The Use of Imaging Tools in Toxicology Assessments

In the last decade, in vivo imaging methods have become established tools in basic science research. This lecture is designed provide a general overview of ultrasound imaging utilized in basic science with applications to drug discovery and toxicological research. Five cardiovascular models will be described as examples including: myocardial hypertrophy, myocardial infarction, Marfan’s disease, atherosclerosis and cancer therapy-induced cardiac injury. The second half of the presentation will focus on the use of ultrasound for cancer studies to measure tumor volume, tumor blood flow and gene expression of tumor blood vessels. Following this short review, attendees should have basic understanding of the various ultrasound imaging applications used in cardiovascular disease drug discovery, toxicological and cancer research.

Imaging Tissue Hypoxia
Michael J. Welch, Washington University at St. Louis

An important parameter in toxicology assessment for various agents is the effect of agents on tissue hypoxia. Tissue hypoxia has been imaged utilizing many techniques including magnetic resonance imaging, optical techniques and radionuclide techniques. Two general approaches have been taken to image hypoxia utilizing positron emission tomography (PET). The first approach is the synthesis of radiolabeled labeled nitroimidazoles. The second approach uses inorganic complexes labeled with copper radionuclides which are stable in normoxic tissue and unstable in hypoxic tissue. One of these agents (Cu-ATSM) has been studied in human, both in Japan and the United States. The imaging techniques described could have an important role in monitoring changes in hypoxia of a variety of new drugs.

Radionuclide and PET Imaging for Toxicology in Oncology
Peter L. Choyke, National Cancer Institute

Although there is intense interest in the use of imaging biomarkers to accelerate oncologic drug development, interest is largely focused on drug targeting and effects. An equally important role for imaging biomarkers is the assessment of "off-target" effects that can determine the fate of otherwise promising drugs. The use of radiolabeled antibodies to detect off-target accumulation has proven useful for trastuzumab, an antibody directed against an epithelial growth factor receptor. PET agents (e.g. Fluoro-L-Thymidine) may be useful in identifying unintended antiproliferative effects of chemotherapy in vivo. Thus, radionuclide and PET imaging may play an important role in toxicology monitoring in new oncology drugs.

Pathology Image Data and Drug Safety: Compliance with 21 CFR Parts 58 and 11 In a Virtual World
Robert W. Dunstan and Steven J. Potts; Investigative Pathology Unit, Biogen Idec, and Aperio Technologies.

In most toxicology studies, the greatest use of imaging (defined simply as the use of a mechanical instrument to enhance/improve morphologic assessment) is by a brightfield microscope for histologic assessment of tissue changes. In the next 3 years, there is a strong likelihood that all such evaluations will be performed on a computer screen using digital images. In addition, the use of digital images allows for the transition from semiquantitative interpretation to quantitative assessment. The issues associated with adapting this technology to an FDA-approved GLP environment (or adapting the GLP environment to this new technology) will be discussed.