•  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.

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