Include mercaptopurine, thioguanine and azathioprine.
Principal mechanism of activity is the incorporation of 6-thioguanine nucleotides into DNA.
Are inactive prodrugs that require 6-thioguanine metabolism to exert cytotoxic affects.
Activation of the prodrug is catalyzed year multiple enzymes including hypoxanthome phosphoribosyl transferase.
6-mercaptopurine and 6-thioguanine useful in the treatment of childhood lymphoblastic leukemia.
6-mercaptopurine exerts cyto-toxic effects in part by conversion to thioguanine nucleotide metabolites that are incorporated into DNA with resultant damage.
6-mercaptopurine utilized in maintenance phase of treatment of childhood acute lymphoblastic leukemia.
6-thioguanine useful for intensive treatment of childhood acute lymphoblastic leukemia.
6-mercaptopurine and 6-thioguanine are pro-drugs which undergo intestinal and hepatic metabolic changes to form thioguanine nucleotides, which are incorporated into DNA in place of endogenous purine guanine.
Breaks in DNA and chromotid damage are the primary mechanisms of cytotoxicity.
The gene thiopurine methyltransferase (TPMT) modifies the metabolism of 6 mercaptopurine and can modify both the disease control and toxicity in children with ALL.
It is necessary to maximize adherence to 6-MP maintenance therapy to thiopurine exposure to minimize relapse children with ALL(Bhatia S et al).
About 15% of patients develop adverse drug reactions that necessary drug withdrawal.
Thiohpurine induced myelosuppression has a cumulative of 7% and usually occurs within a few weeks of starting the drug.
Most patients are asymptomatic, but serious opportunistic infections may occur and there is an estimated mortality of 1%.
The enzyme thiopurine S-methyltransferase (TPMT) converts thipurines to methylated metabolites, reducing the production of active thioguanine nucleotides.
Genetic variation in the TPMT gene can result in decreased TPMT enzyme activity and higher production of 6-thioguanine nucleotides, predisposing patients to bone marrow suppression.
Pre-treatment testing of TPMT is recommended to identify patients at risk for thiopurine induced myelosuppressio.
TPMT variants are found only in 25% of patients of European ancestry.