title: Acute molecular markers of rodent hepatic carcinogenesis identified by transcription profiling.
abstract: Currently, the only way to identify nongenotoxic hepatocarcinogens is through long-term repeat dose studies such as the 2 year rodent carcinogenicity assay. Such assays are both time consuming and expensive and require large amounts of active pharmaceutical or chemical ingredients. Thus, the results of the 2 year assay are not known until very late in the discovery and development process for new pharmaceutical entities. Although in many cases nongenotoxic carcinogenicity in rodents is considered to be irrelevant for humans, a positive finding in a 2 year carcinogenicity assay may increase the number of studies to demonstrate the lack of relevance to humans, delay final submission and subsequent registration of a product, and may result in a "black box" carcinogenicity warning on the label. To develop early identifiers of carcinogenicity, we applied transcription profiling using several prototype rodent genotoxic and nongenotoxic carcinogens, as well as two noncarcinogenic hepatotoxicants, in a 5 day repeat dose in vivo toxicology study. Fluorescent-labeled probes generated from liver mRNA prepared from male Sprague-Dawley rats treated with one of three dose levels of bemitradine, clofibrate, doxylamine, methapyrilene, phenobarbital, tamoxifen, 2-acetylaminofluorene, 4-acetylaminofluorene, or isoniazid were hybridized against rat cDNA microarrays. Correlation of the resulting data with an estimated carcinogenic potential of each compound and dose level identified several candidate molecular markers of rodent nongenotoxic carcinogenicity, including transforming growth factor-beta stimulated clone 22 and NAD(P)H cytochrome P450 oxidoreductase.
authors.affiliation: Pfizer Corporation, World Wide Safety Science, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, USA. a. kramer@pfizer.com
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kramer
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Curtiss
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
authors.forename: Carl L
authors.initials: CL
authors.lastname: Alden
authors.forename: Eric A G
authors.initials: EA
authors.lastname: Blomme
authors.forename: William C
authors.initials: WC
authors.lastname: Curtiss
authors.forename: Julio C
authors.initials: JC
authors.lastname: Davila
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger