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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

Overlay of gene expression on the p53 signaling pathway. The rat p53 signaling pathway is overlaid with the average of the log base 2 ratio values from the replicate samples. Red denotes induction, green repression and yellow no change. Gray indicates that the gene was not mapped. The legend illustrates the segmentation of the genes according to the data from a given treatment.
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Figure 6: Overlay of gene expression on the p53 signaling pathway. The rat p53 signaling pathway is overlaid with the average of the log base 2 ratio values from the replicate samples. Red denotes induction, green repression and yellow no change. Gray indicates that the gene was not mapped. The legend illustrates the segmentation of the genes according to the data from a given treatment.

Mentions: Pathways related to DNA damage and p53-mediated cell cycle arrest were identified as highly connected and were uniquely enriched in some samples. We then visualized the changes in gene expression within the rat p53 signaling Wikipathway at the 24 h time point in the study (Figure 6). As indicated by the relative expression to time-matched controls, MDM2, GADD45, SCOTIN, CASP8, and IGFB3 were up-regulated whereas the cyclins, p53, SIAH, GTSE1, and PARP1 were down-regulated. Regulation of several genes that also play roles in the apoptosis pathways (Figure 4) and cell cycle regulation (Figure 4) was also observed 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)

Overlay of gene expression on the p53 signaling pathway. The rat p53 signaling pathway is overlaid with the average of the log base 2 ratio values from the replicate samples. Red denotes induction, green repression and yellow no change. Gray indicates that the gene was not mapped. The legend illustrates the segmentation of the genes according to the data from a given treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Overlay of gene expression on the p53 signaling pathway. The rat p53 signaling pathway is overlaid with the average of the log base 2 ratio values from the replicate samples. Red denotes induction, green repression and yellow no change. Gray indicates that the gene was not mapped. The legend illustrates the segmentation of the genes according to the data from a given treatment.
Mentions: Pathways related to DNA damage and p53-mediated cell cycle arrest were identified as highly connected and were uniquely enriched in some samples. We then visualized the changes in gene expression within the rat p53 signaling Wikipathway at the 24 h time point in the study (Figure 6). As indicated by the relative expression to time-matched controls, MDM2, GADD45, SCOTIN, CASP8, and IGFB3 were up-regulated whereas the cyclins, p53, SIAH, GTSE1, and PARP1 were down-regulated. Regulation of several genes that also play roles in the apoptosis pathways (Figure 4) and cell cycle regulation (Figure 4) was also observed 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