title: A mouse-based strategy for cyclophosphamide pharmacogenomic discovery.
abstract: Genome-wide mapping approaches are needed to more fully understand the genetic basis of chemotherapy response. Because of technical and ethical limitations, cancer pharmacogenomics has not yet benefited from traditional robust familial genetic strategies. We have therefore explored the use of the inbred mouse as a genetic model system in which to study response to the cytotoxic agent cyclophosphamide. Multiple phenotypes have been assessed in response to cyclophosphamide in up to 19 inbred mouse strains, including in vitro hematopoietic progenitor cell toxicity and the mobilization of hematopoietic progenitor cells into peripheral blood. Hematopoietic progenitor cell toxicity in vitro varied 2-fold among strains, whereas in vivo progenitor cell mobilization varied almost 75-fold among strains. Males mobilized more hematopoietic progenitor cells than did females, and the low-mobilization phenotype was dominant to the high-mobilization phenotype in F1 hybrid animals. In an initial attempt to analyze candidate genes, genetic variation was assessed in three cytochrome P-450 genes involved in the metabolism of cyclophosphamide. Resequencing of eight strains identified 26 polymorphisms in these genes that may influence response to cyclophosphamide. Distinct regions of high- and low-polymorphism rates were identified, and two common haplotypes were shared among the strains for each gene that exhibited variation. This phenotypic and genotypic variation among inbred strains provides a framework for cyclophosphamide pharmacogenomic discovery.
authors.affiliation: Washington Univ. School of Medicine, Dept. of Medicine, Campus Box 8069, St. Louis, MO 63110, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Watters
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Kloss
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000506:poisoning*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000506:poisoning*; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008297:Male; D051379:Mice / Q000235:genetics; D008815:Mice, Inbred Strains; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D018906:Antineoplastic Agents, Alkylating; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating