Antimetabolites

• Purine Antagonists

  • 6-Thiopurines (Mercaptopurine [6-MP]; Thioguanine [6-TG])

  • Mercaptopurine (Purinethol)

    • Mechanism of Action:Activation by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form 6-thioinosinic acid which inhibits enzymes involved in purine metabolism. (thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) also active)

    • Clinical Use:

      • childhood acute leukemia

      • the analog, azathioprine (Imuran)-- immunosuppressive agent.

  • Thioguanine

    • purine nucleotide pathway enzyme-inhibitor

      • decreased intracellular concentration of guanine nucleotides

      • inhibition of glycoprotein synthesis

      • Mechanism of Action: inhibits DNA/RNA synthesis

    • Clinical Use:

      • Synergistic with cytarabine in treating adult acute leukemia.

    • Drug resistance

      • Decreased HGPRT activity

      • In acute leukemia -- increased alkaline phosphatase, which dephosphorylates thiopurines nucleotides

    •  Adverse Effects:

      • Both mercaptopurine and thioguanine, given orally, are excreted in the urine.

        • 6-MP is converted to an inactive metabolite, 6-thioruric acid, by xanthine oxidase .6-TG: requires deamination before metabolism by xanthine oxidase.

        • In cancer (hematologic) chemotherapy, allopurinol is used to inhibit xanthine oxidase, to prevent hyperuricemia associated with tumor cell lysis {xanthine oxidase inhibition blocks purine degradation -- purines (more soluble) are excreted instead of uric acid (less soluble)}

          • use of allopurinol thus blocks acute gout and nephrotoxicity.

        •  However, the combination of allopurinol and 6-mercaptopurine, because of xanthine oxidase inhibition, can lead to mercaptopurine toxicity; This interaction does not occur with 6-TG.

  • Fludarabine phosphate

    • parenteral administration; renal excretion

    • dephosphorylated to active form:

    • Mechanism of Action: DNA synthesis inhibition

    • Clinical Use:

      • lymphoproliferative disease

    • Adverse Effect: dose-limiting -- myelosuppression.

  • Cladribine:  (Leustatin)

    • phosphorylated by deoxycytidine kinase

      • incorporated into DNA

      • Mechanism of Action: increased strand breaks (inhibition of repair mechanisms)

    • Clinical Use:

      • Hairy cell leukemia

    • Adverse Effects:

      • Transient severe myelosuppression; possibly associated with infection.

  • Pentostatin:

    • irreversible inhibitor adenosine deaminase

      • results in toxic accumulation of deoxyadenosine nucleotides (especially in lymphocytes)

    • Adverse Effects:

      • immunosuppression (T cell mediated immunity)

      • myelosuppression

      • kidney function impairment

      • CNS toxicity

      • liver toxicity

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Mercaptopurine

Thioguanine

Fludarabine 

Cladribine

Pentostatin

• Primary Reference:  ¹Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911
• ²Angstadt, C., Purine and Pyrimidine Metabolism http://www.mcphu.edu/netbiochem/pupyr/pp.htm