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Davis M, Li J, Knight E, et al. Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity. Front Genet. 2015;6:14doi: 10.3389/fgene.2015.00014.
Davis, M., Li, J., Knight, E., Eldridge, S. R., Daniels, K. K., & Bushel, P. R. (2015). Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity. Frontiers in genetics, 614. https://doi.org/10.3389/fgene.2015.00014
Davis, Myrtle, et al. "Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity." Frontiers in genetics vol. 6 (2015): 14. doi: https://doi.org/10.3389/fgene.2015.00014
Davis M, Li J, Knight E, Eldridge SR, Daniels KK, Bushel PR. Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity. Front Genet. 2015 Feb 12;6:14. doi: 10.3389/fgene.2015.00014. eCollection 2015. PMID: 25729387; PMCID: PMC4325931.
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Front Genet. 2015 Feb 12;6:14. doi: 10.3389/fgene.2015.00014. eCollection 2015.

Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity.

Frontiers in genetics

Myrtle Davis, Jianying Li, Elaine Knight, Sandy R Eldridge, Kellye K Daniels, Pierre R Bushel

Affiliations

  1. Toxicology and Pharmacology Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute Bethesda, MD, USA.
  2. Kelly Government Solutions, Research Triangle Park NC, USA ; Microarray and Genome Informatics Group, National Institute of Environmental Health Sciences, Research Triangle Park NC, USA.
  3. Toxicology and Pathology Services, Southern Research Institute Birmingham, AL, USA.
  4. Microarray and Genome Informatics Group, National Institute of Environmental Health Sciences, Research Triangle Park NC, USA ; Biostatistics Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park NC, USA.

PMID: 25729387 PMCID: PMC4325931 DOI: 10.3389/fgene.2015.00014

Abstract

Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether "microarray profiles" could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. We compared the mRNA responses within bone marrow of Sprague-Dawley rats after a single 30 min treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control for 1, 6, and 24 h. We also examined the histopathology of the bone marrow following all treatments. Drug-related histopathological lesions were limited to bone marrow hypocellularity for animals dosed with either agent alone or in combination. Lesions had an earlier onset and higher incidence for animals given topotecan alone or in combination with oxaliplatin. Severity increased from mild to moderate when topotecan was administered prior to oxaliplatin compared with administering oxaliplatin first. Notably, six patterns of co-expressed genes were detected at the 1 h time point that indicate regulatory expression of genes that are dependent on the order of the administration. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. These data also demonstrate the potential for early mRNA patterns derived from target organs of toxicity to inform toxicological risk and molecular mechanisms for agents given in combination.

Keywords: EPIG; bone marrow; combination; enhanced toxicity; oxaliplatin; topotecan; toxicogenomics

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