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Jul 1, 2009 (Vol. 29, No. 13)

Upgrading Cell-Based Viability Assays

Novel Approaches More Accurately Reflect the In Vivo Human State

  • Pharmas and biotechs struggle to screen large quantities of compounds, hoping to eliminate early those that would prove more destructive than beneficial. One avenue toward a successful resolution of this challenge is the cell-based viability assay, a rapid and convenient technique for use in drug discovery. A number of companies have taken advantage of novel approaches to offer a variety of innovative upgrades to this platform.

    Animal testing of toxic compounds was widely used in the past as an alternative to classic in vitro testing methods of viability and cytotoxicity, such as dye-exclusion or colony-formation assays. These were laborious approaches—time-consuming, insensitive, and poorly suited for high-throughput screening. But animal testing is expensive and also low throughput. Moreover, ethical concerns over the infliction of severe pain and suffering to sentient creatures, combined with the inadequacy of animal models due to species differences, have motivated the development of cell-based assays that truly reflect the in vivo human state.

  • Genotoxicity Assays

    Gentronix was founded in 1999 by Richard Walmsley, Ph.D., with a yeast cell-based genotoxicity assay as the original technology. Today, the company seeks to minimize late preclinical failure by eliminating unsatisfactory candidates before they advance to these later stages of evaluation.

    According to Dr. Walmsley, the ICH guidelines mandate that regulatory genotoxicity assessment be performed before the candidate enters into clinical trials. Positive genotoxicity data can lead to costly delays in clinical trials while further in vitro and in vivo studies are carried out to make a full risk assessment. That is why screening much earlier than preclinical safety assessment is a good idea.

    To meet these challenges, the company has developed the mammalian cell GreenScreen HC platform, named after its use of the green fluorescent protein reporter. The reporter responds to the GADD45a gene, which mediates the adaptive response to genotoxic stress. Its complex regulatory elements respond to all classes of genotoxins including direct-acting mutagens, clastogens, and aneugens resulting in a fluorescence reaction in responsive cells.

    The procedure is extremely rapid—yielding results over a two-day period—and has been validated in a number of studies published in peer-reviewed journals. The goal is to help narrow large numbers of potential compounds down to the handful that will be viable drug candidates. An important feature of the platform is its ability to detect promutagens and procarcinogens—compounds that must be converted by liver enzymes to an active form from their initial inactive state.


Readers' Comments

Posted 07/10/2009 by Sr. Director, Business Development

Very insightful article that highlights multiple new technologies being advanced. One concern that I do not see being addressed is the drive to make our in vitro assays more physiologically relevant by removing and replacing non-human components when possible. Cells do b ehave differently when cultured on plastic or Matrigel when compared to fully human ECMs. There are dramatic morphological as well as molecular gene expression differences that lead to aberrant and misleading results. Minimizing these impacts on in vitro assays and maximizing human physiological relevance is the future of cell-based assays.

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