title: Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure.
abstract: Hydroxycarbamide (hydroxyurea) provides laboratory and clinical benefits for adults and children with sickle cell anaemia (SCA). Given its mechanism of action and prior reports of genotoxicity, concern exists regarding long-term toxicities and possible carcinogenicity. We performed cross-sectional analyses of chromosome stability using peripheral blood mononuclear cells (PBMC) from 51 children with SCA and 3-12 years of hydroxycarbamide exposure (mean age 13·2 ± 4·1 years), compared to 28 children before treatment (9·4 ± 4·7 years). Chromosome damage was less for children receiving hydroxycarbamide than untreated patients (0·8 ± 1·2 vs. 1·9 ± 1·5 breaks per 100 cells, P = 0·004). There were no differences in repairing chromosome breaks after in vitro radiation; PBMC from children taking hydroxycarbamide had equivalent 2 Gy-induced chromosome breaks compared to untreated patients (30·8 ± 16·1 vs. 31·7 ± 8·9 per 100 cells, P = not significant). Radiation plus hydroxycarbamide resulted in similar numbers of unrepaired breaks in cells from children on hydroxycarbamide compared to untreated patients (95·8 ± 44·2 vs. 76·1 ± 23·1 per 100 cells, P = 0·08), but no differences were noted with longer exposure (97·9 ± 42·8 breaks per 100 cells for 3-6 years of hydroxycarbamide exposure vs. 91·2 ± 48·4 for 9-12 years of exposure). These observations provide important safety data regarding long-term risks of hydroxycarbamide exposure for children with SCA, and suggest low in vivo mutagenicity and carcinogenicity.
authors.affiliation: Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. patrick.mcgann@stjude.org
authors.forename: Patrick T
authors.initials: PT
authors.lastname: McGann
authors.forename: Thad A
authors.initials: TA
authors.lastname: Howard
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Flanagan
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics*; D000986:Antisickling Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations / Q000139:chemically induced*; D003430:Cross-Sectional Studies; D004249:DNA Damage; D004260:DNA Repair; D004334:Drug Administration Schedule; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged
chemical_list: D000986:Antisickling Agents; D006918:Hydroxyurea