Establishment and validation of classifiers to predict genotoxic and non-genotoxic carcinogens / 中国药学杂志

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.

Key principles of nonclinical safety evaluation for pediatric drugs and characteristics of traditional Chinese materia medica evaluation / 中国药理学与毒理学杂志

In current research and development of new drugs,the demand for toxicological study using neonatal and juvenile animals is becoming increasingly urgent. In this paper,we discussed the characteristics,importance and necessity of nonclinical safety evaluation for pediatric drugs,considerations for research design,selection of animal species and age,route and duration of drug administration and evaluation indexes. In addition,the characteristics of nonclinical safety evaluation of new traditional Chinese materia medica used for children were analyzed. It is hoped that these studies will not only provide support and reference for nonclinical safety evaluation of pediatric drugs but help accumulate material in formulating relevant guidelines.

Current approaches to assess QTc prolongation for small molecule drug development / 中国药理学与毒理学杂志

Assessment of QTc prolongation is a critical step for small molecule drug development.ICH S7B continues to be the main frame to guide the assessment for this potential cardiovascular risk.The ICH guideline outlines a 3-step approach to QTc prolongation,including in vitro bERG inhibition,ex vivo action potential duration (APD),and in vivo animal telemetry approch.Dog,monkey,swine,rabbit,ferret,and guinea pig are the common laboratory animals used for in vivo electrophysiology studies,especially using conscious Beagle Dog. In addition to all these guideline standard studies,many newly developed approaches,such as receptor binding for hERG inhibition,ex vivo methods such as perfused rabbit heart or guinea pig heartare are useful models for this purpose.All these methods display good correlation to clinic outcomes,and are low cost and have rapid turn-around time in nature; so that,they can help rapidly and predict this potential cardiac liability,resulting into accelerating process for small molecule drug candidate development.

Current trends of nonclinical safety evaluation for new drugs / 中国药理学与毒理学杂志

Nonclinical safety evaluation plays a critical role in the process of new drug development.International Conference on Harmonization (ICH) guideline M3 (R2) provides a key direction for the nonclinical safety evaluation process.Proper strategies and toxicological studies should be considered together to move the drug candidates forward efficiently and quickly to support clinical plans and market registration.Updates on ICH guidelines,such as ICH S6 and ICH S9,have great impact on the direction of development.With the increasing cost of development and competition in the industry,elements like predictivity,animal models,and regulatory compliance are also very important in the process.Therefore,an insight into all these factors is essential to toxicologists in the safety evaluation process.The ability to use the overall knowledge will result in a quicker and better new drug development program.