Azathioprine

• Chemistry, imidazolyl derivative of mercaptopurine (6-MP; 6-mercaptopurine)

  • Structural analog

  • Antimetabolite

• Primary use:  azathioprine: immunosuppression

• Prototype: cytotoxic immunosuppressive drugs

  • Kills profilerative cells

• Pharmacokinetic/Pharmacodynamics: azathioprine

  • Well absorbed from the GI tract

  • Metabolized to mercaptopurine (primarily)

  • Xanthine oxidase converts azathioprine to 6-thiouric acid

    •  Patients on xanthine oxidase inhibitors (allopurinol for management of hyperuricemia)-- dosage reduction required to prevent toxicity

  • Urinary excretion

  • Small amounts of mercaptopurine and unchanged drug also renally excreted

•  Mechanism of Immunosuppression Action:  azathioprine

  • Interference with nucleic acid metabolism

    • Reducing significant lymphoid cell proliferation following antigenic stimulation

  • Cytotoxic purine analogues: destroyed stimulated lymphoid cells

  • Blockade of:

    •   Cellular immunity

    •   Primary and secondary serum antibody responses

•  Clinical Use: azathioprine; mercaptopurine

  • Renal allograft maintenance

  • Effective/possibly effective,  management of:

    •   Acute glomerulonephritis

    •   Real component of systemic lupus erythematosus

    •   Rheumatoid arthritis

    •   Crohn's disease

    •   Multiple sclerosis

    •   Prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura

    •   Autoimmune hemolytic anemias

  • Toxicities:  azathioprine, mercaptopurine

    • Bone marrow depression

    • Leukopenia:  most common

    • Anemia

    • Thrombocytopenia which may cause bleeding

    • Skin rashes

    • Drug fever

    • Nausea and Vomiting

Cyclophosphamide

• Alkylating agent

• Very potent immunosuppressive agent

• Induces tolerance for marrow/immune cell grafting (does not prevent later graft vs. host syndrome)

• Kills proliferating lymphoid cells

  •  Alkylates some resting cells

• Lower doses (< 120 mg/kg):

  • Clinical Use: Efficacious for managing:

    • Autoimmune disorders

      • Systemic lupus erythematosus

      • Autoimmune hemolytic anemia

      • Antibody-induced pure red cell aplasia

      • Wegener's gramulomatosis

    • Acquired factor XIII antibodies/bleeding disorders

• Adverse Effects: large doses

  •  Pancytopenia

  •  Hemorrhagic cystitis

Vincristine

• Mechanism of action: microtubule depolymerization

  • Mitotic arrest at metaphase; interferes with chromosome segregation

• Clinical Use: Vincristine

  • Immunosuppression: idiopathic thrombocytopenic purpura refractory to prednisone

  • Useful in treating some other rapidly proliferating neoplasms

  • In combination with prednisone: induction of remission in children with acute leukemia

•   Adverse Effects:  vincristine

  • Aignificant frequency of neurotoxic reactions

  • Occasional: bone marrow depression

Vinblastine

• Mechanism of action: microtubule depolymerization

  • May prevent mast cell degranulation (binding to microtubule units)

    • Reduce histamine release

• Mitotic arrest at metaphase; interferes with chromosome segregation

• Clinical Use: Vinblastine

  • Systemic treatment of Hodgkin's disease

  • Lymphomas

•   Adverse Effects: Vinblastine

  • Nausea

  • Vomiting

  • Alopecia

  • Bone marrow suppression

 Methotrexate (MTX)

• Mechanism of Action: Folic acid antagonist: acts at catalytic site 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:  methotrexate

  •   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.

Dactinomycin

• IV administration; 50 percent remains unmetabolized.

• Mechanism of action: intercalation between guanine-cytosine base pairs

  •   Inhibits DNA-dependent RNA synthesis

  •   Blocks protein synthesis

• Clinical Uses:  Dactinomycin

  • In combination with vincristine and surgery (may include radiotherapy) in treatment of Wilms' tumor

  • With methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma.

  • May be useful in preventing acute renal transplant rejection

•   Adverse Effects:  Dactinomycin

  •  Major dose limiting toxicity: bone marrow suppression (all blood elements affected -- particularly platelets and leukocytes)

    • Occasional severe thrombocytopenia

  •  Nausea

  •  Vomiting

  •  Diarrhea

  •  Oral ulcers

  •  Dactinomycin: immunosuppressive (patient should not receive live virus vaccines)

  •  Alopecia/skin abnormalities

  •  Interaction with radiation ("radiation recall")