We describe two multiple sclerosis patients who developed pancytopenia following treatment with azathioprine. They were found to have the homozygous polymorphism for thiopurine methyltransferase deficiency and recovered after cessation of drug therapy. We review the literature concerning this molecular derangement and underscore the importance of performing surveillance testing for allelic characterization prior to treatment intervention with this agent for immune-mediated disorders.
Tidd DM , Paterson ARP.A biochemical mechanism for the delayed cytotoxic reactions of 6-mercaptopurine . Cancer Res1974; 34: 738-746 .
6.
Marathias VM , Sawicki MJ , Bolton PH.6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation . Nucleic Acids Res1999; 27: 2860-2866 .
7.
Weinshilboum RM , Sladek S.Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity . Am J Human Genet1980; 32: 651-662 .
8.
Lewis RW , Olivier G.In vitro oxidation of 6-MP and its metallocomplexes by xanthine oxidase . Res Commun Chem Pathol Pharmacol1977; 18: 377-380 .
9.
Schultz E , von Ahsen M , Oellerich M.Genotyping of eight thiopurine methyltransferase mutations: three-color multiplexing, two-color/shared anchor, and fluorescence-quenching hybridization probe assays based on thermodynamic nearest-neighbor probe design . Clin Chem2000; 46: 1728-1737 .
10.
Indjova D , Atanasova S , Shipkiva M , Armstrong VW , Oellerich M , Svinarov D.Phenotypic and genotypic analysis of thiopurine s-methyltransferase polymorphism in the Bulgarian population . Ther Drug Monit2003; 25: 631-636 .
11.
Lennard L , Van Loon JA , Weinshilboum RM.Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism . Clin Pharmacol Ther1989; 46: 149-154 .
12.
Clunie GPR , Lennard L.Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine . Rheumatology2004; 43: 13-18 .
13.
Evans WE.Pharmacogenetics of thiopurine s-methyltransferase and thiopurine therapy . Ther Drug Monit2004; 26: 186-191 .
14.
Coulthard SA , Rabello C , Robson J.A comparison of molecular and enzyme-based assays for the detection of thiopurine methyltransferase mutations . Br J Haematol2000; 110: 599-604 .
15.
Veenstra DL , Higashi MK , Phillips KA.[electronic resource] Assessing the cost-effectiveness of pharmacogenomics . AAPS PharmSci2000; 2: E29-E29 .
16.
Oh KT , Anis AH , Bae SC.Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea . Rheumatology2004; 43: 156-163 .
17.
Tavadia SM , Tdlarski PR , Reis MD , Mittmann N , Pinkerton PH , Shear Net al.Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case . J Am Acad Dermatol2000; 42: 628-632 .
18.
Marra CA , Esdaile JM , Anis AH.Practical pharmacogenetics: the cost effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine . J Rheumatol2002; 29: 2507-2512 .