Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine

Black, Alison; McLeod, Howard L.; Capell, H A; Powrie, Robert H.; Matowe, Lloyd; Pritchard, Stuart C.; Collie-Duguid, Elaina Susan Renata; Reid, David M.

doi:10.7326/0003-4819-129-9-199811010-00007

Cited by 345 publications

(196 citation statements)

References 13 publications

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…Genetic polymorphisms in the thiopurine S-methyl transferase (TPMT) gene have been associated with decreased TPMT activity and the development of myelotoxicity due to high thioguanine metabolite concentrations. 3,4 Moreover, inosine triphosphate pyrophosphatase (ITPA) deficiency has recently been associated with AZA toxicity because of the accumulation of 6-thioinosine-triphosphate. 5,6 Theoretically, low TPMT activity might also augment the therapeutic efficacy of thiopurines and lead to better long-term clinical outcomes.…”

mentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

View full text Add to dashboard Cite

There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P¼0.903) or ITPA (P¼0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy. Keywords: azathioprine; inflammatory bowel disease; inosine triphosphate pyrophosphatase; relapse; thiopurine S-methyl transferase INTRODUCTION Thiopurine drugs, 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA), are effective for the induction and maintenance of remission in patients with inflammatory bowel disease (IBD). 1,2 There has been tremendous interest with regard to thiopurine metabolism as a means of identifying ways in which individual therapy might maximize clinical response and minimize adverse effects. Genetic polymorphisms in the thiopurine S-methyl transferase (TPMT) gene have been associated with decreased TPMT activity and the development of myelotoxicity due to high thioguanine metabolite concentrations. 3,4 Moreover, inosine triphosphate pyrophosphatase (ITPA) deficiency has recently been associated with AZA toxicity because of the accumulation of 6-thioinosine-triphosphate. 5,6 Theoretically, low TPMT activity might also augment the therapeutic efficacy of thiopurines and lead to better long-term clinical outcomes. To confirm the usefulness of the TPMT/ITPA genotype or TPMT activity in clinical prediction, research regarding the relevance of measurement for prevention of both adverse effects and clinical outcomes is necessary. However, the impact of the TPMT/ITPA genotype on long-term clinical response of IBD patients treated with AZA/6-MP has not yet been examined. In this study, we investigated whether TPMT/ ITPA genotypes could affect long-term clinical outcomes as measured by disease relapse in Korean patients with IBD undergoing AZA or 6-MP treatment. MATERIALS AND METHODSA total of 204 patients with IBD (105 patients with Crohn's disease, 59 with ulcerative colitis and 40 with intestinal Behcet's disease) were initiated on AZA treatment during the s...

show abstract

mentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

View full text Add to dashboard Cite

show abstract

“…It was discovered that several rare variants in the TPMT gene correlated with decreased activity; homozygous individuals suffered substantial haematopoietic toxicity (Krynetski et al, 1996). Recently, it has been reported that children with inactivating TPMT variants are at a greater risk for relapse, perhaps reflecting inadequate administration of thiopurines (Black et al, 1998). Pediatric leukaemia patients with TPMT variants, who receive cranial irradiation, have a greater likelihood for secondary brain tumours.…”

Section: Outcome and Snpsmentioning

confidence: 99%

SNPs in cancer research and treatment

2004

View full text Add to dashboard Cite

Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10 -15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools (i.e., the single-nucleotide polymorphism, SNP) to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care.

show abstract

“…Moreover, combination therapy is more effective than treatment with steroids [1,14,28] or 5-aminosalicylic acids (5-ASA) alone [29]. Also, the combination of thiopurines and oral cyclosporine has proven to be safe and effective for maintenance of intravenous cyclosporine-induced remission of severe steroid-refractory UC [30,31], though monotherapy with thiopurines may be sufficient [32].…”

Section: Efficacymentioning

confidence: 99%

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

Derijks

Hommes²

2006

Curr Gastroenterol Rep

View full text Add to dashboard Cite

Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine

Abstract: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

Cited by 345 publications

References 13 publications

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

SNPs in cancer research and treatment

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

Contact Info

Product

Resources

About