الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Acute lymphoblastic leukaemia (ALL) is the most frequent type of childhood malignancy. It accounts for 30% of all cancers detected in children under the age of 15 years. It is often grouped according to cell lineages and frequently manifests as weariness, pallor, lymphadenopathy, hepatosplenomegaly, and bone pain. ALL is distinguished by uncontrolled proliferation of abnormal cells and a cessation in the formation of normal lymphoid progenitor cells. As a result, normal bone marrow cells are replaced by malignant lymphoblasts, impairing homeostatic hematogenous and immunological activities. Identifying risk factors for childhood leukaemia (e.g., environmental, genetic, infectious) is a crucial step toward lowering the disease’s overall burden.
Tobacco smoke contains over 4,000 chemicals, some of which are carcinogenic. Carcinogens are the primary cause of malignancies caused by smoking. Tobacco use has been related to an increased risk of developing ALL in children. Children who are exposed to smoking have a 6% increased risk of having ALL. Tobacco carcinogens have been shown to harm both somatic and germ cells. Tobacco smoking may be a substantial source of these harmful components intake not only for smokers but also for non-smokers via passive smoking. Smoking is not only related with lower levels of various antioxidant vitamins and trace elements, but also with an elevated morbidity and mortality risk for a variety of diseases due to its effect on endothelial function via oxidative stress and inflammation. The imbalance between the formation of free radicals/reactive oxygen species (ROS) and the antioxidant defence mechanisms causes oxidative stress, which can activate numerous transcription factors and influence their transcriptional pathways. Oxidative stress is linked to the treatment and prognosis of leukaemia and plays a key role in its onset and progression.
ALL cancers are often treated aggressively with numerous chemotherapeutic drugs that carry a variety of toxicity risks. ALL treatment success is associated to sufficient maintenance therapy required to prolong the achieved remission. 6-mercaptopurine (6-MP) is a widely used chemotherapeutic drug in the treatment of ALL. Despite the recognised efficacy of 6-MP in ALL, treatment of this disease remains challenging because of significant variability in toxicity among individuals, including life-threatening leukopenia. This significant toxicity frequently leads to the cessation or abandonment of potentially beneficial anticancer therapy, which contributes to an increased prevalence of late relapse. 6-MP intolerance is primarily caused by a decrease in the activity of the enzyme thiopurine S-methyltransferase (TPMT), which is involved in 6-MP metabolism and exhibits extensive inter-individual variability, owing in part to genetic polymorphisms. Molecular testing is a viable way to examine TPMT enzyme performance in ALL people prior to starting 6-mercaptopurine therapy. A patient with low thiopurine methyltransferase activity may be susceptible to haematological damage. In such cases, a lower 6-MP dose is recommended.
The purpose of this study was to see how passive smoking and thiopurine methyltransferase genetic variations affected 6-mercaptopurine toxicity in children with Acute Lymphoblastic Leukemia. This study included 50 children with ALL who were chosen as patients, and 50 healthy children who were chosen as controls.
Blood samples were collected from all participants (patients and controls) prior to the start of maintenance therapy to assess the level of cotinine as a biomarker of passive tobacco smoking; malondialdehyde (MDA) and total antioxidant capacity (TAC) to assess oxidative stress status; TPMT genotyping to detect genetic variants; and assessment of 6-MP toxicity- related factors including haematological parameters (CBC), hepatic enzymes (ALT and AST), and renal function (creatinine). After six months of maintenance, all of these 6-MP toxicity-related markers were reassessed, and all data were statistically analysed using the R-statistics programme version 4.0.4.
In the current study, there was a highly statistically significant difference in cotinine levels between patients and the control group. This implies that the patients were exposed to passive smoking. MDA levels in patients were substantially greater than in the control group, but TAC levels were significantly lower. This demonstrates that all of the ALL children were experiencing oxidative stress. Both haemoglobin concentration and platelet count were significantly lower in patients before 6-MP treatment than in the control group, which was predominantly due to infiltrating blasts suppressing normal haematopoiesis in the bone marrow.
The prevalence of TPMT genetic variants in ALL children in the current study was 8% (4/50) only with hetero type (TPMT*3C), whereas all children in the control group were wild type (50/50). The current findings show that children in the control group have the same level of AST and ALT as the patients prior to therapy. These levels, however, increased considerably following therapy, indicating that thiopurines contribute to drug-induced liver injury. However, there was no statistically significant difference in creatinine levels when comparing the control group to patients before medication or before and after treatment groups. This suggests that 6-MP has no significant effect on the kidney.
To assess the toxic effect of 6-MP on the liver and bone marrow of ALL children and its relationship to the TPMT genotype, the correlations between TPMT genotypes and 6-MP toxicity related markers (haematological parameters and liver functions) were determined. The primary worry was the WBC count. The WBC count was severely reduced in 75% of heterogeneous patients. In contrast, the majority of individuals with the wild-genotype had mild-to-moderate declines in WBC count, with only 9% having severe decreases. This significant DROP in WBC counts indicates myelosuppression.
Furthermore, the correlation between cotinine levels and toxicity related- markers (haematological parameters and liver enzymes) after six months of 6-MP medication was evaluated. All of these correlations were found to be non-significant, implying that there was no susceptibility to nicotine effects regardless of parental consumption.
According to these current findings, TPMT polymorphism enhanced the risk of 6-MP-related haematological toxicity and myelosuppression, with the heterozygous form having the most severe consequence. This emphasises the necessity of identifying common TPMT variations in ALL children prior to treatment regimens with 6-MP medicines, which could aid in adjusting 6-MP doses and reducing related toxicity. Furthermore, the current findings show that passive smoking history had no effect on 6-MP-induced myelosuppression.