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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

Reconstruction of the p53 signaling gene regulatory network. The 19 genes mapped in the rat p53 signaling Wikipathway is used to reconstruct the network based interactions derived from the gene expression data. For (A) topotecan followed by oxaliplatin and (B) oxaliplatin followed by topotecan, the average of the biological replicates' gene expression data at each time point were used to reconstruct the gene regulatory network depending of the order of administration of the two drugs. A red arrow indicates activation, a blue arrow indicates inactivation. The labeling of the nodes is based on the UniGene symbol.
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Figure 7: Reconstruction of the p53 signaling gene regulatory network. The 19 genes mapped in the rat p53 signaling Wikipathway is used to reconstruct the network based interactions derived from the gene expression data. For (A) topotecan followed by oxaliplatin and (B) oxaliplatin followed by topotecan, the average of the biological replicates' gene expression data at each time point were used to reconstruct the gene regulatory network depending of the order of administration of the two drugs. A red arrow indicates activation, a blue arrow indicates inactivation. The labeling of the nodes is based on the UniGene symbol.

Mentions: The enrichment of GO biological processes from the samples where oxaliplatin is given first followed by vehicle for topotecan revealed DNA damage, regulation of p53 signaling transduction (Figure 5). In addition, the overlay of gene expression data on the p53 signaling pathway revealed regulation of key components of the cascade at 24 h (Figure 6). We therefore sort out to reconstruct the gene regulatory network based on the 19 genes mapped to the rat p53 signaling Wikipathway. This would allow us to compare the gene interactions from the time point data in the samples where topotecan is given first followed by oxaliplatin vs. when oxaliplatin is given first followed by topotecan. Using the Gene Regulatory Network Inference (GRNInfer) software with the default setting to control the sparseness and the complexity of the network reconstruction, gene networks based on the average of the four replicate time point studies for each order of administration were revealed (Figure 7). When topotecan is given first followed by oxaliplatin, MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) and GADD45g are central hubs interacting with p53, cyclin-dependent kinases, several cysteine-aspartic acid proteases (CASPs), BID, two CASPs (CASP8 and CASP3) and other components (Figure 7A). On the other hand, when oxaliplatin is given first followed by topotecan, CASP8 and the G-2 and S-phase expressed 1 gene (GTSE1) are the central hubs of the network interacting with p53, the cyclin-dependent kinases, CASP9, Kras, FAS, BID and other components (Figure 7B). Essentially the activation and inactivation shown for components in the networks are caused by different central regulators depending on the order of administration.


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)

Reconstruction of the p53 signaling gene regulatory network. The 19 genes mapped in the rat p53 signaling Wikipathway is used to reconstruct the network based interactions derived from the gene expression data. For (A) topotecan followed by oxaliplatin and (B) oxaliplatin followed by topotecan, the average of the biological replicates' gene expression data at each time point were used to reconstruct the gene regulatory network depending of the order of administration of the two drugs. A red arrow indicates activation, a blue arrow indicates inactivation. The labeling of the nodes is based on the UniGene symbol.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Reconstruction of the p53 signaling gene regulatory network. The 19 genes mapped in the rat p53 signaling Wikipathway is used to reconstruct the network based interactions derived from the gene expression data. For (A) topotecan followed by oxaliplatin and (B) oxaliplatin followed by topotecan, the average of the biological replicates' gene expression data at each time point were used to reconstruct the gene regulatory network depending of the order of administration of the two drugs. A red arrow indicates activation, a blue arrow indicates inactivation. The labeling of the nodes is based on the UniGene symbol.
Mentions: The enrichment of GO biological processes from the samples where oxaliplatin is given first followed by vehicle for topotecan revealed DNA damage, regulation of p53 signaling transduction (Figure 5). In addition, the overlay of gene expression data on the p53 signaling pathway revealed regulation of key components of the cascade at 24 h (Figure 6). We therefore sort out to reconstruct the gene regulatory network based on the 19 genes mapped to the rat p53 signaling Wikipathway. This would allow us to compare the gene interactions from the time point data in the samples where topotecan is given first followed by oxaliplatin vs. when oxaliplatin is given first followed by topotecan. Using the Gene Regulatory Network Inference (GRNInfer) software with the default setting to control the sparseness and the complexity of the network reconstruction, gene networks based on the average of the four replicate time point studies for each order of administration were revealed (Figure 7). When topotecan is given first followed by oxaliplatin, MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) and GADD45g are central hubs interacting with p53, cyclin-dependent kinases, several cysteine-aspartic acid proteases (CASPs), BID, two CASPs (CASP8 and CASP3) and other components (Figure 7A). On the other hand, when oxaliplatin is given first followed by topotecan, CASP8 and the G-2 and S-phase expressed 1 gene (GTSE1) are the central hubs of the network interacting with p53, the cyclin-dependent kinases, CASP9, Kras, FAS, BID and other components (Figure 7B). Essentially the activation and inactivation shown for components in the networks are caused by different central regulators depending on the order of administration.

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