B-33. Cancer chemotherapy I (antimetabolites)

Question 1

Antimetabolite drugs

Answer 1

• Methotrexate
• Premetrexed
• 5-Fluorouracil
• Capecitabine
• 6-Mercaptopurine
• 6-Thioguanine
• Cytarabine
• Gemcitabine
• Bleomycin
• Actinomycin D

Question 2

How are healthy cells vs tumor cells effected by antimetabolites? Which part of the cell cycle is halted by antimetabolites?

Answer 2

Tumor cells are more rapidly-dividing and thus more sensitive to anti-metabolites than healthy cells. Antimetabolites are “cell-cycle specific”, stopping cells in S phase.

Question 3

Resistance mechanism of tumor cells to antimetabolites

Answer 3

1. Decreased cellular drug uptake
2. Decreased activating enzyme activity
3. Increased enzymatic degradation
4. Increased repair mechanisms

Question 4

Side effect of all antimetabolites

Answer 4

Side Effects: all antimetabolites result in some degree of myelosuppression and GI effects (mucositis + diarrhea)

Question 5

Antifolate drugs include

Answer 5

Methotrexate and Pemetrexed

Question 6

How do Antifolate drugs work

Answer 6

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.

Question 7

Methotrexate MOA

Answer 7

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

Question 8

Kinetics of Methotrexate How is it given? Drugs that inhibit it’s renal elimination?

Answer 8

• Methotrexate Kinetics: oral or parenteral; given IV if high conc. desired systemically; intrathecally for CNS effects
  
  • NSAIDs, penicillins + cephalosporins inhibit MTX renal elimination

Question 9

Methotrexate Indications

Answer 9

• Indications of Methotrexate:
  
  • Solid tumors - breast cc. (combo with CP + 5-FU); head + neck, lung cc.
  • Lymphoma - NHL (including w/ CNS involvement)
  • Autoimmune conditions - RA, psoriasis, IBD, SLE (lower doses)
  • Childhood Tumors - Wilms’, choriocarcinoma (as monotherapy), etc.
  • (Abortion / Early Ectopic Pregnancy - in combo with misoprostol; inhibits trophoblast division)

Question 10

Side effects of Methotrexate

Answer 10

• Side Effects:
  
  • 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
  • • ↑ LFTs common; fibrosis/cirrhosis more rare)
  • Pulmonary Fibrosis - restrictive lung disease

Question 11

Pemedtrexed indication

Answer 11

Pemetrexed - similar to MTX; indicated in NSCLC, mesothelioma, solid tumors (combo w/ cisplatin)

Question 12

Pyrimidine antagonist

Answer 12

• Pyrimidine Antagonists:
  
  1. 5-Fluorouracil
  2. Capecitabine
  3. Cytarabine
  4. Gemcitabine

Question 13

5-Fluorouracil (5-FU) MOA

Answer 13

• 5-Fluorouracil (5-FU) 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!

Question 14

5-Fluorouracil (5-FU) kinetics

Answer 14

Given IV; short DOA → multiple hours infusion

Question 15

5-Fluorouracil (5-FU) side effects

Answer 15

• 5-Fluorouracil (5-FU) Side Effects:
  
  • Cardiotoxic and neurotoxic
  • Skin reactions - photosensitivity, hyperpigmentation and rashes

Question 16

5-Fluorouracil (5-FU) indications

Answer 16

• 5-fluorouracil indications:
  
  • Solid tumors - breast cc. (combo with CP / MTX); colorectal and gastric cc.; BCC; head + neck, liver and pancreas cc.

Question 17

Capecitabine MOA? Kinetics? Indication?

Answer 17

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

Question 18

Deoxycytidine Analogs: inhibit DNA polymerases (drugs)

Answer 18

Cytarabine and Gemcitabine

Question 19

• Cytarabine
  
  • MOA?
  • Kinetics?
  • Indication?
  • Side effects?

Answer 19

Cytarabine

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

Question 20

• Gemcitabine
  
  • MOA?
  • Indication?
  • Side effects?

Answer 20

Gemcitabine

• MOA: similar to cytarabine; metabolites can cause chain termination + inhibit ribonucleotide reductase
• Indication:
  
  • Solid tumors - pancreatic, NSCLC, ovarian + bladder cc.
  • Some lymphomas + leukemias
• Side Effects:
  
  • • severe, life-threatening
  • Flu-like syndrome
  • • hand/foot paresthesia

Question 21

Purine antagonist (drugs)

Answer 21

• Purine Antagonists:
  
  1. 6-Mercaptopurine
  2. 6-Thioguanine
  3. Cladribine and fludarabine

Question 22

• 6-Mercaptopurine (6-MP)
  
  • MOA?
  • Kinetics?
  • Side effects?
  • Indication in chemotherapy?

Answer 22

6-Mercaptopurine (6-MP)

• 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
• Kinetics: good oral availability; metabolized by xanthine oxidase
  
  • allopurinol inhibits XO → must ↓ 6-MP dose ifusing allopurinol for tumor lysis syndrome
• Side Effects:
  
  • Hepatoxicity
• Indication:
  
  • ALL - acute lymphocytic leukemia

Question 23

• 6-Thioguanine (6-TG)
  • MOA?
  • Kinetics?
  • Indications?

Answer 23

• 6-Thioguanine (6-TG)
  • MOA: same as 6-MP
  • Kinetics: no interaction with allopurinol!
  • Indications: AML - acute myeloid leukemia

Question 24

• Fludarabine and cladribine
  
  • MOA?
  • Kinetics?
  • Side Effects?
  • Indications?

Answer 24

• Fludarabine and cladribine
  
  • 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
  • Kinetics: given parenterally with short DOA → multiple days of admin
  • Side Effects:
    
    • Immunosuppression- very strong; infection reactivation, esp. P. jiroveci (give w/ 1 yr TMP-SMX)
    • CNS toxicity - at high doses
  • Indications:
    
    • Leukemias and lymphomas - CLL; NHL; cladribine is DOC for hairy cell leukemia