Abstract
Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukaemia (CML), can cause lower gastrointestinal (GI) toxicity which is manifested as diarrhoea. The mechanisms are not fully understood. The enteroendocrine signalling compound, serotonin (5-HT), is important for regulating peristaltic motion, fluid secretion and visceral hypersensitivity in the GI tract, and has been implicated in diseases such as irritable bowel syndrome. In this study, we have evaluated whether TKI-induced diarrhoea may be related to variation in the serotonin re-uptake transporter (SERT) gene. CML patients with and without diarrhoea on the SPIRIT2 trial (imatinib, n = 319; and dasatinib, n = 297) were genotyped for the promoter 5-HTTLPR, intron 2 VNTR and rs25531 polymorphisms by PCR-based methods. Diarrhoea was more prevalent in imatinib, than in dasatinib treated patients (P = 0.015), which when stratified by gender was seen to be driven by female patients (P = 0.036). Logistic regression analysis revealed that age, and the dominant HTTLPR with the rs25531 single nucleotide polymorphism (SNP) model, explained the occurrence of diarrhoea in ~10% of imatinib-treated female CML patients. These data suggest SERT polymorphisms influence imatinib-induced diarrhoea but not that of dasatinib.
Highlights
Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukaemia (CML), can cause lower gastrointestinal (GI) toxicity which is manifested as diarrhoea
Of the patients recruited to the SPIRIT2 trial, we excluded patients from this study for the following reasons: 1) no consent or sample given; 2) mention of constipation; 3) co-morbidities involving the GI tract; 4) documented co-medications that would influence diarrhoea or serotonin levels including selective serotonin re-uptake inhibitors; and 5) no PCR product due to poor DNA
A study performed in 2622 European-American subjects, using the National Institute of Mental Health repository, found that the 5-HTTLPR short allele frequency was 43%24, which is identical to our findings
Summary
Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukaemia (CML), can cause lower gastrointestinal (GI) toxicity which is manifested as diarrhoea. Logistic regression analysis revealed that age, and the dominant HTTLPR with the rs25531 single nucleotide polymorphism (SNP) model, explained the occurrence of diarrhoea in ~10% of imatinib-treated female CML patients. These data suggest SERT polymorphisms influence imatinib-induced diarrhoea but not that of dasatinib. Regulation of circulatory levels of 5-HT is performed by the serotonin reuptake transporter (SERT) Both GI epithelial cells and platelets express high levels of SERT and are capable of sequestering excess 5-HT which, when required, can be released as part of a tissue damage response[7]
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