Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity.

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. Six patterns of co-expressed genes were detected at the 1-hour time point which indicate regulatory expression of genes dependent on the order of the administration. When topotecan is given first, several signal transduction transcription factors associated with cancer or inactivation of a tumor suppressor were co-regulating gene expression. 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.

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Davis M, Li J, Knight E, Eldridge SR, Daniels KK, Bushel PR