Thiopurine Pharmacogenetics

Thiopurines are a family of drugs that include mercaptopurine (MP) [a daily component of maintenance therapy for childhood acute lymphoblastic leukemia (ALL) treatment (89) and commonly used in the treatment of inflammatory bowel disease], thioguanine (used to treat acute myeloblastic lukemias), and azathioprine (a commonly prescribed immuno-suppressant used in solid organ transplants, rheumatic disease, and dermatologic disorders). The principal cytotoxic mechanism of these agents is the incorporation of thioguanine nucleotides (TGN) into DNA (Fig. 3). Thus, thiopurines are inactive prodrugs

Thioguanine nucleotides incorporation into DNA

Figure 3 6-MP is converted by HPRT to TGN, its active metabolites. Thioguanine nucleotides exert anticancer effects and myelotoxicity via incorporation into DNA. 6-MP is inactivated via methylation by TPMT to the active metabolite 6-MeMP. Inactivation can also occur through oxidation by xanthine oxidase (XO, not shown). Abbreviations: 6-MP, 6-mercapropurine; HPRT, hypoxanthine phosphoribosyl transferase; TGN, thioguanine nucleotides; TPMT, thiopurine methyl-transferase; 6-MeMP, 6-methylmercaptopurine.

6-MeMP (inactive)

6-MeMP (inactive)

that require metabolism to TGN to exert cytotoxicity. This activation is catalyzed by multiple enzymes, of which the first one is hypoxanthine phosphoribosyl transferase (HPRT). Alternatively, these agents can be inactivated via oxidation by xanthine oxidase (XO) or via methylation by thiopurine methyltransferase (TPMT). TPMT catalyzes the S-methyl-ation of the thiopurine agents, such as azathioprine, MP, and thioguanine (89,90), thereby shunting the drug away from TGN formation.

TPMT polymorphisms have been associated with the therapeutic efficacy and toxicity of MPs. TPMT activity is highly variable and polymorphic in all large populations studied to date; approximately 90% of the individuals have high activity, 10% have intermediate activity, and 0.3% have low or no detectable enzyme activity (91,92). Although eight TPMT alleles have been identified, three alleles {TPMT*2, TPMT*3A, TPMT*3C) account for about 95% of the intermediate or low enzyme activity cases (89,93-96). All three alleles are associated with lower enzyme activity due to enhanced rates of proteolysis of the mutant proteins (97). The presence of TPMT*2, TPMT*3A, or TPMT*3C is predictive of TPMT activity; patients heterozygous for these alleles all have intermediate activity, and subjects homozygous for these alleles are TPMT-deficient (96,98). In addition, compound heterozygotes (TPMT*2/3A, TPMT*2/TPMT*3C, TPMT*3A/3C) are also TPMT-deficient, as would be expected (96). Numerous studies have shown that TPMT-deficient patients are at very high risk of developing severe hematopoietic toxicity if treated with conventional doses of thiopurines (99,100). Studies have also shown that patients who are heterozygous at the TPMT locus are at intermediate risk of dose-limiting toxicity (101,102). In a study of 67 patients treated with azathioprine for rheumatic disease, six patients (9%) were heterozygous for mutant TPMT alleles, and therapy was discontinued in five of the six patients because of low leukocyte count within 1 month of starting the treatment (101). The sixth patient had documented noncompliance with azathioprine therapy. Patients with wild-type TPMT received therapy for a median of 39 weeks without complications, compared with a median of two weeks in patients heterozygous for mutant TPMT alleles. Futhermore, Relling et al. (102) showed that TPMT-deficient patients tolerated full doses of MP for only 7% of the scheduled weeks, whereas heterozygous and homozygous wild-type patients tolerated full doses for 65% and 84% of the scheduled weeks of therapy over the 2.5 years of treatment, respectively (102). However, another study using lower doses of 6-MP found no significant difference between heterozygous and homozygous wild-type TPMT patients in the median number of weeks in which 6-MP treatment could not be given at full dose due to hematological toxicity (103).

These studies demonstrate that the influence of TPMT genotype on hematopoietic toxicity is most dramatic for homozygous mutant patients but is also of clinical relevance for heterozygous individuals, which represent about 10% of the patients treated with these medications. The remaining 90% of the population carry two wild-type TPMT alleles; these individuals have full TPMT activity and do not require dose reduction. By using polymerase chain reaction (PCR)-based assays to detect the three signature mutations in these alleles, a rapid and relatively inexpensive assay is available to identify >90% of all mutant alleles (96,104). These results can then be used prospectively to determine safe starting doses for thiopurine therapy. Prospective analysis of TPMT genotype and/ or phenotype are now integrating into standard practice for many areas of medicine, in particular the treatment of inflammatory bowel disease, rheumatologic disease, and dermato-logical disorders. However, the use of TPMT testing would benefit from additional prospective studies of TPMT-guided dosing or some other method for objectively evaluating the utility of testing the patient's outcome.

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