Affiliation:
1. Litron Laboratories Rochester New York USA
2. Division of Hematology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA
3. J.P. Wilmot Cancer Institute University of Rochester Medical Center Rochester New York USA
4. Toxicology Consulting Services Bonita Springs Florida USA
Abstract
AbstractHydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture‐ and animal‐based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof‐of‐principle experiments with testicular cancer patients exposed to a cisplatin‐based regimen validated the ability of flow cytometric blood‐based micronucleated reticulocyte (MN‐RET) and PIG‐A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross‐sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN‐RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN‐RET in both the cross‐sectional and prospective studies. However, no evidence of PIG‐A gene mutation was found in hydroxyurea‐treated children, despite the fact that the two assays use the same rapidly‐dividing, highly‐exposed cell type. Collectively, these results reinforce the complementary nature of MN‐RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA.
Funder
Doris Duke Charitable Foundation
National Heart, Lung, and Blood Institute
National Institute of Environmental Health Sciences
Subject
Health, Toxicology and Mutagenesis,Genetics (clinical),Epidemiology
Cited by
3 articles.
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