The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration.
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.
Rao
V Koneti
VK
Center for Cancer Research, National Cancer Institute, NIH, Building 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Knutsen
Turid
T
Ried
Thomas
T
Wangsa
Darawalee
D
Flynn
Bernard Mike
BM
Langham
Gregory
G
Egorin
Merrill J
MJ
Cole
Diane
D
Balis
Frank
F
Steinberg
Seth M
SM
Bates
Susan
S
Fojo
Tito
T
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
D001399:Azure Stains; D005047:Etoposide; D013852:Thiotepa; D017239:Paclitaxel