ABSTRACT
Carcinogenic test is an important part of non-clinical safety evaluation of new drugs, which aims to evaluate and predict the human carcinogenic risk in long-term drug use by examining the potential carcinogenic effects of drugs on animals. Historical control data may be vital in the interpretation of rare tumors and unexpected increases or decreases of tumors in treated animals compared to controls. Foreign institutions have accumulated a considerable amount of historical control data that can be attributed to the pathological working group and peer review. Such data is valuable and referable, and can be used as a reliable comparator for concurrent study-specific control data. Different experimental animal strains have evolved in history from the F344 rat and B6C3F1 mice, which were traditionally employed by the National Toxicology Program (NTP), to the SD rats, CD-1 mice, and Wistar rats that were routinely used by industrial firms, and finally to the strains of the p53+/- and Tg.rasH2 transgenic mice. It is true that each strain of rodent animal used in carcinogenicity test has different characters in tumorigenesis. Carcinogenicity tests are increasing in China, but the background data that can be referred to is limited so that how to accumulate and use our own historical control data has become challenging. This article summarizes and compares the tumor lesion data of the collected rodent animals, and concludes that different strains have specific types of tumors with gender-related difference.
ABSTRACT
OBJECTIVE: To establish classifiers to predict genotoxic and non-genotoxic carcinogens using toxicogenomics methods, explore the effect of exposure time and validated the prediction performance of the classifiers. METHODS: The primary mouse hepatocyte model was treated for 24 and 48 h with two genotoxic carcinogens, aflatoxin Bl (AFB1), benzo(a) pyrene (BAP) and two non-genotoxic carcinogens, thioacetamide (TAA), wyeth-14643 (WY). The differentially expressed genes were input to prediction analysis for microarray (PAM) software to screen out classifiers. The functions and interrelations of genes in classifiers were studied by gene set enrichment analysis (GSEA) and the protein-protein interactions were predicted using STRING database. Two additional carcinogens to validate the prediction performance of the classifiers were used. Finally, the experiment of QuantiGene Multiplex assay (Q-GP) to validate the microarray data was used. RESULTS: Forty-eight h classifiers had a better predicted capability than that of 24 h classifiers. p53 pathway, TNF-α signaling pathway, fatty acid metabolism, PPAR signaling pathway involved in the classifires were enriched by GSEA. Carcinogenic protein-protein interaction network and metabolism-related protein-protein interaction network are obtained using STRING database. The predicted probability of the two additional carcinogens using 48 h classifiers was nearly 100% and data between QuantiGene Multiplex assay and microarray assay had a high conformity. CONCLUSION: The classifiers which could be used to discriminate the potential genotoxic carcinogens and non-genotoxic carcinogens and to predict modes of action for unknown compounds, are successfully established and validated. This might be a promising candidate in vitro method for carcinogenicity study in the field of nonclinical safety evaluation of drugs.
ABSTRACT
Objective To investigate the spontaneous neoplastic lesions and their incidences in rats .Methods Sixty male and 60 female specific pathogen-free Wistar rats (4-weeks old ) were used in this study .The rats were acclima-ted for 1 week prior to initiation of the experiment .They were fed with conventional feed for 104 weeks and then sacrificed for histopathological examination .Results Various neoplastic lesions of the rats and their incidences were analyzed and reported.For male rats, their total tumor incidence was 49.12%, the benign tumor incidence was 38.60%and the malig-nant tumor incidence was 17.54%.The benign neoplastic lesions mainly were pituitary adenoma ( 19.30%) , testis Leydig cell tumor (5.26%) and subcutaneous fibroma (5.26%).The malignant neoplastic lesions mainly were squamous cell carcinoma (7.02%) and lymphoid hematopoietic system tumors (3.51%).For female rats, their total tumor inci-dence was 60.34%, the benign tumor incidence was 50.00%and the malignant tumor incidence was 15.52%.The benign neoplastic lesions mainly were breast fibroadenoma (25.86%) and pituitary adenoma (24.14%).The malignant neoplas-tic lesions mainly were adenocarcinoma (5.17%) and breast cancer (3.45%).Conclusions The spontaneous neoplastic lesions and their incidences reported in this paper provide another data of the spontaneous tumors of SPF Wistar rats and may provide some reference for relevant technical staffs .