Hydroxyurea (hydroxycarbamide) genotoxicity in pediatric patients with sickle cell disease

Rodríguez, Anar; Duez, Pierre; Dedeken, Laurence; Cotton, Frédéric; Ferster, Alina

doi:10.1002/pbc.27022

Cited by 12 publications

(14 citation statements)

References 29 publications

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“…Friedrisch et al, 14 used the comet assay to analyze peripheral blood leukocytes of 28 patients with SCD treated with HU, and of 28 individuals without SCD, and they found higher levels of DNA damage in the group of patients treated with HU. Nevertheless, in this study by Friedrisch et al, 14 it is not possible to distinguish if the effects observed result from exposure to HU or due to the disease itself, as suggested by Rodriguez et al, 7 Moreover, another study presented with data in reference to 293 blood samples of 105 children, in a median of 2 years of HU therapy, in which the exposure to the drug was associated with significantly increased frequencies of MN in reticulocytes, reflecting the chromosome damage that occurred in the erythroblasts. 15…”

Section: Discussionmentioning

confidence: 65%

“…Similar to our findings, some reports in literature indicated treatment conditions in which HU did not lead to induction of DNA damage. Rodriguez et al, 7 employed the comet assay and found no significant difference in DNA damage between patients with SCD, treated, or not, with HU, with doses ≤30mg/kg/day. Using the CBMN-cyt assay in lymphocytes, Maluf et al, 16 found a small increase in the number of MN in the group of patients treated with HU, which correlated with duration of treatment and the final HU dose.…”

Section: Discussionmentioning

confidence: 99%

“…Friedrisch et al, 14 usaram o ensaio cometa para analisar leucócitos do sangue periférico de 28 pacientes com DF tratados com HU, e de 28 indivíduos sem DF, e encontraram maiores níveis de danos no DNA no grupo de pacientes tratados com HU. Entretanto, neste estudo de Friedrisch et al, 14 não é possível distinguir se os efeitos observados são decorrentes da exposição à HU ou decorrentes da própria doença, como sugerido por Rodriguez et al 7 Adicionalmente, outro estudo apresentou dados referentes a 293 amostras de sangue de 105 crianças, em uma mediana de 2 anos de terapia com HU, na qual a exposição ao fármaco foi associada a frequências significativamente aumentadas de MN em reticulócitos, que refletem os danos cromossômicos que ocorreram nos eritroblastos. 15…”

Section: Discussionunclassified

“…Thus, patient monitoring can be used with methodologies for DNA damage evaluation, in order to better understand the genotoxicity of this drug in treatment of SCD. 7…”

Section: Introductionmentioning

confidence: 99%

“…Assim, para uma maior compreensão sobre a genotoxicidade desse fármaco quando usado em tratamento de pacientes com DF, pode ser empregado o monitoramento dos pacientes com metodologias de avaliação de danos ao DNA. 7…”

Section: Introductionunclassified

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Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease

Oliveira

Boy

Santos

et al. 2019

Einstein (São Paulo)

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Objective To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea.Methods The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers – micronuclei, nucleoplasmic bridges and nuclear buds - were counted.Results Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups.Conclusion In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionunclassified

“…Thus, patient monitoring can be used with methodologies for DNA damage evaluation, in order to better understand the genotoxicity of this drug in treatment of SCD. 7…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionunclassified

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Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease

Oliveira

Boy

Santos

et al. 2019

Einstein (São Paulo)

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Incidence of cancer and related deaths in hemoglobinopathies: A follow‐up of 4631 patients between 1970 and 2021

Origa

Gianesin²,

Longo

et al. 2022

Cancer

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Background The correlation between thalassemia and malignancies other than hepatocellular carcinoma (HCC) and the possible relationship between other hemoglobinopathies and tumor risk have been poorly evaluated. Methods Eight Italian specialized centers evaluated the incidence of malignant neoplasms in hemoglobinopathies as well as their sites and features. The study cohort included 4631 patients followed between 1970 and 2021 (transfusion‐dependent β‐thalassemia, 55.6%; non–transfusion‐dependent thalassemia, 17.7%; sickle cell disease, 17.6%; hemoglobin H disease, 8.3%). Results A total of 197 diagnoses of cancer were reported (incidence rate, 442 cases per 100,000 person‐years). The liver was the most frequent site of tumors in both sexes, with a higher incidence (190 cases per 100,000 person‐years) in comparison with the general population found in all types of hemoglobinopathies (except hemoglobin H disease). In recent years, tumors have become the second cause of death in patients with transfusion‐dependent thalassemia. A lower risk of breast and prostate cancer was observed in the whole group of patients with hemoglobinopathies. The first cancer diagnoses dated back to the 1980s, and the incidence rate sharply increased after the 2000s. However, although the incidence rate of cancers of all sites but the liver continued to show an increasing trend, the incidence of HCC showed stability. Conclusions These findings provide novel insights into the relationship between cancer and hemoglobinopathies and suggest that the overall risk is not increased in these patients. HCC has been confirmed as the most frequent tumor, but advances in chelation and the drugs that have led to the eradication of hepatitis C may explain the recent steadiness in the number of diagnoses that is reported here.

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Efficacy and toxicity of hydroxyurea in mast cell activation syndrome patients refractory to standard medical therapy: retrospective case series

Weinstock

Brook²,

Molderings

2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Determine efficacy and adverse events (AEs) of hydroxyurea (HU) in mast cell activation syndrome (MCAS) patients who were refractory to standard medical therapy. An electronic chart review was performed to find MCAS patients who received HU in a MCAS medical practice. Diagnosis of MCAS was established on the basis of mast cell (MC) activation symptoms in ≥ 5 systems plus ≥ 1 abnormal MC mediators and/or ≥ 20 MC/high power field on duodenal biopsies. Medicines not providing significant clinical improvement prior to HU were tabulated. The following symptoms were evaluated by patients on a 0–10 scale prior to and at the study conclusion: bone pain, abdominal pain, diarrhea, bloating, and nausea. Safety labs were obtained on a regular basis. Twenty out of three hundred ten (8.4%) MCAS patients received HU. Patients included 22 females, average age 42.4 years. Dysautonomia was present in 60%. An average of 10.6 (SD 1.7, range 8–13) medications were used prior to adding HU to various concomitant medications. Average dose of HU was 634 mg. In 20 patients who continued therapy for ≥ 2 months, there was statistically significant reduction of bone pain, abdominal pain, diarrhea, bloating, and nausea. Fourteen patients noted prolonged success with therapy. Six patients stopped HU within 6 weeks owing to AEs. Four patients treated ≥ 2 months had AEs and 2 led to HU cessation. All AEs were reversible. Refractory MCAS patients showed clear significant improvement in bone pain and gastrointestinal symptoms on HU. Systematic monitoring was effective in preventing the occurrence of severe HU-induced adverse events.

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Hydroxyurea (hydroxycarbamide) genotoxicity in pediatric patients with sickle cell disease

Cited by 12 publications

References 29 publications

Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease

Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease

Incidence of cancer and related deaths in hemoglobinopathies: A follow‐up of 4631 patients between 1970 and 2021

Efficacy and toxicity of hydroxyurea in mast cell activation syndrome patients refractory to standard medical therapy: retrospective case series

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