Interactions between 6-mercaptopurine therapy and thiopurinemethyl-transferase (TPMT) activity
Thiopurine-methyl-transferase (TPMT) is a key enzyme in the catabolism of 6-mercaptopurine into inactive 6methylmercaptopurine. Its activity is regulated by a genetic polymorphism. In a North American Caucasian population and in English children treated for acute lymphoblastic leukaemia 89 % have high activity, 11% have intermediate activity, and less than i % have undetectable activity [1]. The last are at high risk of 6-mercaptopurine toxicity. Other factors might be involved in the regulation of enzyme activity. It has previously been reported that men can tolerate a higher dose of 6-mercaptopurine than women [2]. This observation was recently supported by a Norwegian study showing higher enzyme activity in men [3], contrasting with the results of two other studies [1, 4]. In addition, the results of the former study suggested a geographical relation, in that the population living in the Northern part of the country had a greater enzyme activity than the Southern population. They also showed an interaction between enzyme activity and the use of diuretics or non-steroidal anti-inflammatory drugs. Furthermore, it has previously been suggested that the activity of TPMT may be induced by 6-mercaptopurine [4]; however, no serial measurements were performed while on treatment, so that the effect of long-term 6-mercaptopurine on TPMT activity over time is not fully understood. To address this problem directly, we have prospectively studied TPMT activity in 23 children treated in our institution for acute lymphoblastic leukaemia. The maintenance treatment consisted of daily oral 6-mercaptopurine (50 mg. m -2. day -1) adjusted to maintain granulocytes between 2 and 3 x 109/1, weekly oral methotrexate (25 rag-m -2-week -1) and for half of the patients monthly