Purine antagonist

• Examples of purine antagonist include

  mercaptopurine, thioguanine, azathioprine, fludarabine
• Mercaptopurine and thioguanine are prodrugs.

  • metabolized to the monophosphate nucleotide form
  • inhibit the conversion of inosine monophosphate to adenine and guanine nucleotides.
  • the monophosphate nucleotide can be further metabolized to triphosphate form, incorporate into both DNA and RNA
• Interaction between mercaptopurine and allopurinol.

  1. mercaptopurine

  • drug choice for acute leukemia
  • pt with acute leukemia is at high risk of tumor lysis syndrome (TLS)
  • treatment: allopurinol, used to prevent TLS in patient without preexisting hyperuricemia (uric acid > 8mg/dL)

  - SE with this tx: increase toxicity of mercaptopurine

  - therefore, dose adjustment is needed

  - reduce 6-MP dose to 25-33% of usual dose
• Pyrimidine antagonists interfere with DNA synthesis by preventing incorporation of pyrimidines into DNA or RNA. They act by competing with natural substrates for enzymes involved in the biosynthetic pathway of pyrimidines. Pyrimidine antagonists have broad spectrum activity against most types of cancer cells but they are not effective against rapidly dividing normal tissues because these tissues rely on exogenous sources of pyrimidines.
• Allopurinol is a xanthine oxidase inhibitor. It is used to prevent TLS patient without preexisting hyperuricemia (uric acid > 8mgldl). It reduces nucleic acid (byproduct) to uric acid, thereby helping to prevent urate nephropathy and subsequent oliguric renal failure.
• Tumor lysis syndrome (TLS) is an metabolite abnormality due to sudden release of intracellular contents due to cellular integration induced by chemotherapy