Pyrimidine antagonist

• Example of pyrimidine antagonist include 5-fluorouracil, capecitabine, cytarabine, gemcitabine
• capecitabine & 5-fluorouracil

  • oral chemotherapy
  • prodrug, must be metabolized to nucleotide form - fluorodeoxyuridine monophosphate
• MOA of capecitabine and 5-fluorouracil

  • interference with both thymidine formation & RNA function
• MOA of 5-Fluorouracil:

  In the presence of folates, fluorodeoxyuridine monophosphates binds tightly to & interferes with the function of thymidylate synthase (required for synthesis of thymidine)
• Other MOA of 5-fluorouracil:

  • cytotoxic effect of 5-FU -> combine effects of both DNA & RNA mediated events

  1. 5-fluorouridine-triphosphate (FUTP): a metabolite of 5-FU, affects RNA site by incorporating into RNA to replace uracil as a false base, interfering with the RNA processing & transcription.
  2. 5-fluorodeoxyurinetriphosphate (FdUTP): another metabolite of 5-FU, affects cellular DNA by incorporating incorporating into cellular DNA, inhibiting the DNA synthesis & function.
• 5-fluorouracil toxicities:

  
  

  1.. schedule dependent

  2. bolus injection

  • N&V, alopecia, diarrhea, severe ulceration of oral & GI mucosa, myelosuppression, anorexia
  • Management: -

  (a) cryotherapy (ice ship when infusing 5-FU, vasoconstriction, mimic drug delivery to the site - for mucositis)

  (b) allopurinol mouthwash (reduce oral toxicity)

  3. continuous infusion regimen

  • hand-foot syndrome
  • less hematologic and gastrointestinal

  4. cardiotoxicity

  • can rechallenge with nitrate

  5. chest pain during and after infusion
• 5-FU bolus injection can cause N&V, diarrhea, alopecia, severe ulceration of oral and GI mucosa, myelosuppression, anorexia.

  What is the management?

  cryotherapy, allopurinol mouthwash
• what is the SE of continuous infusion of 5-FU?

  Hand-foot syndrome, but its is less hematologic and gastrointestinal