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Pediatr Blood Cancer. 2016 Sep;63(9):1539-45. doi: 10.1002/pbc.26045. Epub 2016 May 10.

Association Between Combined Presence of Hepatitis C Virus and Polymorphisms in Different Genes With Toxicities of Methotrexate and 6-Mercaptopurine in Children With Acute Lymphoblastic Leukemia.

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Department of Clinical Pharmacy, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.
Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pediatrics, Hematology-Oncology Division, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.



The aim of the present study is to determine the correlation of hepatitis C virus (HCV) infection and polymorphisms in different genes with toxicity of either methotrexate (MTX) or 6-mercaptopurine (6-MP) administered to children with acute lymphoblastic leukemia (ALL).


One hundred children with low-risk ALL, who were treated according to the St. Jude Total therapy XV, were recruited. The recruited children were receiving MTX and 6-MP during maintenance phase. Patients were excluded from the study if they had other types of leukemia. Genotyping analyses for the thiopurine methyltransferase (TPMT), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferase (GST) genes were performed using a combination of polymerase chain reaction (PCR) and PCR-RFLP (where RFLP is restriction fragment length polymorphism) protocols. Relevant clinical data on adverse drug reactions were collected objectively (blinded to genotypes) from the patient medical records.


There was a significant correlation between the combined presence of HCV and TPMT*3B G460A gene polymorphisms and grades 2-4 hepatotoxicity as aspartate aminotransferase (AST) elevation (P < 0.04). The same observation was seen when comparing either the presence of HCV alone or the presence of the gene polymorphism alone. A significant association between the combined presence of HCV and MTHFR C677T polymorphism and grades 2-4 hepatotoxicity as alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) elevation was observed (P values <0.001, 0.02, and 0.001, respectively). The presence of HCV infection had a significant negative effect on hepatic transaminases.


The present data support a role for combining analysis of genetic variation in drug-metabolizing enzymes and the presence of HCV in the assessment of specific drugs toxicities in multiagent chemotherapeutic treatment regimens.


HCV; acute lymphoblastic leukemia; chemotherapy; children; genetic polymorphism; toxicities

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