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. 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.

Toxicogenomics in biomarker discovery.

In the area of toxicology, the subdiscipline of toxicogenomics has emerged, which is the use of genome-scale mRNA expression profiling to monitor responses to adverse xenobiotic exposure. Toxicogenomics is being investigated for use in the triage of compounds through predicting potential toxicity, defining mechanisms of toxicity, and identifying potential biomarkers of toxicity. Whereas various approaches have been reported for the development of algorithms predictive of toxicity and for the interpretation of gene expression data for deriving mechanisms of toxicity, there are no clearly defined methods for the discovery of biomarkers using gene expression technologies. Ways in which toxicogenomics may be used for biomarker discovery include analysis of large databases of gene expression profiles followed by in silico mining of the database for differentially expressed genes; the analysis of gene expression data from preclinical studies to find differentially expressed genes that correlate with pathology (coincident biomarker) or precede pathology (leading biomarker) within a lead series; or gene expression profiling can be performed directly on the blood from preclinical studies or clinical trials to find biomarkers that can be obtained noninvasively. This chapter broadly discusses the issues and the utility of applying toxicogenomics to biomarker discovery.

Biomarkers of drug-induced adverse events.

Many drugs on the market have the potential to cause undesirable side effects. Biomarkers used today, at best, diagnose an existing injury, such as cell death or abnormal functioning of an organ. More valuable would be biomarkers that could be used to prevent a patient from receiving an inappropriate drug or to identify very early signs of injury so the offending drug may be discontinued prior to overt tissue injury. Biomarkers currently used to identify drug-induced injury to the liver, heart and kidney will be discussed, as will some newer biomarkers. Progress on finding new biomarkers through the use of pharmacogenetics and pharmacogenomic approaches, consortia that may assist in their discovery and qualification for use, regulatory issues and the pharmacoeconomic considerations that may drive or hinder such new tests are also described.

From the bench to the clinic and back again: translational biomarker discovery using in silico mining of pharmacogenomic data.

To improve drug efficacy and safety and advance medical intervention in diseases, new biomarkers are urgently needed. Pharmacogenomics can provide a tool to discover and begin to qualify biomarkers useful for these indications and is readily applicable to multiple species. One can begin and end with genes or focus on tissue-derived expression analysis of those genes that encode secreted proteins to discover potential biomarkers that can be monitored in body fluids. The paper will discuss issues surrounding such investigations, show examples of translational biomarkers and end with a summary of the US FDA's work in this field over the last 6 years.