DNA damage in blood leukocytes of individuals with sickle cell disease treated with hydroxyurea

Friedrisch, João Ricardo; Prá, Daniel; Maluf, Sharbel Weidner; Bittar, Christina; Mergener, Michelle; Pollo, Tiago Antonio; Kayser, Michele Luz; Silva, Maria Aparecida Lima da; Henriques, João Antônio Pêgas; Silla, Lúcia Mariano da Rocha

doi:10.1016/j.mrgentox.2007.09.005

Cited by 41 publications

(42 citation statements)

References 31 publications

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“…In this study, patients with SCA treated with HU had significantly elevated DI values when compared with the patients with SCA who were not treated with HU. Furthermore, the DI values were significantly higher in patients treated for longer periods (>20 months).Similar results were found in two previous studies that evaluated the DNA Damage Index in total peripheral white blood cell counts of SCA patients treated with HU (Friedrisch et al, 2008;Rocha et al, 2012). Taken together, these studies provide evidence for measurable genotoxicity from HU exposure in patients with SCA, but little evidence to support cumulative mutagenicity or carcinogenic potential.…”

Section: Discussionsupporting

confidence: 88%

“…In the literature, the HU ability to cause cancer is controversial and the long-term efficacy and safety of HU in treating patients with SCA remains inconclusive (Steinberg et al, 2010). Some studies have shown that HU is genotoxic while other studies suggest that HU has low mutagenicity in vivo (Hanft et al, 2000;Friedrisch et al, 2008). Furthermore, some reports relate that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition and this effect could be related to in vivo toxicity (Juul et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

Pedrosa

Barbosa

Santos

et al. 2014

Braz. J. Pharm. Sci.

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Hydroxyurea (HU) is the most important advance in the treatment of sickle cell anaemia (SCA) for preventing complications and improving quality of life for patients. However, some aspects of treatment with HU remain unclear, including their effect on and potential toxicity to other blood cells such as neutrophils. This study used the measurement of Lactate Dehydrogenase (LDH) and Methyl ThiazolTetrazolium (MTT) and the comet assay to investigate the cytotoxicity and damage index (DI) of the DNA in the neutrophils of patients with SCA using HU.In the LDH and MTT assays, a cytoprotective effect was observed in the group of patients treated, as well as an absence of toxicity. When compared to patients without the treatment, the SS group (n=20, 13 women and 07 men, aged 18-69 years), and the group of healthy individuals (AA) used as a control group (n=52, 28 women and 24 men, aged 19-60 years), The SSHU group (n=21, 11 women and 10 men, aged 19-63 years) showed a significant reduction (p<0.001) in LDH activity and an increase in the percentage of viable cells by the MTT (p<0.001). However, the SSHU group presented significantly higher DI values (49.57±6.0 U/A) when compared to the AA group (7.43 ± 0,94U/A) and the SS group (22.73 ±5.58 U/A) (p<0.0001), especially when treated for longer periods (>20 months), demonstrating that despite the cytoprotective effects in terms of cell viability, the use of HU can induce DNA damage in neutrophils.Uniterms: Hydroxyurea/cytotoxicity. Sickle cell anaemia/treatment. Neutrophils/DNA damage. Deoxyribonucleic acid/damage.A hidroxiuréia (HU) constitui o avanço mais importante no tratamento da anemia falciforme (AF) por prevenir complicações e aumentar a qualidade de vida dos pacientes. Entretanto, alguns aspectos do tratamento com HU permanecem obscuros, incluindo a sua ação e potencial toxicidade em outras células sanguíneas, tais como neutrófilos. Este estudo utilizou a mensuração da lactato desidrogenase (LDH) e do metil tiazoltetrazólio (MTT) e o ensaio do cometa para investigar a citotoxicidade e índice de dano (ID) ao DNA em neutrófilos de pacientes com AF em uso do medicamento. Nos ensaios de LDH e MTT, observou-se além de ausência de toxicidade, uma ação citoprotetora no grupo de pacientes tratados, Grupo SSHU (n=21, 11 mulheres e 10 homens, com idades entre 19-63 anos), quando comparados aos pacientes sem tratamento, Grupo SS (n=20, 13 mulheres e 07 homens, 18-69 anos), e grupo de indivíduos saudáveis (AA) usado como controle (n=52, 28 mulheres e 24 homens, 19-60 anos), com redução significativa (p<0,001) na atividade de LDH e aumento no percentual de células viáveis pelo MTT (p<0,001). Entretanto, o grupo SSHU apresentou valores de ID significativamente elevados (49,57±6,0 U/A), quando comparados ao grupo AA (7,43 ± 0,94U/A) e grupo SS (22,73 ±5,58 U/A) (p<0,0001), especialmente quando tratados por períodos mais longos (>20 meses), demonstrando que apesar dos efeitos citoprotetores quanto à viabilidade celular, o uso da HU pode induzir lesão ao DNA de neutrófilos.Unitermo...

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

Pedrosa

Barbosa

Santos

et al. 2014

Braz. J. Pharm. Sci.

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“…However, HU also promotes a reduction in the number of neutrophils, reduced expression of erythrocyte adhesion molecules, and increased synthesis and bioavailability of nitric oxide by the activation of guanylyl cyclase and subsequent increase in cyclic GMP (Friedrisch et al, 2008;Gladwin et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Elias

Carvalho

Soares

et al. 2014

Braz. J. Pharm. Sci.

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Sickle cell anemia (SCA) is a recessively inherited disease characterized by chronic hemolytic anemia, chronic inflammation, and acute episodes of hemolysis. Hydroxyurea (HU) is widely used to increase the levels of fetal hemoglobin (HbF). The objective of this study was to standardize and validate a method for the quantification of HU in human plasma by using ultra high performance liquid chromatography (UPLC) in order to determine the plasma HU levels in adult patients with SCA who had been treated with HU. We used an analytical reverse phase column (Nucleosil C18) with a mobile phase consisting of acetonitrile/water (16.7/83.3). The retention times of HU, urea, and methylurea were 6.7, 7.7, and 11.4 min, respectively. All parameters of the validation process were defined. To determine the precision and accuracy of quality controls, HU in plasma was used at concentrations of 100, 740, and 1600 µM, with methylurea as the internal standard. Linearity was assessed in the range of 50-1600 µM HU in plasma, obtaining a correlation coefficient of 0.99. The method was accurate and precise and can be used for the quantitative determination of HU for therapeutic monitoring of patients with SCA treated with HU.

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“…Current therapy methods of breast cancer such as surgery, radio therapy and chemotherapy improved survival of women suffering breast cancer [3]. Among chemotherapy agents, Hydroxyurea (HU) is commonly used as an anti-cancer agent [4]. For instance, HU is an effective reagent which was widely applied for treatment of acute angina, breast cancer, several hematological malignancies including chronic myelogenous leukemia (CML), sickle cell anemia, myeloproliferative disorders, and other known cancers previously [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Evaluation of the Efficacy of Liposomal and Pegylated Liposomal Hydroxyurea

et al. 2013

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Breast cancer is one of the most frequent cancer types within women population. Hydroxyurea (HU) is a chemotherapy compound for treatment of patients with cancer diagnosis, including breast cancer associated with several adverse effects. In this study, we applied nanotechnology to decreased drug side effects along with improvement of therapeutic index. Liposomation is widely used in modern pharmacological developments in order to enhance the effects of the drugs. To achieve this, in this study a mixture of phosphatidylcholine and cholesterol was made up and HU was added to the resultant mixture, was then pegylated using Polyethylene Glycol 2000 to increase resistance, applicability and solubility. The mean diameters of nanoliposomal and pegylated nanoliposomal HU were measured by Zeta sizer device and obtained about 402.5 and 338.2 nm. The efficiency of non-pegylated and pegylated liposomal HU was 70.8 and 64.2, respectively. Releasing HU in both formulations was estimated about 25.8 and 21.7 %. Also, this study investigated the cytotoxicity effect of nanoliposomal and pegylated nanoliposomal HU using MTT assay. Results of this investigation showed that the cytotoxic properties of pegylated HU was 3.6 % more than those non-pegylated form, while was 38.93 % more than ordinary from of HU. This study showed that the stability, releasing pattern and cytotoxicity of the pegylated nanoliposomal HU is better than that of nanoliposomal HU.

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DNA damage in blood leukocytes of individuals with sickle cell disease treated with hydroxyurea

Cited by 41 publications

References 31 publications

Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

In Vitro Evaluation of the Efficacy of Liposomal and Pegylated Liposomal Hydroxyurea

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