Mutation Research 583 (2005) 105–119 The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration V. Koneti Rao a , Turid Knutsen a , Thomas Ried a , Darawalee Wangsa a , Bernard Mike Flynn b , Gregory Langham c , Merrill J. Egorin d , Diane Cole a , Frank Balis a , Seth M. Steinberg a , Susan Bates a , Tito Fojo a,∗ a Center for Cancer Research, National Cancer Institute, NIH, Building 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA b Veterinary Medicine and Resource Branch, NIMH/NIH, Bethesda, MD 20892, USA c NCI/Division of Laboratory Animals, NCI, NIH, Bethesda, MD 20892, USA d University of Pittsburgh Cancer Center, Pittsburgh, PA 15213, USA Received 8 April 2004; received in revised form 10 December 2004; accepted 26 January 2005 Available online 27 April 2005 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. © 2005 Published by Elsevier B.V. Keywords: Drug resistance; Chromosomal damage; Genotoxicity; Secondary malignancies; CIV chemotherapy Abbreviations: AUCs, areas under the concentration versus time curve; CIV, Continuous intravenous infusion ∗ Corresponding author. Tel.: +1 310 402 1357; fax: +1 301 402 1608. E-mail address: tfojo@helix.nih.gov (T. Fojo). 1383-5718/$ – see front matter © 2005 Published by Elsevier B.V. doi:10.1016/j.mrgentox.2005.01.013