480 R. E. HANDSCHUMACHER AND A. I). WELCH 



Before discussing in further detail the proposed sites or mechanisms of 

 action of mercaptopurine, the metabolic disposition of this drug must be 

 considered. Most of the conversions are the counterparts of enzymic re- 

 actions for which the natural purines are substrates. Oxidation of mercap- 

 topurine by xanthine oxidase preparations forms thiouric acid (2,8-dihy- 

 droxy-6-mercaptopurine), 174 ' 175 which is a major catabolite found both in 

 mammalian 174 and bacterial systems. 176 From resting cell suspensions of 

 Bacillus cereus, the intermediate oxidation product thioxanthine (2-hy- 

 droxy-6-mercaptopurine) has also been isolated. 176 Following administra- 

 tion of mercaptopurine to mice, rats, and leukemic patients, small amounts 

 of 6-methylmercaptopurine 177 and an unidentified metabolite have been 

 isolated from the urine. 178 Another route of catabolism is desulfurization of 

 mercaptopurine, 174 ' 179, 179a presumably to yield hypoxanthine, a reaction 

 which although limited in some species has considerable significance, since 

 hypoxanthine effectively overcomes many of the inhibitory effects of the 

 analog. This reaction accounts in part for the incorporation of the radio- 

 activity into the purines of the nucleic acids of animals 174 and particularly 

 of microorganisms 180 treated with mercaptopnrine-8-C 14 . Of greater inter- 

 est, however, are the reactions which result in the formation of anabolic 

 derivatives of this antimetabolite. 



The formation in vivo of the ribonucleotides of mercaptopurine has been 

 demonstrated in mammalian and bacterial systems. 173 ■ 179 ■ 179a ' 181, 18 ' 2 In almost 

 all cases, populations of cells selected for resistance to mercaptopurine are 

 inefficient in this conversion as well as in the utilization of the analog as a 

 source of natural purines via desulfurization. Such evidence prompted the 

 chemical synthesis of mercaptopurine ribonucleoside 183 in an attempt to 

 overcome the inefficient conversion in resistant lines of cells, as well as to 

 reduce the steps required in the formation of the ribonucleotide derivatives 



174 G. B. Elion, S. Bieber, and G. H. Hitchings, Ann. N. V. Acad. Set. 60, 297 (1954). 



175 T. L. Loo, J. Am. Chem. Soc. 81, 3039 (1959). 



176 N. H. Carey and H. G. Mandel, Abstr. Meeting Am. Soc. Pharmacol. Exptl. Therap., 

 Ann Arbor, p. 8 (1958). 



177 E. J. Sarcione and L. Stiitzman, Proc. Am. Assoc. Cancer Research 2, 342 (1958). 



178 G. B. Elion and G. H. Hitchings, Federation Proc. 16, 177 (1957). 



179 R. W. Brockman, C. Sparks, D. J. Hutchison, and H. E. Skipper, Cancer Research 

 19, 177 (1959). 



179a R. W. Brockman, L. L. Bennett, Jr., M. S. Simpson, A. R. Wilson, J. R. Thomson, 

 and H. E. Skipper, Cancer Research 19, 856 (1959). 



180 M. E. Balis, V. Hylin, M. K. Coultas, and D. J. Hutchison, Cancer Research 18, 

 440 (1958). 



181 R. W. Brockman, C. Sparks, and M. S. Simpson, Biochim. et Biophys. Acta 26, 

 671 (1957). 



182 A. R. P. Paterson, Proc. Am. Assoc. Cancer Research 3, 50 (1959). 



183 J. A. Johnson and H. J. Thomas, J. Am. Chem. Soc. 78, 3863 (1956). 



