DNA damage in leukocytes of sickle cell anemia patients is associated with hydroxyurea therapy and with HBB*S haplotype

Abstract

Hydroxyurea (HU) is the primary pharmacologic agent for preventing the complications and improving the quality of life of sickle cell anemia (SCA) patients. Although HU has been associated with an increased risk of leukemia in some patients with myeloproliferative disorders, the mutagenic and carcinogenic potential of HU has not been established. This study used the alkaline comet assay to investigate DNA damage in peripheral blood leukocytes from 41 individuals with SCA treated with HU (SCAHU) and from 26 normal individuals. The presence of HbS and the analysis of the haplotypes of the beta S gene cluster were done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The damage index (DI) in the SCAHU group was significantly higher than in controls (p<0.001). Neither gender nor age was associated with DNA damage in controls or SCAHU individuals. Among the SCAHU individuals, DI was significantly influenced by length of HU treatment (p=0.0039) and BMI (p=0.001). Individuals with length of HU treatment≥20 months and BMI≤20kg/m(2) had a significantly greater DI than those with length of HU treatment<20 months and BMI>20kg/m(2). No significant influence of mean HU dose was observed on DI (p=0.950). However, individuals who received a mean HU dose≥20mg/kg showed a higher DI than those who received less. Furthermore, an association was observed between DI damage and HBB*S gene haplotypes. DI values for the Bantu/Bantu haplotype was greater when compared to the Benin/Benin haplotype; and the Bantu/Benin haplotype had a DI lower than the Bantu/Bantu haplotype and greater than the Benin/Benin haplotype. Our results show that DNA damage in sickle cell anemia is associated not only with treatment with HU but also with genotype.

The effect of hydroxyurea on compound heterozygotes for sickle cell‐hemoglobin D‐Punjab—A single centre experience in eastern India

“…In the BABY‐HUG Phase III Clinical Trial, it was reported that HU treatment was not associated with any significant increase in genotoxicity in infants with SCA compared to placebo treatment . A small number of studies have reported that genotoxicity was significantly less in patients who received HU at a lower dose and for lesser duration . This may be due the potential advantage of low dose HU leading to less DNA damage.…”

Is chronic use of hydroxyurea safe for patients with sickle cell anemia? An account of genotoxicity and mutagenicity

“…Our research group reported in previous studies with the same population of the present study that patients with SCA using HU had statistically higher DI in DNA compared to the CG; however, the DI was not evaluated in patients with SCA without use of HU [Silva Rocha et al, ; Pedrosa et al, ]. The increased DNA damage in SCA‐NoHU patients compared with individuals in the CG can be attributed to the chronic inflammation present in the disease with the production of reactive oxygen species, which can cause DNA damage [Cançado et al, ].…”

Sickle cell disease and acute leukemia: one case report and an extensive review

“…The leukemogenic risk could theoretically increase with the duration of drug exposure. The index of DNA damage in peripheral blood leukocytes from HU-treated patients with SCD was demonstrated higher than in controls and was confirmed influenced by the duration and the dose of HU treatment, and by the HbS genotype [ 45 , 46 ]. The leukemic risk of HU has never been confirmed in patients with chronic myeloproliferative diseases [ 47 , 48 ], and no increased risks of malignancy were reported in large series of SCD patients [ 49 – 51 ].…”