Limits...
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

Heatmap of gene expression data analyzed by EPIG. (A) The 1393 gene probes categorized to the 16 EPIG patterns (y-axis color column) across the 1, 6, and 24 h time points are in rows and the samples are in columns. (B) Patterns 8, 9, 11, 14–16 from the samples at just the 1 h time point. The labeling of samples is according to the time and order in which the agent was given (either 1st or second). Oxali is oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). Veh1 is the vehicle used for Oxali, and Veh2 is the vehicle used for Topo. The data is the log base 2 ratio (treated sample to the average of the time-matched control) and the scale on the bottom displays the color range for the log base 2 ratio values. Red denotes upregulation, blue downregulation, and gray relatively no change.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4325931&req=5

Figure 3: Heatmap of gene expression data analyzed by EPIG. (A) The 1393 gene probes categorized to the 16 EPIG patterns (y-axis color column) across the 1, 6, and 24 h time points are in rows and the samples are in columns. (B) Patterns 8, 9, 11, 14–16 from the samples at just the 1 h time point. The labeling of samples is according to the time and order in which the agent was given (either 1st or second). Oxali is oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). Veh1 is the vehicle used for Oxali, and Veh2 is the vehicle used for Topo. The data is the log base 2 ratio (treated sample to the average of the time-matched control) and the scale on the bottom displays the color range for the log base 2 ratio values. Red denotes upregulation, blue downregulation, and gray relatively no change.

Mentions: The heat map in Figure 3A shows gene expression patterns across all treatment groups and time points. There is a clear time response in the patterns of gene expression from the treatments where by the 24 h time point, the patterns of expression are either maximally induced or maximally repressed. A list of representative pattern-specific genes showing at least 4-fold differences from their respective controls at the 24 h bone marrow collection time point is provided in Table 3 (up-regulated) and Table 4 (down-regulated). Notably, several genes related to chondrogenesis, bone repair, and differentiation were profoundly increased in response to combination treatment when compared to individual treatments. As show in the visualization of just the 1 h time points (Figure 3B), the co-expressed genes in patterns 8, 9 and pattern 11 vary depending on whether topotecan was given before or after the vehicle or oxaliplatin. On other hand, the co-expressed genes in patterns 14–16, vary depending on whether oxaliplatin was given before or after the vehicle. The 244 probes in patterns 8, 9, and 11, representing 59 co-expressed genes, enrich for pathways related to mRNA splicing, splicesomes, metabolism, cell cycle and DNA replication. The 188 probes in patterns 14–16, representing 45 co-expressed genes, enrich for pathways related to chromosome organization, chromatin packaging and remodeling. Full lists of genes derived from each pattern with absolute fold change of 4 or greater from their respective controls and p < 0.05, are provided in Supplementary Table 1.


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)

Heatmap of gene expression data analyzed by EPIG. (A) The 1393 gene probes categorized to the 16 EPIG patterns (y-axis color column) across the 1, 6, and 24 h time points are in rows and the samples are in columns. (B) Patterns 8, 9, 11, 14–16 from the samples at just the 1 h time point. The labeling of samples is according to the time and order in which the agent was given (either 1st or second). Oxali is oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). Veh1 is the vehicle used for Oxali, and Veh2 is the vehicle used for Topo. The data is the log base 2 ratio (treated sample to the average of the time-matched control) and the scale on the bottom displays the color range for the log base 2 ratio values. Red denotes upregulation, blue downregulation, and gray relatively no change.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Heatmap of gene expression data analyzed by EPIG. (A) The 1393 gene probes categorized to the 16 EPIG patterns (y-axis color column) across the 1, 6, and 24 h time points are in rows and the samples are in columns. (B) Patterns 8, 9, 11, 14–16 from the samples at just the 1 h time point. The labeling of samples is according to the time and order in which the agent was given (either 1st or second). Oxali is oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). Veh1 is the vehicle used for Oxali, and Veh2 is the vehicle used for Topo. The data is the log base 2 ratio (treated sample to the average of the time-matched control) and the scale on the bottom displays the color range for the log base 2 ratio values. Red denotes upregulation, blue downregulation, and gray relatively no change.
Mentions: The heat map in Figure 3A shows gene expression patterns across all treatment groups and time points. There is a clear time response in the patterns of gene expression from the treatments where by the 24 h time point, the patterns of expression are either maximally induced or maximally repressed. A list of representative pattern-specific genes showing at least 4-fold differences from their respective controls at the 24 h bone marrow collection time point is provided in Table 3 (up-regulated) and Table 4 (down-regulated). Notably, several genes related to chondrogenesis, bone repair, and differentiation were profoundly increased in response to combination treatment when compared to individual treatments. As show in the visualization of just the 1 h time points (Figure 3B), the co-expressed genes in patterns 8, 9 and pattern 11 vary depending on whether topotecan was given before or after the vehicle or oxaliplatin. On other hand, the co-expressed genes in patterns 14–16, vary depending on whether oxaliplatin was given before or after the vehicle. The 244 probes in patterns 8, 9, and 11, representing 59 co-expressed genes, enrich for pathways related to mRNA splicing, splicesomes, metabolism, cell cycle and DNA replication. The 188 probes in patterns 14–16, representing 45 co-expressed genes, enrich for pathways related to chromosome organization, chromatin packaging and remodeling. Full lists of genes derived from each pattern with absolute fold change of 4 or greater from their respective controls and p < 0.05, are provided in Supplementary Table 1.

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