• Structural analogues: Neoplastic cells' metabolic differences -- increased susceptibility to actions of antimetabolites.

• Most antimetabolites interfere with nucleic acid synthesis or nucleotide synthesis.

•  Methotrexate (MTX)

  • Mechanism of Action: Folic acid antagonist: acts at catalytic side of dihydrofolate reductase

  • Polyglutamate: important in methotrexate action

  • Tumor resistance to methotrexate:

    • Decreased drug transport into the cell

    • Altered dihydrofolate reductase enzyme -- lower affinity for methotrexate

    • Decreased polyglutamate formation

    • Quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message)

  •  Adverse effects:

    • Bone marrow suppression

    • Dermatologic

    • GI mucosa

    • Adverse effects reversed by leucovorin (citrovorum factor)

      • Leucovorin "rescue" may be used in cases of over dosage or in high-dose methotrexate protocols

  • Other uses:

    • Treatment of rheumatoid arthritis

    • In combination with a prostaglandin: induces abortion

• 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

• Pyrimidine Antagonists:

  • Flurouracil (5-FU), normally given by IV administration (oral absorption erratic)

    • Biotransformed to ribosyl- and deoxyribosyl- derivatives.

      • Mechanism of Action:

        • One derivative, 5-fluoro-2'-deoxyuridine 5'-phosphate (FdUMP), inhibits thymidylate synthase and its cofactor,a tetrahydrofolate derivative, resulting in inhibition of thymidine nucleotide synthesis.

        • Another derivative, 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function.

        • Cytotoxicity:effects on both RNA and DNA

    • Clinical Use: Systemically -- adenocarcinomas; Topically: skin cancer

    • Floxuridine (FUDR): similar to 5-FU, used for hepatic artery infusion.

    •  Major Toxicity: myelosuppression, mucositis.

  • Cytarabine (ara-C) IV administration

    • Mechanism of Action:S phase-specific antimetabolite

      • Biotransformed to active forms: ara-CTP, competitive inhibitor of DNA polymerase.

        • Blocks DNA synthesis; no effect on RNA or protein synthesis

      • Cytarabine incorporated into RNA and DNA -- interfering with chain elongation

    • Clearance: deamination (inactive form)

    • S phase specificity: highly schedule-dependent

    • Clinical Use: almost exclusively for acute myelogenous leukemia

    •  Adverse Effects:

      • Nausea

      • Alopecia

      • Stomatitis

      • Severe myelosuppression

  • Azacitidine (IV administration):

    • Mechanism of Action: active derivatives inhibit orotidylate decarboxylase -- reducing pyrimidine nucleotide synthesis; azacitidine -- incorporated into DNA and RNA; inhibits DNA, RNA, and protein synthesis.

    • Investigational drug -- second-line agent in treatment of acute leukemia

    • Adverse Effect: myelosuppression.

Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911