/RNA and alter their function.
   * Because thymidylate synthase is more directly inhibited by 5-FU than MTX, leucovorin rescue therapy is not effective with 5-FU!
2. Kinetics: given IV; short DOA → multiple hours infusion.
3. Side Effects:
   a. Cardiotoxic and neurotoxic
   b. Skin reactions - photosensitivity, hyperpigmentation and rashes

Indications:

a. Solid tumors - breast cc. (combo with CP / MTX).
b. colorectal and gastric cc.
c. BCC
d. head + neck
e. liver and pancreas cc.

Question 6

Capecitabine (MOA, kinetics, indication, SE)

Answer 6

1. MOA: prodrug of 5-FU; activation requires thymidine phosphorylase which is most active in tumor cells
2. Kinetics: good oral availability
3. Indications: same as 5-FU
4. Side Effects:
   
   • mostly milder than 5-FU, less GI / marrow sfx.
     a. Skin reactions - +/- ulceration, exfoliation
     b. Worse neuropathy than 5-FU

Question 7

Hydroxyurea (MOA, indications)

Answer 7

1. MOA: inhibits ribonucleotide reductase → ↓ UDP-to-dUDP conversion → ↓ pyrimidine deoxynucleotides.
2. Indications:
   a. AML, CLL and head + neck cc.
   b. Sickle cell anemia - to treat veno-occlusive crises via ↑ HbF production.

Question 8

Purine Antagonists

Answer 8

1. 6-Mercaptopurine (6-MP).
2. 6-Thioguanine (6-TG).
3. Fludarabine and cladribine.

Question 9

6-Mercaptopurine (6-MP) (MOA, kinetics, SE, indications)

Answer 9

1. MOA: is a prodrug converted by HGPRT to active metabolites that inhibit PRPP → IMP (inosine monophosphate) and IMP → AMP/GMP conversion + thus de novo purine nucleotide synth.
2. Kinetics: good oral availability; metabolized by xanthine oxidase
   * allopurinol inhibits XO → must ↓ 6-MP dose if using allopurinol for tumor lysis syndrome
3. Side Effects:
   Hepatotoxicity
4. Indications:
   ALL - acute lymphocytic leukemia

Question 10

6-Thioguanine (6-TG) (MOA, kinetics, indications)

Answer 10

1. MOA: same as 6-MP
2. Kinetics: no interaction with allopurinol!
3. Indications: AML - acute myeloid leukemia

Question 11

Fludarabine + Cladribine (MOA, kinetics, SE, indications)

Answer 11

1. MOA: are purine analogs that inhibit DNA polymerase α/β + incorporate into DNA → breakage
   * is resistant to adenosine deaminase (a purine disposal enzyme) → reaches high IC concentrations
2. Kinetics: given parenterally with short DOA → multiple days of admin
3. Side Effects:
   a. Immunosuppression - very strong; infection reactivation, esp. P. jiroveci (give w/ 1 yr TMP-SMX)
   b. CNS toxicity - at high doses
4. Indications:
   Leukemias and lymphomas - CLL; NHL;
   (cladribine is DOC for hairy cell leukemia).

Question 12

Deoxycytidine Analogs

Answer 12

• inhibit DNA polymerases.

1. Cytarabine.
2. Gemcitabine.

Question 13

Cytarabine (MOA, kinetics, indications, SE)

Answer 13

1. MOA: pyrimidine analog; triphosphate metabolites inhibit DNA polymerases α / β
2. Kinetics: given IV for 5-7 day infusion (fast degradation)
3. Indications: leukemias + lymphomas - NHL and AML especially
4. Side Effects: neurotoxicity - hand/foot neuropathy, CNS effects; rarely used due to this

Question 14

Gemcitabine (MOA, indications, SE)

Answer 14

1. MOA: similar to cytarabine; metabolites can cause chain termination + inhibit ribonucleotide reductase
2. Indications:
   a. Solid tumors - pancreatic, NSCLC, ovarian + bladder cc.
   b. Some lymphomas + leukemias
3. Side Effects:
   a. Hypotension - severe, life-threatening
   b. Flu-like syndrome
   c. Neuropathy - hand/foot paresthesia