Academic journal article The Volta Review

High-Throughput Screening of Ototoxic and Otoprotective Pharmacological Drugs

Academic journal article The Volta Review

High-Throughput Screening of Ototoxic and Otoprotective Pharmacological Drugs

Article excerpt

Drug ototoxicity research has relied traditionally on animal models for the discovery and development of therapeutic interventions. More than 50 years of research, however, has delivered few-if any-successful clinical strategies for preventing or ameliorating the ototoxic effects of common pharmacological drugs such as aminoglycoside antibiotics. One of the reasons for this lack of success is that results obtained on animal models frequently cannot be correlated with the responses of human beings. The low levels of human predictability with standard animal ototoxicity tests are associated, in turn, with the fact that the cellular and molecular mechanisms activated by ototoxic drugs are largely unknown. Thus, agents that for unknown reasons and by an unknown mechanism were able to somewhat prevent or ameliorate drug ototoxicity in an animal model generally fail-for unknown reasons-to show similar properties in a clinical trial. The incorporation of high-throughput screening (HTS) models and methods to the arsenal of techniques available to hearing researchers may modify this situation by helping to elucidate the mechanisms of drug toxicity. This knowledge will be crucial in designing acute experiments to be performed on animal models, aimed at identifying effective strategies for the prevention of drug ototoxicity in humans.

Introduction

The pharmaceutical industry introduced high-throughput screening (HTS) methods in the early 1990s as a response to the increasing level of scale and complexity associated with drug discovery (Slater, 2001). The huge advances in genomics and proteomics during that decade made it theoretically possible to know the components of all cells and organisms, and significantly amplified the number of potentially interesting targets for pharmacological drugs (Sundstrom, Morrison, Bradley & Pringle, 2005). In addition, advances in synthetic chemistry, such as combinatorial chemistry, have generated a surge in the number of molecules that can be screened against these targets (Slater, 2001; Sundstrom et al., 2005). HTS techniques, developed by the concerted effort of chemists, biologists, information technology scientists, and engineers, were conceived to answer the demand for better tools to mine more quickly, efficiently, and reliably the plethora of information provided by these notable scientific advances.

HTS relies on miniaturization, parallel processing, and innovations in hardware and assay technologies, especially the use of laboratory robots (Slater, 2001). During the 1990s, the speed of screening increased dramatically. For example, using technologies available in 1992, it would have taken the equivalent of 20 years to screen 1 million compounds. By 1996, the same number of compounds could have been screened in 200 weeks, and only five years later this had been reduced to merely two weeks (Slater, 2001). Just as important, HTS approaches have been incorporated to the arsenal of techniques available for basic and clinical researchers. However, though HTS technologies are now a valuable resource in evaluating drug toxicity and identifying new agents for the prevention of the deleterious effects of toxic drugs, their use in hearing research has been minimal so far. Among the multiple reasons for this are the scarcity of adequate biological systems to be used with HTS, as well as the resistance of many researchers to accept new approaches that do not rely on animal models.

The biomedical sciences in general, and the field of ototoxicity in particular, depend on animal models for the discovery and development of therapeutic interventions (Dunn, Pinkert & Kooyman, 2005). But, by their very nature, animal models are not adequate as HTS subjects (an interesting exception, the zebrafish, will be discussed later). Thus, while animal models are the most biologically relevant systems, they are also the most difficult to study with HTS (Sundstrom et al., 2005). It should be noted, however, that animal models-in addition to being expensive and increasingly unpopular on ethical grounds-are not always the best tool for drug discovery (Sundstrom et al. …

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