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Original Article
352
Rev Bras Hematol Hemoter. 2012;34(5):352-5
Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in
chronic myeloid leukemia patients treated with tyrosine kinase inhibitors
Introduction
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting
from neoplastic transformation of primitive hematopoietic cells. It is characterized by a
balanced translocation between the long arms of chromosome 9 and 22, which induces
formation of the Philadelphia chromosome, resulting from the binding of the BCR gene on
chromosome 22 to the ABL gene on chromosome 9, generating the hybrid BCR-ABL gene
on chromosome 22q. The product of this oncogene is the bcr-abl protein that has a higher
tyrosine kinase activity and is responsible for the pathogenesis of CML
(1-3)
.
Advances in understanding the pathophysiology of the disease are essential
for the development of any molecular therapy for CML. Tyrosine kinase inhibitors
(TKIs) competitively bind to the receptor for BCR-ABL, ATP-dependent, and inhibit
the phosphorylation of tyrosine kinase, thereby avoiding a change in conformation to
the active form and normalizing the mechanisms that regulate cell proliferation with
the inhibition of cell proliferation and induction of leukemic apoptose
(3-6)
. Imatinib,
a TKI, has revolutionized the treatment of CML. Despite the enduring responses of
imatinib, some chronic phase patients and a higher proportion of advanced phase
patients exhibit intolerance or resistance to this medication
(7)
. Primary resistance
occurs when there is failure to achieve a significant hematologic or cytogenetic
response by the patient from the beginning of treatment. Secondary resistance is the
resurgence of the leukemic clone after an initial response to the drug
(7,8)
. To treat
patients who are resistant or intolerant to imatinib, a new generation of BCR-ABL
TKIs has been developed, including dasatinib and nilotinib
(9,10)
.
The mechanism whereby the (9:22) translocation occurs is unknown, although some
studies suggest that oxidative stress may be involved in the genesis of CML
(11-13)
. Moreover,
BCR-ABL positive cells are a source of reactive oxygen species (ROS), which cause
oxidative DNA damage and may contribute to the formation of additional abnormalities
leading to disease progression to the more advanced stages (accelerated and blast crisis
phases) or resistance to TKIs such as imatinib
(14-16)
.
The present study aimed to investigate markers of oxidative stress in CML patients
treated with TKIs.
Maria Juracy Petrola
1
Alana Joselina Montenegro de Castro
1
Maria Helena da Silva Pitombeira
1
Maritza Cavalcante Barbosa
1
Acy Telles de Souza Quixadá
2
Fernando Barroso Duarte
1
Romelia Pinheiro Gonçalves
1
1
Universidade Federal do Ceará - UFC,
Fortaleza, CE, Brazil
2
Hospital Universitário Walter Cantídio -
HUWC, Fortaleza, CE, Brazil
Conflict-of-interest disclosure:
The authors declare no competing financial
interest
Submitted: 3/27/2012
Accepted: 6/15/2012
Corresponding author:
Romélia Pinheiro Gonçalves
Faculdade de Farmácia da Universidade
Federal do Ceará - UFC
Rua Pereira Valente, 640, apto 701, Meireles
60160-250 Fortaleza, CE, Brazil
Phone: 55-85-87879459
romeliapinheiro@ig.com.br
www.rbhh.org or www.scielo.br/rbhh
DOI: 10.5581/1516-8484.20120091
Background:
Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic
progenitor cells resulting from the (9:22)(q34,11) translocation. The tyrosine kinase abl fusion protein,
the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the
production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen
species can facilitate genomic instability and may contribute to disease progression.
Objetive:
To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic
myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored
at a referral hospital in Fortaleza, Ceará.
Methods:
A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to
treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences
between groups were observed using the Student t-test and Fisher’s exact test. The results are expressed as mean ±
standard error of mean. The significance level was set for a p-value < 0.05 in all analyses.
Results:
The results show significantly higher mean concentrations of nitrite and malondialdehyde in
chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients
on imatinib.
Conclusion:
It follows that chronic myeloid leukemia patients present higher oxidative activity and that the
increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors.
Keywords:
Leukemia, myelogenous, chronic, BCR-ABL positive; Oxidative stress; Protein-tyrosine kinases;
Malondialdehyde