title: The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration.
abstract: We utilized a non-human primate model, the rhesus monkey (Macaca mulatta), to quantitate the extent of chromosomal damage in bone marrow cells following chemotherapy. Thiotepa, etoposide, and paclitaxel were chosen as the chemotherapy agents due to their distinct mechanisms of action. Chromosomal aberrations were quantitated using traditional Giemsa stain. We sought to evaluate the extent to which genotoxicity was dependent on the schedule of administration by giving chemotherapy as either a bolus or a 96 h continuous infusion. Neutropenia and areas under the concentration curve (AUCs) were monitored to ensure comparable cytotoxicity and dose administered. At least 100 metaphases were scored in each marrow sample by an investigator unaware of the treatment history of the animals. All three drugs produced a statistically significant higher percentage of abnormal metaphases following bolus chemotherapy (p<0.0001, p=0.0015 and p<0.0001 for thiotepa, etoposide and paclitaxel, respectively). We conclude that infusional administration of thiotepa, etoposide and paclitaxel is less genotoxic to normal bone marrow cells than is bolus administration. These results suggest infusional regimens may be considered where there are concerns about long-term genotoxic sequelae, including secondary cancer, teratogenicity, or possibly the development of drug resistance. We believe this approach provides a reproducible model in which drugs and eventually, regimens can be compared.
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Building 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.forename: Turid
authors.initials: T
authors.lastname: Knutsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Darawalee
authors.initials: D
authors.lastname: Wangsa
authors.forename: Bernard Mike
authors.initials: BM
authors.lastname: Flynn
authors.forename: Gregory
authors.initials: G
authors.lastname: Langham
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Diane
authors.initials: D
authors.lastname: Cole
authors.forename: Frank
authors.initials: F
authors.lastname: Balis
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Susan
authors.initials: S
authors.lastname: Bates
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001399:Azure Stains; D001854:Bone Marrow Cells / Q000473:pathology*; D002869:Chromosome Aberrations / Q000139:chemically induced*; D020223:Chromosome Painting / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D009503:Neutropenia / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013852:Thiotepa / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001399:Azure Stains; D005047:Etoposide; D013852:Thiotepa; D017239:Paclitaxel