Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease

Abstract

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.

Hydroxyurea—The Good, the Bad and the Ugly

“…Due to this fact, HU is a common anti-cancer drug. It does not significantly increase the level of DNA damage in patients with sickle cell disease [ 32 ], and recently it has been reported as a promising agent in preventing cognitive decline in Alzheimer’s disease. HU also increases fetal hemoglobin levels, which alters the kinetics of hemoglobin S polymerization [ 138 ], and has been shown to decrease the adhesion of blood cells to vascular endothelial cells [ 139 ].…”

“…Many inhibitors of replication, such as HU, are in fact used as active agents in chemotherapy [ 4 , 25 , 26 ], so there is a very practical value in the theoretical knowledge of the exact mechanisms by which they affect living cells [ 27 , 28 ]. The cytotoxic effects of HU are usually linked to the accumulation of DNA strand breaks [ 29 , 30 ] or to the reactive forms of HU by-products after prolonged incubation, such as ROS [ 16 , 31 , 32 , 33 ]. In this review, we summarize recent findings regarding the impact of hydroxyurea on living organisms.…”

Evidências Científicas Acerca Da Indução De Genotoxicidade Provocada Pela Hidroxiuréia Em Pacientes Com Anemia Falciforme

“…Do ponto de vista biológico as condições mutagênicas sofridas pela cadeia polipeptídica da hemoglobina desenvolvem automaticamente reduzidas cargas de eletricidade favorecendo assim a formação de polímeros provenientes da hemoglobina S (Hbs) encontrados nas células sanguíneas (hemácias) que por meio dessa mutação adquirem a forma de foice, tornando os componentes vulneráveis, fazendo com se torne inviável viver com as dores decorrentes da patologia. A anemia falciforme (AF) pode desencadear múltiplas dificuldades na absorção de nutrientes, causando nos pacientes portadores da mesma, intensas crises de dores, tornando o corpo vulnerável a infecções, alterações cardiovasculares, neurológicas, dentre outras complicações associadas aos demais sistemas (OLIVEIRA et al, 2019).…”

“…O autor supracitado Oliveira et al, (2019) relatou que o uso do fármaco Hidroxiuréia (HU) passa a ser uma referência no tratamento não apenas da AF, como de outras patologias neoplásicas, sendo introduzido no sistema de tratamento da mesma a partir de 1980. Considerou-se de eficácia positiva o uso do fármaco associado ao melhor estado da qualidade de vida do paciente, auxiliando no desenvolvimento de maior concentração da hemoglobina ainda no estágio fetal.…”

“…Atualmente, alguns estudos estão referenciando modelos de testes para detecção de possíveis alterações cromossômicas que possivelmente resultem em danos significativos ao material genético, como o que está relacionado ao uso de HU onde a análise do Citoma do Teste de Micronúcleo é investigada como bloqueio da citocinese desencadeando supostos danos mutagênicos deliberados do componente genotóxico encontrado no fármaco e suas respectivas associações no processo de formação de células carcinogênicas (OLIVEIRA et al, 2019).…”