W. Eckelman, R. Waterhouse, R. Frank
Jul 1, 2001
Citations
0
Influential Citations
4
Citations
Journal
The Journal of Clinical Pharmacology
Abstract
I 1998, the Society of Noninvasive Imaging in Drug Development (SNIDD) held a symposium on the use of imaging in drug research and development (R&D). The symposium was modeled after the case method technique, popularized by the Harvard Business School as a framework for analyzing examples of actual business decisions to subsequently obtain insight into the process. The proceedings of that symposium were published in the August 1999 supplement of the Journal of Clinical Pharmacology. The SNIDD symposium, held in October 2000, built on those initial case reports by examining the role of well-established radiopharmaceuticals in the efficient application of imaging to drug discovery. The first symposium showed how imaging can be an integral part of the drug discovery process; the second symposium discussed the most efficient approaches to including imaging in drug discovery. The meeting opened with the presentation of the Alfred P. Wolf Award to Dr. Joanna Fowler of Brookhaven National Laboratory for her scientific contributions to the development of positron-emission tomography (PET) and its use in drug discovery and development. The scientific sessions started with a discussion of how biochemical markers, such as O-15 water for blood flow and F-18 2-fluoro-2-deoxyglucose (FDG), whose uptake is related to glucose metabolism, can be used to investigate the efficacy of pharmaceuticals. One of the advantages of these radiopharmaceuticals is their ready availability. Krohn et al then compared the ability of FDG and thymidine analogs (proliferation agents) to measure response to therapy. For example, radiolabeled proliferation agents have been used to measure new anticancer agents such as thymidylate synthetase inhibitors. Both FDG and radiolabeled thymidine also have been used to study the effect of IL-2 treatment. The information obtained from FDG and radiolabeled thymidine images differed in half the cases, indicating that thymidine provided different biochemical information. Lammertsma followed with a review of the measurement of tumor response using FDG and PET. Various analytical methods have been used, ranging from visual inspection of the images to using a two-compartment model. This presentation included an overview of the European Organization for Research and Treatment of Cancer recommendations on both the method of analysis and the method of reporting results. This is an active area of discussion by the National Cancer Institute as well, which recently sponsored a similar analysis of the use of FDG in oncology. Dr. Irene Tracey contributed a manuscript on the prospects for human pharmacological functional magnetic resonance imaging (fMRI). The recommended approach to drug testing is to have subjects perform an activation paradigm under the influence of placebo or drug and measure their response by fMRI. If quantitation were possible, this would generate a fMRI dose-response curve. Three groups addressed the development of modulators for multidrug resistance. Multidrug resistance has emerged as a major obstacle to successful chemotherapy because many chemotherapeutics are removed from the tumor by energy-dependent efflux pumps. Various radiopharmaceuticals are being developed to measure the ability of modulators to block the efflux of chemotherapeutics, thereby improving the efficacy of the treatment. These radiopharmaceuticals can also be used to screen patients for resistance to a particular chemotherapeutic agent. Monitoring biochemical changes in the brain using PET and single photon-emission computed tomogra-