Nursing Pharmacology: Antimetabolites
2Purines
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) is an 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
Lver toxicity
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