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

Representative images of bone marrow hypocellularity in femur from male rats 24 h after a single 30 min IV infusion dose of oxaliplatin, topotecan or combination of oxaliplatin followed by topotecan. Hematoxylin and eosin stained tissue sections; 10X objective; bars = 100 μm. (A) Male rat exposed to vehicle control. (B) Minimal hypocellularity in male rat exposed to oxaliplatin. (C) Mild hypocellularity in male rat exposed to topotecan. (D) Moderate hypocellularity in male rat exposed to oxaliplatin followed by topotecan. Bone marrow hypocellularity was graded based on the estimated percentage of cell loss with minimal hypocellularity = 10–20% cell loss, mild hypocellularity = 30–40% cell loss, moderate hypocellularity = 50–60% cell loss, and marked hypocellularity = greater than 60% cell loss.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Representative images of bone marrow hypocellularity in femur from male rats 24 h after a single 30 min IV infusion dose of oxaliplatin, topotecan or combination of oxaliplatin followed by topotecan. Hematoxylin and eosin stained tissue sections; 10X objective; bars = 100 μm. (A) Male rat exposed to vehicle control. (B) Minimal hypocellularity in male rat exposed to oxaliplatin. (C) Mild hypocellularity in male rat exposed to topotecan. (D) Moderate hypocellularity in male rat exposed to oxaliplatin followed by topotecan. Bone marrow hypocellularity was graded based on the estimated percentage of cell loss with minimal hypocellularity = 10–20% cell loss, mild hypocellularity = 30–40% cell loss, moderate hypocellularity = 50–60% cell loss, and marked hypocellularity = greater than 60% cell loss.

Mentions: Bone marrow hypocellularity was observed in the bone marrow of animals dosed with topotecan, oxaliplatin, or a combination of these two drugs (Figure 1 and Table 2). Minimal bone marrow hypocellularity consisted of an approximately 10–20% decrease in the normal population of cells which reside in the bone marrow in comparison with control animals. The remaining cell population consisted primarily of band and mature granulocytes (neutrophils and eosinophils), mature erythrocytes, and megakaryocytes. Occasionally apoptotic cells were observed in the bone marrow of some animals. These lesions were observed as early as 1 h after the end of topotecan administration and 6 h after the end of oxaliplatin administration. Bone marrow hypocellularity was observed at a higher and earlier onset of incidence in animals that received topotecan alone or topotecan in combination with oxaliplatin than in dose groups that received only oxaliplatin. One-hour post-treatment, bone marrow hypocellularity was observed for animals in all of the dose groups administered topotecan alone or topotecan in combination with oxaliplatin, but not in the dose groups given only oxaliplatin. There also appeared to be an increase in severity of bone marrow suppression from mild to moderate when topotecan was given prior to oxaliplatin than when oxaliplatin was given prior to topotecan. These data support a sequence dependency for the severity of bone marrow toxicity for this combination.


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)

Representative images of bone marrow hypocellularity in femur from male rats 24 h after a single 30 min IV infusion dose of oxaliplatin, topotecan or combination of oxaliplatin followed by topotecan. Hematoxylin and eosin stained tissue sections; 10X objective; bars = 100 μm. (A) Male rat exposed to vehicle control. (B) Minimal hypocellularity in male rat exposed to oxaliplatin. (C) Mild hypocellularity in male rat exposed to topotecan. (D) Moderate hypocellularity in male rat exposed to oxaliplatin followed by topotecan. Bone marrow hypocellularity was graded based on the estimated percentage of cell loss with minimal hypocellularity = 10–20% cell loss, mild hypocellularity = 30–40% cell loss, moderate hypocellularity = 50–60% cell loss, and marked hypocellularity = greater than 60% cell loss.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Representative images of bone marrow hypocellularity in femur from male rats 24 h after a single 30 min IV infusion dose of oxaliplatin, topotecan or combination of oxaliplatin followed by topotecan. Hematoxylin and eosin stained tissue sections; 10X objective; bars = 100 μm. (A) Male rat exposed to vehicle control. (B) Minimal hypocellularity in male rat exposed to oxaliplatin. (C) Mild hypocellularity in male rat exposed to topotecan. (D) Moderate hypocellularity in male rat exposed to oxaliplatin followed by topotecan. Bone marrow hypocellularity was graded based on the estimated percentage of cell loss with minimal hypocellularity = 10–20% cell loss, mild hypocellularity = 30–40% cell loss, moderate hypocellularity = 50–60% cell loss, and marked hypocellularity = greater than 60% cell loss.
Mentions: Bone marrow hypocellularity was observed in the bone marrow of animals dosed with topotecan, oxaliplatin, or a combination of these two drugs (Figure 1 and Table 2). Minimal bone marrow hypocellularity consisted of an approximately 10–20% decrease in the normal population of cells which reside in the bone marrow in comparison with control animals. The remaining cell population consisted primarily of band and mature granulocytes (neutrophils and eosinophils), mature erythrocytes, and megakaryocytes. Occasionally apoptotic cells were observed in the bone marrow of some animals. These lesions were observed as early as 1 h after the end of topotecan administration and 6 h after the end of oxaliplatin administration. Bone marrow hypocellularity was observed at a higher and earlier onset of incidence in animals that received topotecan alone or topotecan in combination with oxaliplatin than in dose groups that received only oxaliplatin. One-hour post-treatment, bone marrow hypocellularity was observed for animals in all of the dose groups administered topotecan alone or topotecan in combination with oxaliplatin, but not in the dose groups given only oxaliplatin. There also appeared to be an increase in severity of bone marrow suppression from mild to moderate when topotecan was given prior to oxaliplatin than when oxaliplatin was given prior to topotecan. These data support a sequence dependency for the severity of bone marrow toxicity for this combination.

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