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

Davis M, Li J, Knight E, Eldridge SR, Daniels KK, Bushel PR - Front Genet (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Toxicology and Pharmacology Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute Bethesda, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Clustering of the Enrichment of GO BPs. Clustering and heatmap based on the −log base 10 (p-values) of the 641 Gene Ontology (GO) biological processes (BPs) for each treatment and time point. The GO BPs are on the y-axis, the samples are on the x-axis. The enriched GO BPs were obtained from limma analysis DEGs (absolute fold change >2 and FDR < 0.01). Significance of enrichment was set to p < 0.05. Missing values were imputed as 0 (−log base 10(1), i.e., p = 1), Clustering of the pathways were performed using Pearson correlation dissimilarity (r) and average linkage grouping. Clusters (those with a 1- r ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. The color in the legend denotes the significance of enrichment. The more red the heat map color, the more significant the enrichment.
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Figure 5: Clustering of the Enrichment of GO BPs. Clustering and heatmap based on the −log base 10 (p-values) of the 641 Gene Ontology (GO) biological processes (BPs) for each treatment and time point. The GO BPs are on the y-axis, the samples are on the x-axis. The enriched GO BPs were obtained from limma analysis DEGs (absolute fold change >2 and FDR < 0.01). Significance of enrichment was set to p < 0.05. Missing values were imputed as 0 (−log base 10(1), i.e., p = 1), Clustering of the pathways were performed using Pearson correlation dissimilarity (r) and average linkage grouping. Clusters (those with a 1- r ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. The color in the legend denotes the significance of enrichment. The more red the heat map color, the more significant the enrichment.

Mentions: Genes detected as differentially expressed at each time point (Supplementary Table 5) were used to enrich Gene Ontology (GO) biological processes (BPs). There were 641 GO BPs (Supplementary Table 6) significant (p < 0.05) from the union of all the lists (Supplementary Tables 7–12) [each one matching the order represented by the treatments in Figure 5]. Figure 5 shows the clustering of the 641 GO BPs terms based on the –log base 10 p-values. Clusters (those with a correlation value ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. DNA damage-signal transduction by p53 was highly enriched by the oxaliplatin exposure at the 6 h time point when it was given first but not second. Oxaliplatin given second elicited an ATP catabolic process at 6 h and positive regulation of epithelial to mesenchymal transition at 24 h. Topotecan when given second at 6 h impacted Ras GTPase activity in a positive regulation manner. The GTP catabolic process was enriched at the 6 h time point regardless of the order of administration of topotecan or oxaliplatin. Very few BPs were enriched at the 1 h time points. However, the biological processes highly connected to ventricular cardiac muscle cell development were enriched in a time-dependent manner, maximizing at the 24 h time point.


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

Davis M, Li J, Knight E, Eldridge SR, Daniels KK, Bushel PR - Front Genet (2015)

Clustering of the Enrichment of GO BPs. Clustering and heatmap based on the −log base 10 (p-values) of the 641 Gene Ontology (GO) biological processes (BPs) for each treatment and time point. The GO BPs are on the y-axis, the samples are on the x-axis. The enriched GO BPs were obtained from limma analysis DEGs (absolute fold change >2 and FDR < 0.01). Significance of enrichment was set to p < 0.05. Missing values were imputed as 0 (−log base 10(1), i.e., p = 1), Clustering of the pathways were performed using Pearson correlation dissimilarity (r) and average linkage grouping. Clusters (those with a 1- r ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. The color in the legend denotes the significance of enrichment. The more red the heat map color, the more significant the enrichment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325931&req=5

Figure 5: Clustering of the Enrichment of GO BPs. Clustering and heatmap based on the −log base 10 (p-values) of the 641 Gene Ontology (GO) biological processes (BPs) for each treatment and time point. The GO BPs are on the y-axis, the samples are on the x-axis. The enriched GO BPs were obtained from limma analysis DEGs (absolute fold change >2 and FDR < 0.01). Significance of enrichment was set to p < 0.05. Missing values were imputed as 0 (−log base 10(1), i.e., p = 1), Clustering of the pathways were performed using Pearson correlation dissimilarity (r) and average linkage grouping. Clusters (those with a 1- r ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. The color in the legend denotes the significance of enrichment. The more red the heat map color, the more significant the enrichment.
Mentions: Genes detected as differentially expressed at each time point (Supplementary Table 5) were used to enrich Gene Ontology (GO) biological processes (BPs). There were 641 GO BPs (Supplementary Table 6) significant (p < 0.05) from the union of all the lists (Supplementary Tables 7–12) [each one matching the order represented by the treatments in Figure 5]. Figure 5 shows the clustering of the 641 GO BPs terms based on the –log base 10 p-values. Clusters (those with a correlation value ≥ 0.9) of GO BP terms (n ≥ 30) were labeled according to the node having the maximum number of paths to it within the GO BP subtree directed acyclic graph derived from the terms in the cluster. DNA damage-signal transduction by p53 was highly enriched by the oxaliplatin exposure at the 6 h time point when it was given first but not second. Oxaliplatin given second elicited an ATP catabolic process at 6 h and positive regulation of epithelial to mesenchymal transition at 24 h. Topotecan when given second at 6 h impacted Ras GTPase activity in a positive regulation manner. The GTP catabolic process was enriched at the 6 h time point regardless of the order of administration of topotecan or oxaliplatin. Very few BPs were enriched at the 1 h time points. However, the biological processes highly connected to ventricular cardiac muscle cell development were enriched in a time-dependent manner, maximizing at the 24 h time point.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Toxicology and Pharmacology Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute Bethesda, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus