Multiple Steps—Purine Analogues

6-Mercaptopurine is a structural analogue of hypoxan-thine and is converted to thio-IMP in the salvage pathway. 

Thio-IMP prevents production of AMP and GMP by inhibiting the following reactions  

6-Mercaptopurine is used in the treatment of acute leukemias. However, resistant tumor cells develop rapidly, probably because of altered specificity or lack of phospho-ribosyltransferases, so that thio-IMP (the active inhibitor) is not formed. In support of this mechanism, resistant cells respond to 6-methylmercaptopurine ribonu-cleoside, which is phosphorylated to the corresponding nucleotide. Other mechanisms may include altered cell permeability and increased rate of destruction of 6-mercaptopurine. 

6-Mercaptopurine is partially metabolized to 6-thiouric acid (which lacks antitumor activity) by xanthine oxidase. Allopurinol, a xanthine oxidase inhibitor used in the treatment of gout, potentiates the action of 6-mercaptopurine by preventing its conversion to 6-thiouric acid. This effect is taken into consideration in treatment. Mercaptop-urines are also inactivated by S-methylation carried out by thiopurine S-methyltransferase (TPMT), particularly in hematopoietic tissues which lack xanthine oxidase. Deficiency of TPMT due to polymorphisms causes profound toxicity with the regular therapeutic regime. This is another example of the use of pharmacogenomics. 

Azathiopurine, a derivative of 6-mercaptopurine, functions as an antiproliferative agent. Its principal use is as an immunosuppressive agent. It presumably releases 6-mercaptopurine in the body by reacting with sulfhydryl compounds such as GSH. 

---