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Home > Comparison Between Chemosensitive and Chemoresistant Acute Myelogenous Leukemia in Term of Gene Expression of Selected Molecules Involved in Activation Transportation, Action and Metabolism of Ara-C and Anthracyclines

Comparison Between Chemosensitive and Chemoresistant Acute Myelogenous Leukemia in Term of Gene Expression of Selected Molecules Involved in Activation Transportation, Action and Metabolism of Ara-C and Anthracyclines

Thesis Info

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External Link

Author

Kulsoom, Bibi

Program

PhD

Institute

Ziauddin University

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Biochemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12937/1/Bibi_Kulsoom_Biochemistry_HSR_2018_ZU_Karachi_18.07.2018.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725769704

Similar


INTRODUCTION: Acute myelogenous leukemia (AML) is the malignant transformation of hematopoietic cells belonging to myeloid series in bone marrow. It is an acute emergency and is fatal if not treated. Chemotherapy is the main treatment offered to AML patients. But persistent remission rate is not impressive. Although patients could be stratified into high, intermediate and low risk based on the karyotyping and cytogenetic abnormalities, there are patients in all risk groups who either remain resistant or relapse later in life. The sensitivity and resistance of a tumor cell may be related to the mechanisms that are involved in drug transportation, metabolism, and interaction with its target or efflux processes. OBJECTIVE: The aim of this study was to explore the relationship of gene expression of membrane transporters for drugs hENT1, MDR1, MRP2 and LRP, drug metabolizing enzymes dCK, CDA and dCMPD, drug target molecule topoisomerase IIa as well as the apoptotic pathway regulatory proteins Bax and Bcl-2 with the outcome of chemotherapy comprised of cytosine arabinoside (Ara-C), and daunorubicin (anthracycline group) in AML patients. METHODS: Bone marrow or blood or both were collected from 90 AML patients enrolled in this study during September 2011 to April 2017. Gene expression for the above mentioned genes was analyzed through real time or quantitative polymerase chain reaction (qPCR). Patients were labelled resistant or responsive based on complete remission (CR). Patients were also labelled “good” responders if they had persistent remission till the end of the study period, or “poor” responders if they were either resistant or presented with relapse. Gene expression was labelled low or high based on being lower or higher than that in normal healthy controls. RESULTS: Better clinical response was found associated with acute promyelocytic leukemia (APML) subtype (p<0.001), absent FLT3 mutation (p=0.02), higher gene expression of LRP in marrow (p=0.002) and Topo IIα in blood (p=0.005). APML patients had better overall survival (OS) at one year (p=0.03). Patients without FLT3 mutation had better one year OS (p<0.001) and six month OS (p=0.003). Higher LRP expression in marrow was associated with better one year OS (p=0.02). One year disease free survival (DFS) was better among those who had higher expression of LRP and CDA in marrow (p=0.007 and 0.03 respectively). Higher Topo IIα in blood was associated with better DFS at 6 and 12 months (p=0.04 and 0.04 respectively). The expression of other genes, i.e. hENT1, dCK, dCMPD, MDR1, MRP2, Bax and Bcl-2 did not correlate with clinical response, relapse, DFS or OS. Our logistic regression model predicted persistent remission vs. relapse (p=0.007), alive vs. dead (p=0.018) and good vs. bad responders (p<0.001). CONCLUSION: A diagnosis of APML, absence of FLT3 mutation, and higher expression of LRP and Topo IIa are the most important factors which predict better outcome in AML patients treated with Ara-C and anthracyclines.
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