| Abstract: |
SUMMARYTherapeutic resistance is a major obstacle in the treatment of acute lymphoblastic leukemia. Clinical resistance to anticancer agents may occur at the time of presentation as well as during the course of treatment and relapse. Although many patients with acute lymphoblastic leukemia can achieve complete remission with induction of chemotherapy, a large proportion will eventually relapse with disease resistant to broad spectrum of chemotherapeutic agents.Such resistance has been associated with rapid drug efflux that is mediated by the multidrug resistance gene (MDR1) and more recently with expression of other proteins conferring resistance such as multidrug resistance associated protein (MRP1) and lung resistance associated protein (LRP1).Several mechanisms are thought to be involved in the development of resistance to chemotherapy, including overexpression of the membrane-associated ATP-dependent efflux pump, P-glycoprotein, which is encoded by MDR1. Because many kinds of antileukemic agents can be substrates for this efflux pump, overexpression of MDR1 leads to insufficient concentrations of agents in leukemic cells even at maximum doses. Thus, P-glycoprotein has been shown experimentally to be an attractive protein for explaining the mechanism of multidrug resistance.The aim of the present work is to evaluate the expression of MDR1 gene in acute lymphoblastic leukemia patients and to find out its relation to immunophenotypic pattern and to treatment outcome.The present study included 30 subjects: 20 newly diagnosed ALL patients. Among them 9 (45%) was diagnosed as common ALL; 6 (30%) as Pre-B; 3 (15%) as T-ALL and 2 (10%) as B-ALL and 10 age and sex matched apparently healthy individuals as control group. All patients of this study were subjected to thorough history taking, Full clinical examination, routine laboratory investigations including complete blood picture, bone marrow examination, cytochemistry (peroxidase) and immunophenotyping. Study of multidrug resistance-1 gene (MDR1) expression was performed by the method of real time reverse transcription-polymerase chain reaction (RT-PCR) to all 30 subjects of this study.The result of the present study showed:1. MDR1 gene was expressed on normal cells of the control group as well as blast cells of ALL patients.2. MDR1 gene was overexpressed (MDR1-positive cases) in 30% (6/20) of the patients.3. The difference in the mean values of white cell count, hemoglobin level, platelet count, percentage of peripheral and bone marrow blast cells, as well as sex distribution and FAB subtypes was not statistically significant among MDR1 positive and negative cases.4. Among laboratory parameters, there was a significant positive correlation between MDR1 overexpression only with advanced age in ALL cases.5. There was no significant association between MDR1 positive cases with hepatomegally, splenomegally or lymphadenopathy6. In the whole group of the ALL patients, The number of MDR1 negative patients who entered into complete remission (CR) was significantly higher than those of the MDR1 positive patients.CONCLUSION:From this study, we conclude that MDR1 gene is one of the poor prognostic values in ALL and may be responsible for treatment failure in many patients. Determination of MDR1 status in the leukemic blasts at diagnosis provided a useful tool to select a small patient subgroup with a greater risk for early treatment failure. As shown in this study, except advanced age, the results were found to be independent of sex, WBC count, hemoglobin level, platelet count, percentage of peripheral and bone marrow blast cells and FAB subtypes. It clearly showed the importance of MDR phenotype detection in ALL patients. So, preliminary assessment for MDR1 may hopefully result in a better outcome for this unfortunate group of patients with ALL.
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