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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

EPIG patterns across treatments groups 1, 6, and 24 h post-treatment. The average of the log base 2 ratio (treated sample to the average of the time-matched control) from the top 6 expression profiles with the highest degree of correlation are plotted and displayed on the y-axis. The x-axis contains the treatments and the order of exposure. Oxali = oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). (A) Patterns extracted by EPIG of mRNA from bone marrow samples that were collected 1 h post-treatment administration. The row labeled 1st denotes which agent was administered first. (B) Same as A except analysis of mRNA from bone marrow samples that were collected 6 h post-treatment. (C) Same as A except analysis of mRNA from bone marrow samples collected 24 h post-treatment.
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Figure 2: EPIG patterns across treatments groups 1, 6, and 24 h post-treatment. The average of the log base 2 ratio (treated sample to the average of the time-matched control) from the top 6 expression profiles with the highest degree of correlation are plotted and displayed on the y-axis. The x-axis contains the treatments and the order of exposure. Oxali = oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). (A) Patterns extracted by EPIG of mRNA from bone marrow samples that were collected 1 h post-treatment administration. The row labeled 1st denotes which agent was administered first. (B) Same as A except analysis of mRNA from bone marrow samples that were collected 6 h post-treatment. (C) Same as A except analysis of mRNA from bone marrow samples collected 24 h post-treatment.

Mentions: We focused our analysis on uncovering groups of genes displaying similarity in their expression patterns and comparing the gene responses between treatment groups. The EPIG approach utilizes the underlying structure of gene expression data to extract patterns and identify co-expressed genes that are responsive to experimental conditions (Chou et al., 2007). The response patterns of genes were used to select gene sets that represent potential signatures for effects of the combination treatments that differed from that of the single agents. As shown in Figures 2A–C, several patterns of gene expression are induced or repressed relative to time-matched controls at the 1-, 6-, or 24 h time points respectively. Patterns that identified differences between individual treatment and combination treatment groups are marked with an asterisk in Supplementary Figures 1–3. The Venn diagrams in Supplementary Figure 4 reveal that there is little overlap of co-expressed genes changes (of 4-fold or more) between oxaliplatin and topotecan except for at the 24 h time point where 73 genes overlap.


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)

EPIG patterns across treatments groups 1, 6, and 24 h post-treatment. The average of the log base 2 ratio (treated sample to the average of the time-matched control) from the top 6 expression profiles with the highest degree of correlation are plotted and displayed on the y-axis. The x-axis contains the treatments and the order of exposure. Oxali = oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). (A) Patterns extracted by EPIG of mRNA from bone marrow samples that were collected 1 h post-treatment administration. The row labeled 1st denotes which agent was administered first. (B) Same as A except analysis of mRNA from bone marrow samples that were collected 6 h post-treatment. (C) Same as A except analysis of mRNA from bone marrow samples collected 24 h post-treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: EPIG patterns across treatments groups 1, 6, and 24 h post-treatment. The average of the log base 2 ratio (treated sample to the average of the time-matched control) from the top 6 expression profiles with the highest degree of correlation are plotted and displayed on the y-axis. The x-axis contains the treatments and the order of exposure. Oxali = oxaliplatin (15 mg/kg) and Topo = topotecan (4.7 mg/kg). (A) Patterns extracted by EPIG of mRNA from bone marrow samples that were collected 1 h post-treatment administration. The row labeled 1st denotes which agent was administered first. (B) Same as A except analysis of mRNA from bone marrow samples that were collected 6 h post-treatment. (C) Same as A except analysis of mRNA from bone marrow samples collected 24 h post-treatment.
Mentions: We focused our analysis on uncovering groups of genes displaying similarity in their expression patterns and comparing the gene responses between treatment groups. The EPIG approach utilizes the underlying structure of gene expression data to extract patterns and identify co-expressed genes that are responsive to experimental conditions (Chou et al., 2007). The response patterns of genes were used to select gene sets that represent potential signatures for effects of the combination treatments that differed from that of the single agents. As shown in Figures 2A–C, several patterns of gene expression are induced or repressed relative to time-matched controls at the 1-, 6-, or 24 h time points respectively. Patterns that identified differences between individual treatment and combination treatment groups are marked with an asterisk in Supplementary Figures 1–3. The Venn diagrams in Supplementary Figure 4 reveal that there is little overlap of co-expressed genes changes (of 4-fold or more) between oxaliplatin and topotecan except for at the 24 h time point where 73 genes overlap.

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