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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

Scatter plots of pathways enriched in patterns derived from bone marrow collected post-treatment with topotecan, oxaliplatin, or a combination. Clusters of genes identified by EPIG were then analyzed using Gene Set Enrichment Analysis (GSEA) and Sub-Network Enrichment Analysis (SNEA) algorithms to find enriched pathways. (A) One hour post-treatment. (B) Six hours post-treatment. (C) Twenty-four hours post-treatment. The numbers on the x-axis denote the EPIG pattern which contained the genes that enriched the pathways labeled on the y-axis. A square represents a pathway that was enriched by the genes in the given EPIG pattern.
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Figure 4: Scatter plots of pathways enriched in patterns derived from bone marrow collected post-treatment with topotecan, oxaliplatin, or a combination. Clusters of genes identified by EPIG were then analyzed using Gene Set Enrichment Analysis (GSEA) and Sub-Network Enrichment Analysis (SNEA) algorithms to find enriched pathways. (A) One hour post-treatment. (B) Six hours post-treatment. (C) Twenty-four hours post-treatment. The numbers on the x-axis denote the EPIG pattern which contained the genes that enriched the pathways labeled on the y-axis. A square represents a pathway that was enriched by the genes in the given EPIG pattern.

Mentions: Gene lists within patterns revealing clear differences between control and treatment groups for each time-point were used to obtain pathway enrichment profiles by gene set enrichment analysis (Subramanian et al., 2005). Supplementary Tables 2–4 are lists (1 h, 6 h and 24 h respectively) of pathways from gene set enrichment analyses carried out against reference pathways, provided by Ariadne, within the designated patterns. Pathways common to multiple patterns were also identified and shown in Figure 4. The pathways commonly enriched in all patterns evaluated at all treatment times were those pathways related to chromatin remodeling and cell cycle regulation. Pathways derived from the lists of genes obtained from bone marrow samples 1 and 6 h after dosing were particularly enriched with pathways related to DNA repair, histone biology, cell cycle regulation, hypoxia, glutathione metabolism, and respiratory and oxidative phosphorylation. These regulatory events provide evidence of target-mediated biology for the drug treatments that can be potentially used as a basis for additional toxicodynamic modeling as early as 1 h after administration of a single dose.


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)

Scatter plots of pathways enriched in patterns derived from bone marrow collected post-treatment with topotecan, oxaliplatin, or a combination. Clusters of genes identified by EPIG were then analyzed using Gene Set Enrichment Analysis (GSEA) and Sub-Network Enrichment Analysis (SNEA) algorithms to find enriched pathways. (A) One hour post-treatment. (B) Six hours post-treatment. (C) Twenty-four hours post-treatment. The numbers on the x-axis denote the EPIG pattern which contained the genes that enriched the pathways labeled on the y-axis. A square represents a pathway that was enriched by the genes in the given EPIG pattern.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Scatter plots of pathways enriched in patterns derived from bone marrow collected post-treatment with topotecan, oxaliplatin, or a combination. Clusters of genes identified by EPIG were then analyzed using Gene Set Enrichment Analysis (GSEA) and Sub-Network Enrichment Analysis (SNEA) algorithms to find enriched pathways. (A) One hour post-treatment. (B) Six hours post-treatment. (C) Twenty-four hours post-treatment. The numbers on the x-axis denote the EPIG pattern which contained the genes that enriched the pathways labeled on the y-axis. A square represents a pathway that was enriched by the genes in the given EPIG pattern.
Mentions: Gene lists within patterns revealing clear differences between control and treatment groups for each time-point were used to obtain pathway enrichment profiles by gene set enrichment analysis (Subramanian et al., 2005). Supplementary Tables 2–4 are lists (1 h, 6 h and 24 h respectively) of pathways from gene set enrichment analyses carried out against reference pathways, provided by Ariadne, within the designated patterns. Pathways common to multiple patterns were also identified and shown in Figure 4. The pathways commonly enriched in all patterns evaluated at all treatment times were those pathways related to chromatin remodeling and cell cycle regulation. Pathways derived from the lists of genes obtained from bone marrow samples 1 and 6 h after dosing were particularly enriched with pathways related to DNA repair, histone biology, cell cycle regulation, hypoxia, glutathione metabolism, and respiratory and oxidative phosphorylation. These regulatory events provide evidence of target-mediated biology for the drug treatments that can be potentially used as a basis for additional toxicodynamic modeling as early as 1 h after administration of a single dose.

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