الفهرس 
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Abstract
Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic tissues that is characterized by accumulation of abnormal blast cells, principally in the marrow, and impaired production of normal blood cells. There is considerable heterogeneity between cases of AML as regards morphology, immunological phenotype, associated cytogenetic and molecular abnormalities, and patterns of gene expression. Pretreatment conventional cytogenetic studies identify an acquired clonal abnormality in approximately 50% - 60% of patients with de novo AML, of which 10% - 12% are complex karyotypes that have very poor outcome. The rest 40% - 50% of cases, have no karyotypic abnormality, yielding an AML with normal karyotype. All such cases of cytogenetically normal AML are currently categorized in the intermediate-risk group, yet this group is quite heterogeneous.
The backbone of remission induction consists of an anthracycline (daunorubicin) and cytosine arabinoside (Ara-C), a regimen that has not changed in over 30 years. Daunorubicin is given at a dose of 45 mg/m2/day for 3 days, in combination with Ara-C, which is administered as a continuous infusion at 100 mg/m2/day for 7 days (frequently referred to as 3+7 chemotherapy). It is unusual for induction chemotherapy not to clear most of the leukemic blasts; however, this is at a cost of 3 - 4 weeks of severe pancytopenia. Supportive care throughout the period of marrow suppression is crucial to treatment outcome.
The human genome is constantly attacked by endogenous reactive metabolites, therapeutic drugs and a plethora of environmental mutagens that impact its integrity. Thus it is obvious that the stability of the genome must be under continuous surveillance. Homologous Recombination repair (HR) is a major DNA repair pathway in eukaryotic cells. It is responsible for the repair of DNA gaps, DNA double-stranded breaks (DSBs), and DNA interstrand crosslinks (ICLs). XRCC3 protein is required for the assembly or stabilization of a multimeric form of Rad51 during HR repair. ATP hydrolysis activity of XRCC3 is necessary at another step during HR repair.
The anticancer activity of most chemotherapy drugs relies on the induction of DNA damage in rapidly cycling tumor cells. Consequently, the regula¬tion of DNA repair pathways in tumor cells is a critical factor for their response to chemotherapy drugs and may influence drug toxicity and remission.
Aim of the study:
Evaluation of XRCC3 polymorphism Thr241Met (C→T) in relation to the response to induction chemotherapy as well as the chemotherapy-induced toxicities in adult cytogenetically normal AML patients.
This study included:
This study included 50 adult Egyptian patients (over 18 years old) with newly diagnosed de novo cytogenetically normal AML of both sexes presented to the Department of Hematology, Medical Research Institute, Alexandria University. Those over 60 years old and those with comorbid conditions and/or poor performance status were excluded. Patients with acute promyelocytic leukemia (AML M3) were not enrolled in this study, because of the different chemotherapy regimen adopted for them, and patients who died during monitoring were also excluded.
Patients were subjected to a number of investigations:
Clinical examinations and laboratory tests were performed at presentation and a three milliliter sample of venous blood was collected from each patient. Patients were treated by the standard remission induction protocol (3+7). During chemotherapy, patients were monitored for possible toxic effects induced by chemotherapy. Response to chemotherapy was evaluated after regeneration from chemotherapy-induced bone marrow aplasia, patients who failed to achieve complete remission were subjected to a second similar course of chemotherapy. DNA was extracted from the collected blood samples and the XRCC3 polymorphism (XRCC3 Thr241Met) wase determined using PCR-RFLP. And statistical analysis of the obtained data was performed.
Results of the study:
XRCC3 Thr241Met polymorphism, was not associated with the response to chemotherapy and chemotherapy-induced hepatotoxicity, nephrotoxicity, and cardiac toxicity but was associated with metabolic toxicities. Patients with XRCC3241 CT variant (Thr/Met) were less likely to suffer chemotherapy-induced metabolic toxicities.
Conclusions:
In the current study, we identified XRCC3 codon 241 polymorphism as a prognostic marker in de novo cytogenetically normal AML patients treated with chemotherapy regarding chemotherapy-induced metabolic toxicities. This data represents a step towards better understanding the role played by XRCC3 in DNA repair and response to chemotherapeutic drugs.
Recommendations:
Up to our knowledge, no reports studied XRCC3 polymorphisms 241 C→T in relation to response to chemotherapy as well as chemotherapy-induced toxicities in adult Egyptian patients with newly diagnosed cytogenetically normal AML. Our study included relatively small sample size, therefore, future studies should include larger sample size to confirm our results. In addition, multiple SNPs of genes involved in the different DNA repair pathways should be included in these studies to investigate the associations between variants in different DNA repair genes and outcome of AML therapy