The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia.

BACKGROUND: Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL. METHODS: Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). RESULTS: Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p = 0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034-8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486-19.198). CONCLUSIONS: In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage.

Association Between NR3C1 Gene Polymorphisms and Toxicity Induced by Glucocorticoids Therapy in Saudi Children with Acute Lymphoblastic Leukemia

Background: Glucocorticoids (GCs) are key hormones used for the treatment of acute lymphoblastic leukemia (ALL) in children, but their cytotoxic effects are not well defined. The aim of this study was to evaluate the association between polymorphisms in NR3C1 encoding for protein involved in the GCs metabolism and its role in the development of ALL and the toxicity outcome, in terms of liver toxicity, glucose abnormality and infections, in ALL Saudi children. Methods: The following polymorphisms BCII rs41423247, ER22/23 EK rs6189 and rs6190 and N363S rs6195 in NR3C1 were analyzed in 70 children with ALL treated according to the ALL 2000 study protocol in comparison to 60 control subjects. Treatment toxicities and their association with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). Results: This study demonstrated that the NR3C1 did not contribute to the development of childhood ALL. Homozygous ER22/23EK polymorphism was not found in both ALL patients and in control group whereas the heterozygous polymorphism was only observed in the control group (6.66%). The toxicology data in this study showed a significant difference between ALL patients carrying N363S polymorphism and wild type (40% and 6.51% respectively, P= 0.009) and a high-risk factor in the toxicity of glucose abnormality (OR=10.167; 1.302-79.339). BCII shows increased risk factors towards the liver toxicity (OR=2.667; 0.526-7.330) as well as the glucose abnormality (OR=7.5; 1.039-54.116). Conclusion: This study suggested that the polymorphisms in NR3C1 were not associated with the development of ALL in children. N363S polymorphism was sensitive to glucocorticoids and it may contribute to the glucose abnormality for these patients.