title: Persistence of cisplatin-induced mutagenicity in hematopoietic stem cells: implications for secondary cancer risk following chemotherapy.
abstract: Cisplatin is a cytostatic agent used in the treatment of many types of cancer, but its use is associated with increased incidences of secondary leukemia. We evaluated cisplatin's in vivo genotoxic potential by analyzing peripheral blood for Pig-a mutant phenotype erythrocytes and for chromosomal damage in the form of micronuclei. Mutant phenotype reticuloyte and erythrocyte frequencies, based on anti-CD59 antibody labeling and flow cytometric analysis, were determined in male Sprague Dawley rats treated for 28 consecutive days (days 1-28) with up to 0.4 mg cisplatin/kg/day, and sampled on days -4, 15, 29, and 56. Vehicle and highest dose groups were evaluated at additional time points post-treatment up to 6 months. Day 4 and 29 blood samples were also analyzed for micronucleated reticulocyte frequency using flow cytometry and anti-CD71-based labeling. Mutant phenotype reticulocytes were significantly elevated at doses ≥0.1 mg/kg/day, and mutant phenotype erythrocytes were elevated at doses ≥0.05 mg/kg/day. In the 0.4 mg/kg/day group, these effects persisted for the 6 month observation period. Cisplatin also induced a modest but statistically significant increase in micronucleus frequency at the highest dose tested. The prolonged persistence in the production of mutant erythrocytes following cisplatin exposure suggests that this drug mutates hematopoietic stem cells and that this damage may ultimately contribute to the increased incidence of secondary leukemias seen in patients cured of primary malignancies with platinum-based regimens.
authors.affiliation: Litron Laboratories, Rochester, New York sdertinger@litronlabs.com.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dertinger
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Svetlana L
authors.initials: SL
authors.lastname: Avlasevich
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Dorothea K
authors.initials: DK
authors.lastname: Torous
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Bemis
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Souk
authors.initials: S
authors.lastname: Phonethepswath
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Carson
authors.initials: C
authors.lastname: Labash
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Kristine
authors.initials: K
authors.lastname: Carlson
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: Jared
authors.initials: J
authors.lastname: Mereness
authors.affiliation: Litron Laboratories, Rochester, New York.
authors.forename: John
authors.initials: J
authors.lastname: Cottom
authors.affiliation: Department of Pediatrics and Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York.
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.affiliation: Toxicology Consulting Services, Bonita Springs, Florida.
authors.forename: James T
authors.initials: JT
authors.lastname: MacGregor
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D016609:Neoplasms, Second Primary / Q000139:chemically induced*; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D002945:Cisplatin
keywords: Pig-a gene; cisplatin; flow cytometry; genotoxicity; micronuclei; mutation; stem cells