Genetic Variants in 6-Mercaptopurine Pathway as Potential Factors of Hematological Toxicity in Acute Lymphoblastic Leukemia Patients

Hareedy, Mohammad Salem; Desoky, Ehab S El; Woillard, Jean‐Baptiste; Thabet, Romany Helmy; Ali, Amany M.; Marquet, Pierre; Picard, Nicolas

doi:10.2217/pgs.15.62

Cited by 36 publications

(24 citation statements)

References 38 publications

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“…More data on the relationship between ITPA genotype and ADRs of thiopurine drugs have been reported in the literature . Some studies concerning the paediatric population are available with only two studies on paediatric patients with immune disease (IBD) . In paediatric populations, a relation between ITPA genotype with hepatotoxicity was reported in some studies but not all .…”

Section: Discussionmentioning

confidence: 99%

“… reported a significant association between inosine triphosphatase IVS2+21A→C variants with thrombocytopenia, Hareedy et al . found significant associations between ITPA single‐nucleotide polymorphisms (SNPs) and haematological toxicity manifestations (neutropenia and leukopenia), Dorababu et al . reported that TPMT and ITPA genotypes together can explain 27% of the variability in haematological toxicity, and Azimi et al .…”

Section: Discussionmentioning

confidence: 99%

“…The potential implication of ITPA in the occurrence of ADRs of AZA has been investigated. However, a number of contradictory results have been reported, from an impact of ITPA polymorphism on toxicity to no significant association . This issue remains unresolved, and no obvious statement about the benefit of introducing ITPA assay into clinical practice is currently available .…”

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confidence: 99%

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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“…Moreover, considering there is an obligation to get both an informed consent and an informed assent, we believe this is a good starting number of subjects. In relation to that, there are several recent published studies with relatively small number of children (Roy Moulik et al, 2015 ; Amitai et al, 2016 ) and even more, with adults with ALL (Hareedy et al, 2015 ). Despite this, we truly believe our results are only a preliminary contribution regarding the ALL susceptibility of our Mexican pediatric population.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

et al. 2016

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Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

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“…In previous years, there has been substantial development in understanding the chemotherapeutics mechanisms of pharmacogenetics and pharmacogenomics (13–15). The cytotoxic effect of chemotherapeutics against tumor cells has significant associations with the expression of specific genes or gene polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia

Huang

Wang

Qian

et al. 2017

Molecular Medicine Reports

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The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A5*3. PCR was then used to express the mRNA expression of CYP3A5. A midazolam probe method was used to detect CYP3A enzyme activity, and DNR concentrations were measured using high performance liquid chromatography. Children with different genotypes had different mRNA expression levels of CYP3A5, and CYP3A enzyme activity in children with the CYP3A5*1 allele was higher, compared with that in children with the CYP3A5*3 allele. In addition, the area under the curve (AUC)0–24 h and AUC0-∞ of DNR were significantly different in children with different genotypes, however, no statistically significant differences were found in half-life or maximum concentration. The AUC of DNR was increased in children with acute lymphatic leukemia who suffered from cardiotoxicity, compared with those in the normal group. The CYP3A5*3 gene polymorphism was closely associated with the mRNA expression of CYP3A5, CYP3A enzyme activity and DNR plasma drug concentration, and exhibited different drug adverse reactions.

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Genetic Variants in 6-Mercaptopurine Pathway as Potential Factors of Hematological Toxicity in Acute Lymphoblastic Leukemia Patients

Abstract: Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Cited by 36 publications

References 38 publications

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia

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