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Antimetabolites

  • 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

 

 

 
 
 

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