Non-genotoxic carcinogenicity study accepted for publication by leading scientific journal

transADMET lines can play an invaluable role in determining the relevance of rodent liver tumours to human safety assessment.

Hudson, New York/Dundee, Scotland – CXR Biosciences Ltd and TaconicArtemis GmbH are pleased to announce that the prestigious Toxicological Sciences Journal has accepted for publication a manuscript which demonstrates that transgenic ADME mice (transADMET™) containing human versions of the pregnane X receptor (PXR) or constitutive androstane receptor (CAR) gene support the hypertrophic but not the hyperplastic response to murine non-genotoxic hepatocarcinogens. The study elegantly illustrates the utility of transADMET mice in determining the relevance of rodent liver tumours to human safety assessment.

Tumour findings are common endpoints in the preclinical testing of drug candidates and in chemical safety assessment. Such in vivo carcinogenesis is rarely genotoxic in nature, as directly genotoxic compounds are identified using in vitro tests or at an early point in the drug development process. However, there are currently no sufficiently accurate and well-validated short-term assays for identifying non-genotoxic carcinogens, thus necessitating an expensive 2-year rodent bioassay.

The issue is complicated by the fact that some non genotoxic carcinogens cause tumours in rodent studies by a mechanism that may be species specific and therefore of unknown relevance to man. In response, CXR Biosciences and TaconicArtemis, collaborators in a research programme funded by Scottish Enterprise, have developed a series of innovative mouse models (“transADMET™”) for the improved prediction of human response to potential carcinogens. In the transADMET™ models, key murine genes involved in non genotoxic carcinogenicity (such as PXR and CAR), as well as drug metabolism and disposition, have either been exchanged for their human counterparts, or knocked out for use as controls.

This announcement follows the recent successes of Dr. Cliff Elcombe, Director of Research and Co-Founder of CXR Biosciences Ltd, who was awarded “The Best Presentation in Risk Assessment” at the Annual Meeting of the Society of Toxicology (SOT) in Salt Lake City, UT, USA. At the annual largest meeting for world experts in toxicology, with over 6000 attendees, Dr. Elcombe was honoured for his work using transADMET™ models to investigate the molecular mechanisms of toxicity and carcinogenesis. He presented data which demonstrated how these novel tools could play an invaluable role in determining the relevance of preclinical rodent liver tumours to human safety assessment.

Reference (Access the paper here)

Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not he hyperplastic response to the murine non-genotoxic hepatocarinogens phenobarbital and chlordane in vivo. ., Ross, J., Plummer, S., Rode, A., Scheer, N S., Vogel, O., Wolf, C.R., and Elcombe, C., (2010) J. Tox. Sci..

About CXR CXR Biosciences Ltd. is commercializing innovative approaches to transform the drug development and chemical safety assessment process. As well as introducing new technology platforms, CXR also helps customers to take their candidate compounds through development efficiently, or to resolve problems that have been encountered, through the provision of customized solutions. The company has business relationships with many of the world’s leading pharmaceutical companies, chemical companies, biotechnology companies, universities and research institutions. CXR Biosciences Ltd. is located in Dundee, Scotland. More information can be found at www.cxrbiosciences.com.

About Taconic Taconic is a leading provider of life sciences solutions to researchers worldwide, offering innovative lab animal models and scientific services that facilitate in vivo studies and advance drug discovery. Taconic’s wide range of advanced solutions include custom model design, generation and production, off-the-shelf model repositories, compound profiling, contract research, contract breeding, genetic monitoring and health testing. Headquartered in New York’s Hudson River Valley, Taconic operates seven breeding facilities and three service laboratories in the U.S. and Europe and maintains a staff of over 1,200 scientific specialists committed to technological innovation.

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