Thioguanine 6Thioguanine

Thioguanine is an analogue of the natural purine gua-nine in which a hydroxyl group has been replaced by a sulfhydryl group in the 6-position. Two major mechanisms of cytotoxicity have been proposed for 6-thiogua-nine: (1) incorporation of the thio nucleotide analogue into DNA or RNA and (2) feedback inhibition of purine nucleotide synthesis. Both of these actions require initial activation of the drug by the enzyme hypoxanthine guanine-phosphoribosyltransferase (HGPRTase), as follows:

HGPRTase

6-Thioguanine->-6-thioguanosine-5-

(6-TG) monophosphate (6-TGMP)

The product of this reaction, 6-TGMP, can eventually be converted to deoxy-6-thioguanosine-triphos-phate (dTGTP), which has been shown to be incorporated into DNA. Resistance of human leukemia cells to thioguanine has been correlated with decreased activity of HGPRTase and to increased inactivation of the thio nucleotides by alkaline phosphatase.

Thioguanine is slowly absorbed after oral administration; parent drug levels are barely detectable, and peak levels of metabolites occur only after 6 to 8 hours. Total urinary excretion of metabolites in the first 24 hours is 24 to 46% of the administered dose.

Thioguanine is used primarily as part of a combined induction of chemotherapy in acute myelogenous leukemia.

Myelosuppression, with leukopenia and thrombocy-topenia appearing 7 to 10 days after treatment, and mild nausea are the most common adverse effects. Liver toxi-city with jaundice has been reported in some patients but appears to be less common than with mercaptopurine.

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